From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome

array:23 ["pii" => "S0301054609000238" "issn" => "03010546" "doi" => "10.1016/j.aller.2009.04.002" "estado" => "S300" "fechaPublicacion" => "2009-07-01" "aid" => "22" "copyright" => "SEICAP" "copyrightAnyo" => "2009" "documento" => "article" "crossmark" => 0 "subdocumento" => "ssu" "cita" => "Allergol Immunopathol (Madr). 2009;37:208-15" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 10617 "formatos" => array:3 [ "EPUB" => 22 "HTML" => 9654 "PDF" => 941 ] ] "itemSiguiente" => array:18 [ "pii" => "S0301054609000263" "issn" => "03010546" "doi" => "10.1016/j.aller.2009.02.004" "estado" => "S300" "fechaPublicacion" => "2009-07-01" "aid" => "25" "copyright" => "SEICAP" "documento" => "simple-article" "crossmark" => 0 "subdocumento" => "cor" "cita" => "Allergol Immunopathol (Madr). 2009;37:216-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3173 "formatos" => array:3 [ "EPUB" => 15 "HTML" => 2817 "PDF" => 341 ] ] "en" => array:9 [ "idiomaDefecto" => true "cabecera" => "Research Letter" "titulo" => "Helium-oxygen mixtures and acute severe asthma" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "216" "paginaFinal" => "217" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. Cruz, A.R. Ferreira, A. Coimbra, M.G. Castel-Branco" "autores" => array:4 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Cruz" ] 1 => array:2 [ "nombre" => "A.R." "apellidos" => "Ferreira" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Coimbra" ] 3 => array:2 [ "nombre" => "M.G." "apellidos" => "Castel-Branco" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000263?idApp=UINPBA00004N" "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000263/v1_201304101017/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0301054609000226" "issn" => "03010546" "doi" => "10.1016/j.aller.2009.03.003" "estado" => "S300" "fechaPublicacion" => "2009-07-01" "aid" => "21" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2009;37:205-7" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 3406 "formatos" => array:3 [ "EPUB" => 10 "HTML" => 2946 "PDF" => 450 ] ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "SERIES: Tips for researching in the field of allergy(III)" "titulo" => "Patch test in the diagnosis of food allergy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "205" "paginaFinal" => "207" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Cocco, D. Solé" "autores" => array:2 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Cocco" ] 1 => array:2 [ "nombre" => "D." "apellidos" => "Solé" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000226?idApp=UINPBA00004N" "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000226/v1_201304101017/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "REVIEW" "titulo" => "From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "208" "paginaFinal" => "215" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Blanco Quirós, E. Arranz Sanz, D. Bernardo Ordiz, J.A. Garrote Adrados" "autores" => array:4 [ 0 => array:4 [ "nombre" => "A." "apellidos" => "Blanco Quirós" "email" => array:1 [ 0 => "ablanco@ped.uva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor1" ] ] ] 1 => array:3 [ "nombre" => "E." "apellidos" => "Arranz Sanz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 2 => array:3 [ "nombre" => "D." "apellidos" => "Bernardo Ordiz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] ] ] 3 => array:3 [ "nombre" => "J.A." "apellidos" => "Garrote Adrados" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff2" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Pediatrics and Immunology, IBGM, University of Valladolid, Spain" "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Clinical Research Unity, Hospital Clínico Universitario, Valladolid, Spain" "etiqueta" => "b" "identificador" => "aff2" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig4" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1702 "Ancho" => 1622 "Tamanyo" => 137748 ] ] "descripcion" => array:1 [ "en" => "Generation of CD4+ subtype cells. Transforming growth factor B-1 promotes the development of Treg cells by signal transducer and activator of transcription 5 (STAT5) and the nuclear factor FOXP3. The early production of IL-4 favours the development of Th2 by STAT 3/6 and GATA3; IL-12 promotes TH-1 by STAT1/4 and t-bet; and IL-21 and IL-23 promotes TH-17 by STAT 3 and RORgt (Modified from Bacchetta et al. 2007)." ] ] ] "textoCompleto" => "Intractable diarrhoeaAvery proposed the term “Intractable diarrhoea” in 1968, to describe patients with unremitting chronic diarrhoea occurring in infants less than 3 months of age with the result of progressive malnutrition, after excluding an infectious aetiology.<a class="elsevierStyleCrossRef" href="#bib1">1</a> In spite of using intravenous feeding, mortality was frequent and occurred too early, before a complete study could be performed. This term may include a heterogeneous group of diseases (<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>).<elsevierMultimedia ident="tbl1"></elsevierMultimedia>The very rare cases described as “Congenital diarrhoea” may be considered as intractable diarrhoea, however a group with early but no neonatal onset was separated from the congenital diarrhoea group. Later, when intestinal biopsies were easily available, a villous atrophy was frequently recorded, usually severe. Crypts can be hypoplastic, with few mitoses, resembling a graft versus-host disease, or hyperplastic, resulting in a picture indistinguishable from a celiac disease. An inflammatory infiltrate of the lamina propria is always present, thought it is not clear whether gut autoantibodies precede or follow intestinal inflammation.<a class="elsevierStyleCrossRef" href="#bib2">2</a>Autoimmune enteropathyWalker-Smith,<a class="elsevierStyleCrossRef" href="#bib3">3</a> Unsworth,<a class="elsevierStyleCrossRef" href="#bib4">4</a> and later, Savage<a class="elsevierStyleCrossRef" href="#bib5">5</a> investigated autoantibodies in patients with non-congenital intractable diarrhoea that showed villous atrophy, complement fixing gut autoantibodies, and associated to some cases, diabetes mellitus or hypothyroidism.AIE is a rare familial disorder characterized by protracted diarrhoea, lack or poor response to parenteral nutrition, circulating antibodies and/or autoimmune diseases in infants without severe immunodeficiency. It is characterized by a somewhat more delayed onset than congenital enteropathies, often at 4–6 months of age and frequently has other evidence of autoimmune diseases. Dysmorphic features are common in congenital enteropathies but not in AIE.<a class="elsevierStyleCrossRef" href="#bib6">6</a>Autoantibodies were usually determined on human blood group 0 duodenal samples obtained from patients undergoing surgical procedures, although tissue from monkey could be used with satisfactory sensibility.<a class="elsevierStyleCrossRef" href="#bib7">7</a> A cross reaction between gut autoantibodies and renal epithelial cells is commonly reported.<a class="elsevierStyleCrossRef" href="#bib8">8</a> Immunofluorescence analysis showed two different patterns: complement-fixing apical antibodies and cytoplasmatic positive staining (<a class="elsevierStyleCrossRef" href="#fig1">Fig. 1</a>). According to the report of Martin-Villa et al.<a class="elsevierStyleCrossRef" href="#bib9">9</a> patients with complement-fixing apical antibodies may have abnormal T-cell responses in vitro, and a cytoplasmatic pattern was associated to immunoglobulin deficiency, suggesting that different cellular or humoral immunologic alterations may favour a different gut autoantibody pattern. Although a correlation between serum autoantibodies levels and disease activity was found in some cases,<a class="elsevierStyleCrossRef" href="#bib8">8</a> the pathogenic role of gut autoantibodies has never been proven.<elsevierMultimedia ident="fig1"></elsevierMultimedia>High expression of HLA-A, -B, and -C with a stronger reactivity is commonly found in the crypt epithelium. An aberrant expression of DR molecules on the gut surface and crypt epithelium was observed, with a high number of DR positive activated cells in the lamina propria. Nevertheless the expression of HLA-DP and DQ was normal. The inappropriate DR expression in the epithelium is not an exclusive sign of autoimmunity, accompanying also chronic inflammatory processes, such as Crohn disease.Several authors investigated the nature of the gut antigen in AIE. Coletti, et al.<a class="elsevierStyleCrossRef" href="#bib8">8</a> in 1991, using Western immunoblot, identified a 55kD protein located in gut and renal epithelial cells that reacted with serum autoantibodies. Later, Kobayashi<a class="elsevierStyleCrossRef" href="#bib10">10</a> detected a 75kD autoantigen, which was distributed through the whole intestine and kidney, and likely implicated in the development of nephropathy, although not present in the thyroid gland. A tryptophan hydroxylase (TH) was identified as the intestinal autoantigen in autoimmune polyendocrine syndrome type 1 which is accompanied by gastrointestinal symptoms in 20–30% of the cases.<a class="elsevierStyleCrossRef" href="#bib11">11</a> This antigen is mainly present in enterochromaffin cells of the mucosa, and the search for autoantibodies to TH is also recommended in patients with Crohn disease or ulcerative colitis.The majority of reported patients with AIE were young boys with the onset of clinical manifestations at a very early stage, within the first 6 months of life, although it has also been observed in older children and female subjects, interestingly with less bowel involvement.<a class="elsevierStyleCrossRef" href="#bib12">12</a> Several reports describe the involvement of both the small and large bowels. Whether either regions of the gut are simultaneously affected or one region is affected before the other is unclear.<a class="elsevierStyleCrossRef" href="#bib13">13</a>It was presumed that extra-intestinal involvement was commonly present, but in the absence of a systemic evaluation some histological lesions outside gastrointestinal tract could remain unnoticed. Pancreatic lesions, with endocrine or exocrine insufficiency were usually observed, and diabetes mellitus was frequently the first manifestation of the disease, prior to diarrhoea. Atopic eczema showed the typical clinical and histological findings. During remissions the eczema improves and serum IgE levels decreased. Renal involvement is common and biopsy may show interstitial inflammatory nephritis or membranous glomerulonephritis.<a class="elsevierStyleCrossRefs" href="#bib8">8,14</a> The liver injury was usually revealed by hepatomegaly and a moderate increase in serum transaminases. Histology shows a periportal fibrosis, which could be more extensive in some cases, associated to a clinical picture of chronic aggressive hepatitis. Thyroid insufficiency was noted in some cases, with lymphoid cell infiltration that could be accompanied by fibrosis.The mortality of patients with AIE was very high, in spite of new therapies. Nevertheless, the response to treatment was variable, mainly due to the heterogeneity of the disease. Long periods with diet alone have been observed in few cases. On the contrary, other patients were resistant to corticosteroids or immunosuppressive therapy. Cyclosporine induced remission in the majority of cases, and later, the treatment with tacrolimus was reported to be successfully in patients previously resistant to other immunotherapies.IPEX syndromePowell et al.<a class="elsevierStyleCrossRef" href="#bib15">15</a> reported the first case of IPEX syndrome. This rare disease is characterized by immune dysfunction, polyendocrinopathy, enteropathy and X-linked inheritance, which seems to be equivalent to the abnormalities expressed by the scurfy mice, also an X-linked abnormality which was accidentally produced in 1949.<a class="elsevierStyleCrossRefs" href="#bib16">16,17</a> Before the accurate characterization, multiple terms were assigned to IPEX syndrome (<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>).<elsevierMultimedia ident="tbl2"></elsevierMultimedia>Clinical pictureSymptoms of the IPEX syndrome are different from one patient to another; they can even vary within the same family, especially in severity of symptoms. The most common findings are diabetes mellitus, protracted diarrhoea, failure to thrive, eczema and haemolytic anaemia.<a class="elsevierStyleCrossRef" href="#bib17">17</a> Other less common features are thrombocytopenia with platelet-antibodies, autoimmune hypothyroidism and lymphadenopathy with splenomegaly.<ul class="elsevierStyleList"><li class="elsevierStyleListItem">1.Gastrointestinal disease. It is characterized by a severe watery diarrhoea that could be also mucoid or bloody.<a class="elsevierStyleCrossRef" href="#bib18">18</a> Generally a worsening occurs when breast-feeding is switched to regular formula, and many patients develop food allergies, frequently associated to atopic eczema.<a class="elsevierStyleCrossRef" href="#bib19">19</a> The response to dietary manipulation is variable, and symptoms may persist, requiring total parenteral nutrition to reverse the failure to thrive.</li><li class="elsevierStyleListItem">2.Autoimmune endocrinopathies. The onset is very early and the involvement of pancreas and thyroid is the most common feature of IPEX syndrome, whereas the involvement of parathyroids, or adrenals is rare. Insulin-dependent type 1 diabetes begins frequently during the first year of life, although in some cases, glucose intolerance is already present at birth. Thyroiditis is common and can lead to hypothyroidism or hyperthyroidism.</li><li class="elsevierStyleListItem">3.Dermatitis. A mild eczema is the most common finding in the skin and it may onset as an erythematous rash covering all the body.<a class="elsevierStyleCrossRef" href="#bib18">18</a> Other immune-mediated dermatological diseases described are pemphigoid nodularis,<a class="elsevierStyleCrossRef" href="#bib20">20</a> psoriasiform dermatitis or alopecia. Patients with lesions resembling onychomycosis were also published.<a class="elsevierStyleCrossRef" href="#bib21">21</a></li><li class="elsevierStyleListItem">4.Other findings. In addition to the basic triad, other autoimmune alterations were reported in patients with IPEX syndrome. The most common are autoimmune haematological disorders, such as Coombs-positive haemolytic anaemia, thrombocytopenia or neutropenia, which altogether are present in more than 50% of the patients. Renal disease affects about 30% of the cases, mainly as an interstitial nephritis, although membranous glomerulonephritis was also reported.<a class="elsevierStyleCrossRef" href="#bib22">22</a> The severity of the clinical picture is variable; ranging from mild proteinuria and haematuria to rapidly progressive glomerulonephritis, only reverted by stem cell transplantation.<a class="elsevierStyleCrossRef" href="#bib22">22</a> Autoimmune hepatitis is also common. Some patients have neurologic abnormalities with developmental delay or seizures.</li></ul>A high susceptibility to infections and reactions to vaccines was denoted in many patients without an apparent immunodeficiency. Some authors related infections to alterations of the skin and the gut barrier, or to immunosuppressive therapy. The neutropenia may be another influent factor.Until now, only cases with typical IPEX syndrome have been easily identified, however cases with mild and uncompleted clinical pictures are increasingly reported. Two unrelated cases with early onset enteropathy and long-term survival, without type 1 diabetes, were recently published. They showed a novel mutation of FOXP3 gene.<a class="elsevierStyleCrossRef" href="#bib23">23</a>The definitive diagnosis is based on genetic studies and the identification of the mutation, but an easier screening test by immunocytochemical staining of FOXP3 molecule in bowel biopsies has also been proposed.<a class="elsevierStyleCrossRef" href="#bib24">24</a> The Wiskott-Aldrich syndrome and other X-linked diseases with immune abnormalities have some similarities (<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>). Although previously a common genetic origin was proposed for all these entities, definitively a separate identity has been proven for every syndrome.<a class="elsevierStyleCrossRef" href="#bib17">17</a><elsevierMultimedia ident="tbl3"></elsevierMultimedia>Immunologic findingsOur knowledge about immune findings is fragmented and incomplete, even contradictory, because infants are frequently studied during serious illness, malnutrition, infections or immunosuppressive therapy No patognomonic abnormalities and consistent changes in number of cells or immune function have been described.<a class="elsevierStyleCrossRef" href="#bib25">25</a> Nevertheless, IgE serum levels are increased in most patients with IPEX syndrome, and eosinophilia and high IgA are also common. Serum anti-islet, thyroid cell or enterocyte antibodies are present in some patients. Most patients have normal peripheral blood number of CD3+ CD4+ and CD8+ T-cells, with normal proliferative response to mitogens. Some patients showed a low number of NK and B cells, in this case with an associated hypogammaglobulinaemia and recurrent bacterial infections.<a class="elsevierStyleCrossRef" href="#bib26">26</a> The constant finding is the depletion of naive T-cell (CD4+ and CD8+) with increase number of memory T cells.<a class="elsevierStyleCrossRefs" href="#bib26">26,27</a> A high production of different cytokines, lymphocyte strong response to mitogens and increased expression of MHC class II suggest a global activation of the immune response.<a class="elsevierStyleCrossRef" href="#bib17">17</a>A severe villous atrophy accompanied by lymphocytic infiltrates of lamina propria, mucosa and submucosa are characteristic findings of IPEX syndrome. Lymphocytic inflammation of pancreas with complete destruction of islet cells is present in cases with diabetes.<a class="elsevierStyleCrossRef" href="#bib17">17</a> The typical lymphocytic infiltration may also involve other organs, such as thyroid, skin, liver or brain.The IPEX syndrome shares features with other X-linked syndromes, such as Wiskott-Aldrich syndrome, X-linked thrombocytopenia or X-linked congenital neutropenia. Genetic studies have clearly defined the IPEX syndrome as a different entity.FOXP3The FOXP3 gene is located in the short arm of chromosome X (Xq11.23-Xq13.3). It has 11 exons which encode a protein of 431 amino acids. It is expressed predominantly, but not exclusively, in CD4+CD25+ T-cells. Transcription factors are proteins which bind regulatory regions of DNA and augment or suppress the transcription of particular genes. FOXP3 is a member of subfamily of forkhead box (FOX) transcription factors, which play a predominant role in embryonic pattern, development and metabolism.<a class="elsevierStyleCrossRef" href="#bib28">28</a>FOXP3 represses the promoter of several cytokine, such as IL-2 or GM-CSF. It interacts with the nuclear factor of activated T cells (NFAT) and perhaps with acute myeloid leukaemia 1/runt related transcription factor (AML1/Runx1) and nuclear factor-kB, forming complexes that repress different cytokines promoters<a class="elsevierStyleCrossRefs" href="#bib29">29–31</a> (<a class="elsevierStyleCrossRef" href="#fig2">Fig. 2</a>). The binding of NFAT with FOXP3 occurs specifically in CD4+CD25+ Treg cells, whereas in conventional T cells the NFAT exerts the repression function binding through another transcription factor, the activator protein-1 (AP-1).<a class="elsevierStyleCrossRef" href="#bib25">25</a><elsevierMultimedia ident="fig2"></elsevierMultimedia>Three domains are key for the function of FOXP3: a C-terminal region which contains the forkhead domain that directly binds DNA regions; a central domain with a zinc finger and a leucine zipper that promotes the oligomerization of the FOXP3 molecule<a class="elsevierStyleCrossRef" href="#bib32">32</a>; and a repressor domain located in the N-terminal region which binds the NAFT (nuclear factor of activated T cells) molecule<a class="elsevierStyleCrossRef" href="#bib33">33</a> (<a class="elsevierStyleCrossRef" href="#fig3">Fig. 3</a>).<elsevierMultimedia ident="fig3"></elsevierMultimedia>Transgenic mice with increased expression of FOXP3 show decreased number of CD4+ T cells, a low cellularity in lymphoid tissues and a poor response to antigenic stimulation.<a class="elsevierStyleCrossRef" href="#bib28">28</a> Some cytokines (TGF-beta and IL-2), and the stimulation of TCR, have been identified as factors that induce the expression of FOXP3, although their regulation is poorly known yet.Regulatory T cells (Treg)Regulatory T cells constitute a small subset (5–10%) of CD4+ T helper cells that develop in the thymus. They are characterized by the expression of IL-2 receptor alpha chain (CD25), also expressing glucocorticoid-induced TNF receptor (GITR) and cytotoxic T lymphocyte-associated antigen 4 (CTL-4)<a class="elsevierStyleCrossRef" href="#bib25">25</a> (<a class="elsevierStyleCrossRef" href="#fig4">Fig. 4</a>).<elsevierMultimedia ident="fig4"></elsevierMultimedia>Treg cells are of critical importance for the establishment of the self-tolerance and immune homeostasis.<a class="elsevierStyleCrossRef" href="#bib34">34</a> It has been shown that these cells suppress the autoimmune, the antimicrobial and the antitumoral responses<a class="elsevierStyleCrossRef" href="#bib25">25</a> (<a class="elsevierStyleCrossRef" href="#tbl4">Table 4</a>). More recently, a novel anti-atherogenic role was claimed for Treg.<a class="elsevierStyleCrossRef" href="#bib35">35</a> It is noteworthy that antigen simulation is required for the initiation of Treg suppression, but suppressive effects can later occur to bystander cells and systems. They play an important role in controlling exaggerated Th2 response and they are involved in cow's milk allergy as well as in the allergy to inhalants.<a class="elsevierStyleCrossRefs" href="#bib36">36,37</a> The capacity of Treg to induced oral antigen tolerance has been proven in mice<a class="elsevierStyleCrossRefs" href="#bib38">38–40</a> and is also supposed in man. A defect Treg function was associated to autoimmune, allergic and immunodeficient diseases.<a class="elsevierStyleCrossRefs" href="#bib41">41,42</a> In contrast, an increased Treg function has been associated to malignancies.<a class="elsevierStyleCrossRefs" href="#bib43">43–46</a><elsevierMultimedia ident="tbl4"></elsevierMultimedia>FOXP3 plays a crucial role in the generation of Treg, and when it is absent, these cells do not develop in mice nor in man. Transgenic mice (scurfy) which do not express FOXP3 lack Treg. To date, about 20 mutations of FOXP3 have been identified. The majority are missense mutations that affect the integrity of the forkhead domain, but deletions and substitutions have also been identified in the leucine zipper and in the repressor domain. Nevertheless, the genetic basis o the disease seems to be more heterogeneous than initially presumed.The forkhead mutations interfere with nuclear import and DNA binding. Mutations located in N terminal region affect the regulation of FOXP3 on the NFAT protein. Other mutations seem to increase the length of the FOXP3 protein, changing the three-dimensional structure and the function.<a class="elsevierStyleCrossRef" href="#bib25">25</a> In some cases, no mutations in gene FOXP3 are identified and it is supposed that they involve some unknown regulator gene which may be located even outside the X chromosome, because females are affected in some families.<a class="elsevierStyleCrossRefs" href="#bib44">44,47,48</a> Moreover, a case with gene FOXP3 mutation, normal FOXP3 protein expression and Treg deficient function was published, proving that the complex mechanism of this disorder is yet unclear.<a class="elsevierStyleCrossRefs" href="#bib25">25,49</a> Some reports support a genotype-phenotype correlation.<a class="elsevierStyleCrossRef" href="#bib50">50</a>Treatment of IPEX syndromeSymptomatic treatment includes total parenteral nutrition and insulin injections that are commonly needed, as well as red blood or platelet transfusion. In the early years, the therapy of IPEX syndrome was based on immunosuppressive drugs. Steroids, methotrexate, cyclosporin, FK506 and more recently infliximab and rituximab have been used with unequal results, frequently disappointing, because the response is short and late complications may appear. Sirolimus is the latest drug assayed and seems to be less nephrotoxic and better tolerated, improves diarrhoea and villous histology, and decreases the dosage of corticoids. In addition, it allows the expansion of Treg while the growth of effector T cells is inhibited.<a class="elsevierStyleCrossRefs" href="#bib51">51,52</a>In spite of new drugs, bone marrow transplantation is the only definitive cure for patients with IPEX syndrome.<a class="elsevierStyleCrossRef" href="#bib53">53</a> It has been performed in some cases with complete clinical remission, in spite of only a partial engraftment with a chimerical status.<a class="elsevierStyleCrossRef" href="#bib54">54</a> After transplantation, clinical recovery was associated with the emergence of regulatory T cells, the majority expressing markers of memory phenotype.<a class="elsevierStyleCrossRef" href="#bib53">53</a> It was remarkable that the conditioning regimen was itself effective in controlling symptoms in some patients and it was recently noticed that a reduced-intensity conditioning regimen prior to the engraftment resulted in more FOXP3T regulatory cells than more aggressive conditioning.<a class="elsevierStyleCrossRef" href="#bib55">55</a> Correction symptoms were also successfully reached with cord blood donor.<a class="elsevierStyleCrossRef" href="#bib56">56</a> Unfortunately, the excellent results of bone marrow transplantation are frequently transient.<a class="elsevierStyleCrossRef" href="#bib17">17</a>The recovery of diabetes mellitus was obtained in some cases, but in most instances the islet damage is already permanent at the time of bone marrow transplantation.<a class="elsevierStyleCrossRef" href="#bib28">28</a> It is recommended to perform the transplantation in the early phase of the disease in order to avoid irreversible damage and complications.Complications. Malnutrition is the main complication in infants, and infections in later ages, being the most frequent cause of death. Lymphoproliferative haemophagocytic syndrome is another complication which was also published.<a class="elsevierStyleCrossRefs" href="#bib47">47,54</a> The immunosuppressive drugs and their dose are one of the most important risk factors of complications, so the type of therapy must be carefully considered. A patient with IPEX syndrome managed with rapamycin who subsequently developed a lymphoma induced by Epstein Barr virus was recently reported.<a class="elsevierStyleCrossRef" href="#bib57">57</a>IPEX-like syndromesDue to the complexity of Treg function it is not surprising to find patients with similar symptoms and different genetic and immune findings.CD25 deficiency. From the discovery of IL-2R alpha (CD25) defects in 1997,<a class="elsevierStyleCrossRef" href="#bib58">58</a> at least two families were described with a genetic mutation and a lack expression.<a class="elsevierStyleCrossRef" href="#bib59">59</a> The main characteristic data was a massive enlargement of peripheral lymphoid organs, with hepatosplenomegaly, enlarged tonsils and lymphadenopathy. All cases show an inflammatory bowel disease with villous atrophy. One case had clear traits of immunodeficiency, with low T cell number and decreased response to mitogens whereas the second patients showed an IPEX typical pattern with several autoantibodies. It was remarkable that the first patient did not develop diabetes or endocrinopathies, and the diabetes showed a late onset, 6 year of age, in the case with IPEX pattern.<a class="elsevierStyleCrossRefs" href="#bib60">60,61</a>In summary, patients who years ago were diagnosed as AIE may be now considered to have IPEX syndrome. The majority of cases could be confirmed by studying FOXP3 gene mutations. Nevertheless, there are also atypical cases which have appeared with a delayed onset, or affecting female patients. They may be variants of FOXP3 mutation or be related to other molecules also involved in the generation or the function of Treg cells, such as CD25 abnormalities.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xres85644" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec73922" "titulo" => "Keywords" ] 2 => array:1 [ "titulo" => "Intractable diarrhoea" ] 3 => array:1 [ "titulo" => "Autoimmune enteropathy" ] 4 => array:2 [ "titulo" => "IPEX syndrome" "secciones" => array:2 [ 0 => array:1 [ "titulo" => "Clinical picture" ] 1 => array:1 [ "titulo" => "Immunologic findings" ] ] ] 5 => array:2 [ "titulo" => "FOXP3" "secciones" => array:3 [ 0 => array:1 [ "titulo" => "Regulatory T cells (Treg)" ] 1 => array:1 [ "titulo" => "Treatment of IPEX syndrome" ] 2 => array:1 [ "titulo" => "IPEX-like syndromes" ] ] ] 6 => array:1 [ "titulo" => "Conflict of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2009-04-29" "fechaAceptado" => "2009-04-30" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec73922" "palabras" => array:4 [ 0 => "Autoimmune enteropathy" 1 => "IPEX syndrome" 2 => "FOXP3 molecule" 3 => "Regulatory T cells" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The term autoimmune enteropathy (AIE) was applied to a form of “intractable diarrhoea” with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness." ] ] "multimedia" => array:8 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1890 "Ancho" => 2164 "Tamanyo" => 390243 ] ] "descripcion" => array:1 [ "en" => "Indirect immunofluorescence pattern putting the patient's serum on frozen monkey tissue. A. IgA positive antibodies on a longitudinal section of gut (×40), the staining is stronger at brush-border of crypts. B. IgG positive antibodies on a cross section of gut (×100), the immunofluorescence is cytoplasmatic with more intensity over apical border and a think linear staining on basolateral border. C. Staining on monkey kidney showing IgG autoantibodies that react with tubular border but avoiding the glomerulus (×40)." ] ] 1 => array:7 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 970 "Ancho" => 2917 "Tamanyo" => 103514 ] ] "descripcion" => array:1 [ "en" => "Representation of human FOXP3 gene. Repressor domain binds NFAT molecule, Zn finger with leucine zipper domain promotes the oligomerization of FOXP3 molecule and its function; Forkhead domain binds DNA sequence. Arrows indicate the location of mutations in patients with IPEX syndrome (Modified from van der Vliet et al. 2007)." ] ] 2 => array:7 [ "identificador" => "fig3" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1226 "Ancho" => 1632 "Tamanyo" => 96621 ] ] "descripcion" => array:1 [ "en" => "Antigen reaction with T cell receptor (TCR) up-regulates the expression of nuclear factor of activated T cell (NFAT) both, in conventional T cells and CD4+ CD25+ T cells. However, NFAT binds the activator protein 1 (AP1) in conventional T cells, whereas in Treg (CD4+CD25+) reacts with FOXP3 factor. It produces the transcription of a different set of genes, resulting in a final activation reaction in T conventional cells and suppression in Treg cells." ] ] 3 => array:7 [ "identificador" => "fig4" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1702 "Ancho" => 1622 "Tamanyo" => 137748 ] ] "descripcion" => array:1 [ "en" => "Generation of CD4+ subtype cells. Transforming growth factor B-1 promotes the development of Treg cells by signal transducer and activator of transcription 5 (STAT5) and the nuclear factor FOXP3. The early production of IL-4 favours the development of Th2 by STAT 3/6 and GATA3; IL-12 promotes TH-1 by STAT1/4 and t-bet; and IL-21 and IL-23 promotes TH-17 by STAT 3 and RORgt (Modified from Bacchetta et al. 2007)." ] ] 4 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. Congenital diarrhoea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Syndromic or phenotypic diarrhoea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microvillous inclusion disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tufting enteropathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congenital diarrhoea with mutant neurogenin-3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congenital diarrhoea with disorder of glycosylation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. IPEX and IPEX-like syndromes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. Other autoimmune enteropathies \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab164406.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Different forms of intractable diarrhoea of infancy" ] ] 5 => array:7 [ "identificador" => "tbl2" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1. X-linked Autoimmunity-Allergic Dysregulation Syndrome (XLAAD) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2. Insulin-dependent Diabetes Mellitus Diarrhoea Syndrome (DMSD) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3. X-linked Autoimmunity-Immunodeficiency Syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4. X-linked Diarrhoea, Polyendocrinopathy, Fatal Infection Syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5. Autoimmune Enteropathy with Haemolytic Anaemia and Polyendocrinopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6. X-linked Polyendocrinopathy, Immune Dysfunction and Diarrhea (XPID) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7. Diabetes Mellitus, Congenital Insulin-dependent with Fatal Secretory Diarrhoea \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8. Immunodeficiency, Polyendocrinopathy and Enteropathy, X-linked \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab164407.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Ancient terms assigned to IPEX syndrome (Marabelle et al. 2008)" ] ] 6 => array:7 [ "identificador" => "tbl3" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "IPEX: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked.WAS: Wiskott-Aldrich syndrome.XLT: X-linked thrombocytopenia.XLN: X-linked neutropenia.GATA: is a T-cell transcription factor." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Clinical signs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">IPEX \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">WAS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">XLT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">XLN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">GATA-1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmune manifestations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diarrhoea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atopic eczema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recurrent infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abnormal bleeding \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anaemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">± \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">small \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">small \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">large \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">T-cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-random X-chr. inactivation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">− \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab164408.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Differential characteristics of X-linked syndromes with immune abnormalities (Bennett et al. 2001)" ] ] 7 => array:7 [ "identificador" => "tbl4" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Subset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Characteristic protective activity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Main immunopathology \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intracellular bacteria and some virus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Granulomatous disorder \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TH2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Helminths \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Allergic disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TH17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Extracellular bacteria and some fungi \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chronic inflammatory \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmune disorder \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treg \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tolerance against self \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmunity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Control of high response against non-self \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cancer \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Immunodeficiency \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab164409.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Simplified view of protective role and immunopathology involvement of different CD4+ T-cell subset (Romagnani 2006)" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:61 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intractable diarrhea of early infancy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G.B. Avery" 1 => "O. Villacivencio" 2 => "J.R. Lilly" 3 => "J.G. Randolph" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "1968" "volumen" => "41" "paginaInicial" => "712" "paginaFinal" => "722" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5643979" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy in a child: Response to Infliximab Therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.A. Vanderhoof" 1 => "R.J. Young" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "2002" "volumen" => "34" "paginaInicial" => "312" "paginaFinal" => "316" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11964960" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoantibodies against gut epithelium in a child with small-intestinal enteropathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "J.A. Walker-Smith" 1 => "D.J. Unsworth" 2 => "P. Hutchins" 3 => "P. Hutchins" 4 => "A.D. Phillips" 5 => "E.J. Holborow" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1982" "volumen" => "1" "paginaInicial" => "566" "paginaFinal" => "567" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2564107" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune in diarrhoeal disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.J. Unsworth" 1 => "J.A. Walker-Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "1985" "volumen" => "4" "paginaInicial" => "375" "paginaFinal" => "380" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4020570" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhea" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.O. Savage" 1 => "R. Mirakian" 2 => "E.R. Wozniak" 3 => "H.R. Jenkins" 4 => "M. Malone" 5 => "A.D. Phillips" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "1985" "volumen" => "4" "paginaInicial" => "187" "paginaFinal" => "195" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3886868" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy and villous atrophy in adults" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G.R. Corazza" 1 => "F. Biagi" 2 => "U. Volta" 3 => "M.L. Andreani" 4 => "L. de Franceschi" 5 => "G. Gasbarrini" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(97)01042-8" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1997" "volumen" => "350" "paginaInicial" => "106" "paginaFinal" => "109" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9228963" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tuftin enteropathy and skeletal dysplasia: is there a link?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "W. El-Matary" 1 => "A.M. Dalzell" 2 => "G. Kokai" 3 => "J.E. Davidson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00431-006-0231-z" "Revista" => array:6 [ "tituloSerie" => "Eur J Pediatr" "fecha" => "2007" "volumen" => "166" "paginaInicial" => "265" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16900309" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.B. Colletti" 1 => "A.P. Guillot" 2 => "S. Rosen" 3 => "A.K. Bhan" 4 => "C.D. Hobson" 5 => "A.B. Collins" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1991" "volumen" => "118" "paginaInicial" => "858" "paginaFinal" => "864" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2040920" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "T-Lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Martin Villa" 1 => "J.R. Regueiro" 2 => "D. de Juan" 3 => "P. Perez Aciego" 4 => "M. Pérez Blas" 5 => "J. Manzanares" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "1991" "volumen" => "101" "paginaInicial" => "390" "paginaFinal" => "397" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2065915" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A 75-kD autoantigen recognized by sera from patients with X-linked autoimmune enteropathy associated with nephropathy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I. Kobayashi" 1 => "K. Imamura" 2 => "M. Yamada" 3 => "M. Okano" 4 => "A. Yara" 5 => "S. Ikema" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Exp Immunol" "fecha" => "1998" "volumen" => "111" "paginaInicial" => "527" "paginaFinal" => "531" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9528893" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of tryptophan hydroxylase as an intestinal autoantigen" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O. Enkwall" 1 => "H. Hedstrand" 2 => "L. Grimelius" 3 => "J. Haavik" 4 => "J. Perheentupa" 5 => "J. Gustafsson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(97)11050-9" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "1998" "volumen" => "352" "paginaInicial" => "279" "paginaFinal" => "283" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9690408" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy in infants. Pathological study of the disease in two familial cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Lachaux" 1 => "I. Loras-Duclaux" 2 => "R. Bouvier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Virchows Arch" "fecha" => "1998" "volumen" => "433" "paginaInicial" => "481" "paginaFinal" => "485" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9849864" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.M. Hill" 1 => "P.J. Milla" 2 => "G.F. Bottazzo" 3 => "R. Mirakian" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Gut" "fecha" => "1991" "volumen" => "32" "paginaInicial" => "36" "paginaFinal" => "42" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1991636" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Autoimmune enteropathy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P.A. Russo" 1 => "P. Brochu" 2 => "E.G. Seidman" 3 => "C.C. Roy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pediatr Dev Pathol" "fecha" => "1999" "volumen" => "2" "paginaInicial" => "65" "paginaFinal" => "71" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9841709" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "An X-linked syndrome of diarrhea, polyendocrinopathy and fatal infection in infancy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "B.R. Powell" 1 => "N.R. Ruist" 2 => "P. Stenzel" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "1982" "volumen" => "100" "paginaInicial" => "731" "paginaFinal" => "737" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7040622" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "X-linked lymphorreticular disease in the scurfy (sf) mutant mouse" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "V. Godfrey" 1 => "J. Wilkinson" 2 => "L. Russell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Pathol" "fecha" => "1991" "volumen" => "138" "paginaInicial" => "1379" "paginaFinal" => "1387" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2053595" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IPEX is a unique X-linked syndrome characterized by immune disfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.L. Bennett" 1 => "H.D. Ochs" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Curr Opin Pediatr" "fecha" => "2001" "volumen" => "13" "paginaInicial" => "533" "paginaFinal" => "538" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11753102" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "De l’Ipex à foxp3: une nouvelle contribution de la pédiatrie à la comprehension du systeme immunitaire" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Marabelle" 1 => "M. Meyer" 2 => "F. Demeocq" 3 => "A. Lachaux" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.arcped.2007.10.005" "Revista" => array:6 [ "tituloSerie" => "Arch Pediatr" "fecha" => "2008" "volumen" => "15" "paginaInicial" => "55" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18155891" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.R. Torgerson" 1 => "A. Linane" 2 => "N. Moes" 3 => "S. Anover" 4 => "V. Mateo" 5 => "F. Rieux-Laucat" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2007.02.044" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2007" "volumen" => "132" "paginaInicial" => "1705" "paginaFinal" => "1717" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17484868" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) associated with pemphigoid nodularis: a case report and review of the literature" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J.L. McGinness" 1 => "M.M. Bivens" 2 => "K.E. Greer" 3 => "J.W. Patterson" 4 => "F.T. Saulsbury" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2005.08.047" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2006" "volumen" => "55" "paginaInicial" => "143" "paginaFinal" => "148" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16781310" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Norwegian scabies mimicking onychomycosis and scalp dermatitis in a child with IPEX syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "P. McLucas" 1 => "G.J. Fulchiero Jr" 2 => "E. Fernandez" 3 => "J.J. Miller" 4 => "A.L. Zaenglein" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaad.2006.01.008" "Revista" => array:6 [ "tituloSerie" => "J Am Acad Dermatol" "fecha" => "2007" "volumen" => "56" "paginaInicial" => "S48" "paginaFinal" => "S49" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17224384" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an unusual cause of proteinuria in infancy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Moudgil" 1 => "P. Perriello" 2 => "B. Loechelt" 3 => "R. Przygodzki" 4 => "W. Fitzerald" 5 => "N. Kamani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00467-007-0532-0" "Revista" => array:6 [ "tituloSerie" => "Pediatr Nephrol" "fecha" => "2007" "volumen" => "22" "paginaInicial" => "1799" "paginaFinal" => "1802" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17629750" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. De Benedetti" 1 => "A. Insalaco" 2 => "A. Diamanti" 3 => "E. Cortis" 4 => "F. Muratori" 5 => "A. Lamioni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cgh.2005.12.014" "Revista" => array:6 [ "tituloSerie" => "Clin Gastroenterol Hepatol" "fecha" => "2006" "volumen" => "4" "paginaInicial" => "653" "paginaFinal" => "659" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16630773" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A potential screening tool for IPEX syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.L. Heltzer" 1 => "J.K. Choi" 2 => "H.D. Ochs" 3 => "K.E. Sullivan" 4 => "T.R. Torgerson" 5 => "L.M. Ernst" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2350/06-07-0130.1" "Revista" => array:6 [ "tituloSerie" => "Pediatr Dev Pathol" "fecha" => "2007" "volumen" => "10" "paginaInicial" => "98" "paginaFinal" => "105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17378693" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IPEX as a result of mutations in FOXP3" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H.J.J. van der Vliet" 1 => "E.E. Nieuwenhuis" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1155/2007/89017" "Revista" => array:2 [ "tituloSerie" => "Clin Dev Immunol" "fecha" => "2007" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Severe FOXP3+ and naïve T lymphopenia in a non-IPEX form of autoimmune enteropathy combined with an immunodeficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Zuber" 1 => "M. Viguier" 2 => "F. Lemaitre" 3 => "V. Senée" 4 => "N. Patey" 5 => "G. Elain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.gastro.2007.02.034" "Revista" => array:6 [ "tituloSerie" => "Gastroenterology" "fecha" => "2007" "volumen" => "132" "paginaInicial" => "1694" "paginaFinal" => "1704" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17484867" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A remarkable depletion of both naïve CD4+ and CD8+ with high proportion of memory T cells in an IPEX infant with a FOXP3 mutation in the forkhead domain" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B.T. Costa-Carvalho" 1 => "M.I. de Moraes-Pinto" 2 => "L.C. de Almeida" 3 => "M.T. de Seixas Alves" 4 => "R.P. Maia" 5 => "R.L. de Souza" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-3083.2008.02055.x" "Revista" => array:6 [ "tituloSerie" => "Scand J Immunol" "fecha" => "2008" "volumen" => "68" "paginaInicial" => "85" "paginaFinal" => "91" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18489537" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: Forkhead box protein 3 mutations and lack of regulatory T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T.R. Torgerson" 1 => "H.D. Ochs" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2007.08.044" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2007" "volumen" => "120" "paginaInicial" => "744" "paginaFinal" => "750" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17931557" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expresión and effector functions of T helper cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "E. Bettelli" 1 => "M. Dastrange" 2 => "M. Oukka" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1073/pnas.0501675102" "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci U S A" "fecha" => "2005" "volumen" => "102" "paginaInicial" => "5138" "paginaFinal" => "5143" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15790681" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FOXP3 controls regulatory T cell function through cooperation with NFAT" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Wu" 1 => "M. Borde" 2 => "V. Heissmeyer" 3 => "M. Feuerer" 4 => "A.D. Lapan" 5 => "J.C. Stroud" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.cell.2006.05.042" "Revista" => array:6 [ "tituloSerie" => "Cell" "fecha" => "2006" "volumen" => "126" "paginaInicial" => "375" "paginaFinal" => "387" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16873067" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Ono" 1 => "H. Yaguchi" 2 => "N. Ohkura" 3 => "I. Kitabayashi" 4 => "Y. Nagamura" 5 => "T. Nomura" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature05673" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2007" "volumen" => "446" "paginaInicial" => "685" "paginaFinal" => "689" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17377532" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Li" 1 => "A. Samanta" 2 => "X. Song" 3 => "K.T. Iacono" 4 => "P. Brennan" 5 => "T.A. Chatila" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/intimm/dxm043" "Revista" => array:6 [ "tituloSerie" => "Int Immunol" "fecha" => "2007" "volumen" => "19" "paginaInicial" => "825" "paginaFinal" => "835" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17586580" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.E. Lopes" 1 => "T.R. Torgerson" 2 => "L.A. Schubert" 3 => "S.D. Anover" 4 => "E.L. Ocheltree" 5 => "H.D. Ochs" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2006" "volumen" => "177" "paginaInicial" => "3133" "paginaFinal" => "3142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16920951" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.D. Fontenot" 1 => "A.Y. Rudensky" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ni1179" "Revista" => array:6 [ "tituloSerie" => "Nat Immunol" "fecha" => "2005" "volumen" => "6" "paginaInicial" => "331" "paginaFinal" => "337" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15785758" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Nik Tavakoli N, Hambly BD, Sullivan DR, Bao S. Forkhead box protein 3: Essential immune regulatory role. Int J Biochem Cell Biol. 2007 Oct 10 [Epub ahead of print]" ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibition of the allergic response by regulatory T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "P. Stock" 1 => "R.H. DeKruyff" 2 => "D.T. Umetsu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.all.0000200502.69672.44" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Allergy Clin Immunol" "fecha" => "2006" "volumen" => "6" "paginaInicial" => "12" "paginaFinal" => "16" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16505606" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relation of CD4 CD25 regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.M. Ling" 1 => "T. Smith" 2 => "X.D. Nguyen" 3 => "C. Pridgeon" 4 => "M. Dallman" 5 => "J. Arbery" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "2004" "volumen" => "63" "paginaInicial" => "608" "paginaFinal" => "615" ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Innate CD4 CD25 regulatory T cells are required for oral tolerance and inhibition of CD8T cells mediating skin inflammation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "B. Dubois" 1 => "L. Chapat" 2 => "A. Goubier" 3 => "M. Papiernik" 4 => "J.F. Nicolas" 5 => "D. Kaiserlian" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2003-03-0727" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2003" "volumen" => "102" "paginaInicial" => "3295" "paginaFinal" => "3301" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12855551" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Functional CD25- and CD25 mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48h after oral antigen application" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "F. Hauet-Broere" 1 => "W.W. Unger" 2 => "J. Garssen" 3 => "M.A. Hoijer" 4 => "G. Kraal" 5 => "J.N. Samsom" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/eji.200324115" "Revista" => array:6 [ "tituloSerie" => "Eur J Immunol" "fecha" => "2003" "volumen" => "33" "paginaInicial" => "2801" "paginaFinal" => "2810" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14515264" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activation of CD25+CD4+ regulatory T cells by oral antigen administration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "X. Zhang" 1 => "L. Izikson" 2 => "L. Liu" 3 => "H.L. Weiner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2001" "volumen" => "167" "paginaInicial" => "4245" "paginaFinal" => "4253" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11591746" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Role of regulatory T cells and FOXP3 in human disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Bacchetta" 1 => "E. Gambineri" 2 => "M.-G. Roncarolo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2007.06.023" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2007" "volumen" => "120" "paginaInicial" => "227" "paginaFinal" => "235" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17666212" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of the T cell response" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S. Romagnani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2222.2006.02606.x" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Allergy" "fecha" => "2006" "volumen" => "36" "paginaInicial" => "1357" "paginaFinal" => "1366" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17083345" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Karube" 1 => "K. Ohshima" 2 => "T. Tsuchiya" 3 => "T. Yamaguchi" 4 => "R. Kawano" 5 => "J. Suzumiya" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2141.2004.04999.x" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2004" "volumen" => "126" "paginaInicial" => "81" "paginaFinal" => "84" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15198736" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Foxp3 expressing CD4 CD25 (high) regulatory T cells are overrep-resented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Viguier" 1 => "F. Lemaitre" 2 => "O. Verola" 3 => "M.S. Cho" 4 => "G. Gorochov" 5 => "L. Dubertret" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Immunol" "fecha" => "2004" "volumen" => "173" "paginaInicial" => "1444" "paginaFinal" => "1453" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15240741" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.L. Berger" 1 => "R. Tigelaar" 2 => "J. Cohen" 3 => "K. Mariwalla" 4 => "J. Trinh" 5 => "N. Wang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2004-06-2181" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2005" "volumen" => "105" "paginaInicial" => "1640" "paginaFinal" => "1647" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15514008" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L.A. Ormandy" 1 => "T. Hillemann" 2 => "H. Wedemeyer" 3 => "M.P. Manns" 4 => "T.F. Greten" 5 => "F. Ko-rangy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/0008-5472.CAN-04-3232" "Revista" => array:6 [ "tituloSerie" => "Cancer Res" "fecha" => "2005" "volumen" => "65" "paginaInicial" => "2457" "paginaFinal" => "2464" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15781662" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical and molecular features of the immunodysregulation, polyen-docrinopathy, enteropathy, X linked (IPEX) síndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.S. Wildin" 1 => "S. Smyk-Pearson" 2 => "A.H. Filipovich" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Med Genet" "fecha" => "2002" "volumen" => "39" "paginaInicial" => "537" "paginaFinal" => "545" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12161590" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutational análisis of the FOXP 3 gene and evidence for genetic hetero-geneity in the immunodysregulation, polyendocrinopathy, en-teropathy syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.J. Owen" 1 => "C.E. Jennings" 2 => "H. Imrie" 3 => "A. Lachaux" 4 => "N.A. Bridges" 5 => "T.D. Cheetham" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Endocrinol Metabol" "fecha" => "2003" "volumen" => "88" "paginaInicial" => "6034" "paginaFinal" => "6039" ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IPEX and the role of FOXP 3 in the development and function of human Tregs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "S. Le Bras" 1 => "R.S. Geha" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI28880" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2006" "volumen" => "116" "paginaInicial" => "1473" "paginaFinal" => "1475" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16741571" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Fuchizawa" 1 => "Y. Adachi" 2 => "Y. Ito" 3 => "H. Higashiyama" 4 => "H. Kanegane" 5 => "T. Futatani" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.clim.2007.08.004" "Revista" => array:6 [ "tituloSerie" => "Clin Immunol" "fecha" => "2007" "volumen" => "125" "paginaInicial" => "237" "paginaFinal" => "246" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17916446" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib51" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Bindl" 1 => "T. Torgerson" 2 => "L. Perroni" 3 => "N. Youssef" 4 => "H.D. Ochs" 5 => "O. Goulet" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jpeds.2005.04.017" "Revista" => array:6 [ "tituloSerie" => "J Pediatr" "fecha" => "2005" "volumen" => "147" "paginaInicial" => "256" "paginaFinal" => "259" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16126062" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib52" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Yong PL, Russo P, Sullivan KE. Use of Sirolimus in IPEX and IPEX-Like Children. J Clin Immunol. 2008 May 15. [Epub ahead of print]" ] ] ] 52 => array:3 [ "identificador" => "bib53" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune reconstitution and recovery of FOXP3 (forkhead box P3)-expressing T cells after transplantation for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Zhan" 1 => "J. Sinclair" 2 => "S. Adams" 3 => "C.M. Cale" 4 => "S. Murch" 5 => "L. Perroni" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1542/peds.2007-1863" "Revista" => array:6 [ "tituloSerie" => "Pediatrics" "fecha" => "2008" "volumen" => "121" "paginaInicial" => "e998" "paginaFinal" => "e1002" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18316354" "web" => "Medline" ] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib54" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "O. Baud" 1 => "O. Goulet" 2 => "D. Canioni" 3 => "F. LeDeist" 4 => "I. Radford" 5 => "D. Riev" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM200106073442304" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2001" "volumen" => "344" "paginaInicial" => "1758" "paginaFinal" => "1762" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11396442" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib55" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Rao" 1 => "N. Kamani" 2 => "A. Filipovich" 3 => "S.M. Lee" 4 => "S.M. Davies" 5 => "J. Dalal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2006-05-025072" "Revista" => array:6 [ "tituloSerie" => "Blood" "fecha" => "2007" "volumen" => "109" "paginaInicial" => "383" "paginaFinal" => "385" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16990602" "web" => "Medline" ] ] ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib56" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "K.G. Lucas" 1 => "D. Ungar" 2 => "M. Comito" 3 => "M. Bayerl" 4 => "B. Groh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.bmt.1705542" "Revista" => array:6 [ "tituloSerie" => "Bone Marrow Transplant" "fecha" => "2007" "volumen" => "39" "paginaInicial" => "55" "paginaFinal" => "56" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17115064" "web" => "Medline" ] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib57" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epstein Barr virus induced lymphoma in a child with IPEX syndrome" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K.G. Lucas" 1 => "D. Ungar" 2 => "M. Comito" 3 => "B. Groh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/pbc.21341" "Revista" => array:6 [ "tituloSerie" => "Pediatr Blood Cancer" "fecha" => "2008" "volumen" => "50" "paginaInicial" => "1056" "paginaFinal" => "1057" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17828748" "web" => "Medline" ] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib58" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Sharfe N, Dadi HK, Shahar M, Roifman CM. Proc Natl Acad Sci USA 1997; 94: 3168–71" ] ] ] 58 => array:3 [ "identificador" => "bib59" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulatory T cells in human autoimmune diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "T.R. Torgerson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Springer Semin Immun" "fecha" => "2006" "volumen" => "28" "paginaInicial" => "63" "paginaFinal" => "76" ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib60" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Human IL-2 receptor alpha chain deficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "C.M. Roifman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1203/00006450-200007000-00004" "Revista" => array:6 [ "tituloSerie" => "Pediatr Res" "fecha" => "2000" "volumen" => "48" "paginaInicial" => "6" "paginaFinal" => "11" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10879793" "web" => "Medline" ] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib61" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome, and defective IL-10 expression from CD4 lymphocytes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.A. Caudy" 1 => "S.T. Reddy" 2 => "T. Chatila" 3 => "J.P. Atkinson" 4 => "J.W. Verbsky" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2006.10.007" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2007" "volumen" => "119" "paginaInicial" => "482" "paginaFinal" => "487" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17196245" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000238/v1_201304101017/en/main.assets" "Apartado" => array:4 [ "identificador" => "5555" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000003700000004/v1_201304101017/S0301054609000238/v1_201304101017/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000238?idApp=UINPBA00004N"]

Statistics

REVIEW

A. Blanco Quirósa,

Corresponding author

ablanco@ped.uva.es

Corresponding author.

, E. Arranz Sanza, D. Bernardo Ordiza, J.A. Garrote Adradosa,b

a Department of Pediatrics and Immunology, IBGM, University of Valladolid, Spain

b Clinical Research Unity, Hospital Clínico Universitario, Valladolid, Spain

Read

14251

Times
was read the article

1541

Total PDF

12710

Total HTML

Share statistics

 array:23 [
  "pii" => "S0301054609000238"
  "issn" => "03010546"
  "doi" => "10.1016/j.aller.2009.04.002"
  "estado" => "S300"
  "fechaPublicacion" => "2009-07-01"
  "aid" => "22"
  "copyright" => "SEICAP"
  "copyrightAnyo" => "2009"
  "documento" => "article"
  "crossmark" => 0
  "subdocumento" => "ssu"
  "cita" => "Allergol  Immunopathol &#40;Madr&#41;. 2009;37:208-15"
  "abierto" => array:3 [
    "ES" => false
    "ES2" => false
    "LATM" => false
  ]
  "gratuito" => false
  "lecturas" => array:2 [
    "total" => 10617
    "formatos" => array:3 [
      "EPUB" => 22
      "HTML" => 9654
      "PDF" => 941
    ]
  ]
  "itemSiguiente" => array:18 [
    "pii" => "S0301054609000263"
    "issn" => "03010546"
    "doi" => "10.1016/j.aller.2009.02.004"
    "estado" => "S300"
    "fechaPublicacion" => "2009-07-01"
    "aid" => "25"
    "copyright" => "SEICAP"
    "documento" => "simple-article"
    "crossmark" => 0
    "subdocumento" => "cor"
    "cita" => "Allergol  Immunopathol &#40;Madr&#41;. 2009;37:216-7"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 3173
      "formatos" => array:3 [
        "EPUB" => 15
        "HTML" => 2817
        "PDF" => 341
      ]
    ]
    "en" => array:9 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Research Letter</span>"
      "titulo" => "Helium-oxygen mixtures and acute severe asthma"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "216"
          "paginaFinal" => "217"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "L&#46; Cruz, A&#46;R&#46; Ferreira, A&#46; Coimbra, M&#46;G&#46; Castel-Branco"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "L&#46;"
              "apellidos" => "Cruz"
            ]
            1 => array:2 [
              "nombre" => "A&#46;R&#46;"
              "apellidos" => "Ferreira"
            ]
            2 => array:2 [
              "nombre" => "A&#46;"
              "apellidos" => "Coimbra"
            ]
            3 => array:2 [
              "nombre" => "M&#46;G&#46;"
              "apellidos" => "Castel-Branco"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000263?idApp=UINPBA00004N"
    "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000263/v1_201304101017/en/main.assets"
  ]
  "itemAnterior" => array:18 [
    "pii" => "S0301054609000226"
    "issn" => "03010546"
    "doi" => "10.1016/j.aller.2009.03.003"
    "estado" => "S300"
    "fechaPublicacion" => "2009-07-01"
    "aid" => "21"
    "copyright" => "SEICAP"
    "documento" => "article"
    "crossmark" => 0
    "subdocumento" => "fla"
    "cita" => "Allergol  Immunopathol &#40;Madr&#41;. 2009;37:205-7"
    "abierto" => array:3 [
      "ES" => false
      "ES2" => false
      "LATM" => false
    ]
    "gratuito" => false
    "lecturas" => array:2 [
      "total" => 3406
      "formatos" => array:3 [
        "EPUB" => 10
        "HTML" => 2946
        "PDF" => 450
      ]
    ]
    "en" => array:11 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">SERIES&#58; Tips for researching in the field of allergy&#40;III&#41;</span>"
      "titulo" => "Patch test in the diagnosis of food allergy"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "205"
          "paginaFinal" => "207"
        ]
      ]
      "contieneResumen" => array:1 [
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "R&#46; Cocco, D&#46; Sol&#233;"
          "autores" => array:2 [
            0 => array:2 [
              "nombre" => "R&#46;"
              "apellidos" => "Cocco"
            ]
            1 => array:2 [
              "nombre" => "D&#46;"
              "apellidos" => "Sol&#233;"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000226?idApp=UINPBA00004N"
    "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000226/v1_201304101017/en/main.assets"
  ]
  "en" => array:18 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>"
    "titulo" => "From autoimmune enteropathy to the IPEX &#40;immune dysfunction&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked&#41; syndrome"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "208"
        "paginaFinal" => "215"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "A&#46; Blanco Quir&#243;s, E&#46; Arranz Sanz, D&#46; Bernardo Ordiz, J&#46;A&#46; Garrote Adrados"
        "autores" => array:4 [
          0 => array:4 [
            "nombre" => "A&#46;"
            "apellidos" => "Blanco Quir&#243;s"
            "email" => array:1 [
              0 => "ablanco&#64;ped&#46;uva&#46;es"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">¿</span>"
                "identificador" => "cor1"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "E&#46;"
            "apellidos" => "Arranz Sanz"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "D&#46;"
            "apellidos" => "Bernardo Ordiz"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
            ]
          ]
          3 => array:3 [
            "nombre" => "J&#46;A&#46;"
            "apellidos" => "Garrote Adrados"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff1"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff2"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:2 [
          0 => array:3 [
            "entidad" => "Department of Pediatrics and Immunology&#44; IBGM&#44; University of Valladolid&#44; Spain"
            "etiqueta" => "<span class="elsevierStyleSup">a</span>"
            "identificador" => "aff1"
          ]
          1 => array:3 [
            "entidad" => "Clinical Research Unity&#44; Hospital Cl&#237;nico Universitario&#44; Valladolid&#44; Spain"
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "aff2"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor1"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig4"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1702
            "Ancho" => 1622
            "Tamanyo" => 137748
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Generation of CD4&#43; subtype cells&#46; Transforming growth factor B-1 promotes the development of Treg cells by signal transducer and activator of transcription 5 &#40;STAT5&#41; and the nuclear factor FOXP3&#46; The early production of IL-4 favours the development of Th2 by STAT 3&#47;6 and GATA3&#59; IL-12 promotes TH-1 by STAT1&#47;4 and t-bet&#59; and IL-21 and IL-23 promotes TH-17 by STAT 3 and RORgt &#40;Modified from Bacchetta et al&#46; 2007&#41;&#46;</p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Intractable diarrhoea</span><p class="elsevierStylePara elsevierViewall">Avery proposed the term <span class="elsevierStyleItalic">&#8220;Intractable diarrhoea&#8221;</span> in 1968&#44; to describe patients with unremitting chronic diarrhoea occurring in infants less than 3 months of age with the result of progressive malnutrition&#44; after excluding an infectious aetiology&#46;<a class="elsevierStyleCrossRef" href="#bib1"><span class="elsevierStyleSup">1</span></a> In spite of using intravenous feeding&#44; mortality was frequent and occurred too early&#44; before a complete study could be performed&#46; This term may include a heterogeneous group of diseases &#40;<a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">The very rare cases described as <span class="elsevierStyleItalic">&#8220;Congenital diarrhoea&#8221;</span> may be considered as intractable diarrhoea&#44; however a group with early but no neonatal onset was separated from the congenital diarrhoea group&#46; Later&#44; when intestinal biopsies were easily available&#44; a villous atrophy was frequently recorded&#44; usually severe&#46; Crypts can be hypoplastic&#44; with few mitoses&#44; resembling a graft versus-host disease&#44; or hyperplastic&#44; resulting in a picture indistinguishable from a celiac disease&#46; An inflammatory infiltrate of the lamina propria is always present&#44; thought it is not clear whether gut autoantibodies precede or follow intestinal inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib2"><span class="elsevierStyleSup">2</span></a></p></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Autoimmune enteropathy</span><p class="elsevierStylePara elsevierViewall">Walker-Smith&#44;<a class="elsevierStyleCrossRef" href="#bib3"><span class="elsevierStyleSup">3</span></a> Unsworth&#44;<a class="elsevierStyleCrossRef" href="#bib4"><span class="elsevierStyleSup">4</span></a> and later&#44; Savage<a class="elsevierStyleCrossRef" href="#bib5"><span class="elsevierStyleSup">5</span></a> investigated autoantibodies in patients with non-congenital intractable diarrhoea that showed villous atrophy&#44; complement fixing gut autoantibodies&#44; and associated to some cases&#44; diabetes mellitus or hypothyroidism&#46;</p><p class="elsevierStylePara elsevierViewall">AIE is a rare familial disorder characterized by protracted diarrhoea&#44; lack or poor response to parenteral nutrition&#44; circulating antibodies and&#47;or autoimmune diseases in infants without severe immunodeficiency&#46; It is characterized by a somewhat more delayed onset than congenital enteropathies&#44; often at 4&#8211;6 months of age and frequently has other evidence of autoimmune diseases&#46; Dysmorphic features are common in congenital enteropathies but not in AIE&#46;<a class="elsevierStyleCrossRef" href="#bib6"><span class="elsevierStyleSup">6</span></a></p><p class="elsevierStylePara elsevierViewall">Autoantibodies were usually determined on human blood group 0 duodenal samples obtained from patients undergoing surgical procedures&#44; although tissue from monkey could be used with satisfactory sensibility&#46;<a class="elsevierStyleCrossRef" href="#bib7"><span class="elsevierStyleSup">7</span></a> A cross reaction between gut autoantibodies and renal epithelial cells is commonly reported&#46;<a class="elsevierStyleCrossRef" href="#bib8"><span class="elsevierStyleSup">8</span></a> Immunofluorescence analysis showed two different patterns&#58; complement-fixing apical antibodies and cytoplasmatic positive staining &#40;<a class="elsevierStyleCrossRef" href="#fig1">Fig&#46; 1</a>&#41;&#46; According to the report of Martin-Villa et al&#46;<a class="elsevierStyleCrossRef" href="#bib9"><span class="elsevierStyleSup">9</span></a> patients with complement-fixing apical antibodies may have abnormal T-cell responses in vitro&#44; and a cytoplasmatic pattern was associated to immunoglobulin deficiency&#44; suggesting that different cellular or humoral immunologic alterations may favour a different gut autoantibody pattern&#46; Although a correlation between serum autoantibodies levels and disease activity was found in some cases&#44;<a class="elsevierStyleCrossRef" href="#bib8"><span class="elsevierStyleSup">8</span></a> the pathogenic role of gut autoantibodies has never been proven&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">High expression of HLA-A&#44; -B&#44; and -C with a stronger reactivity is commonly found in the crypt epithelium&#46; An aberrant expression of DR molecules on the gut surface and crypt epithelium was observed&#44; with a high number of DR positive activated cells in the lamina propria&#46; Nevertheless the expression of HLA-DP and DQ was normal&#46; The inappropriate DR expression in the epithelium is not an exclusive sign of autoimmunity&#44; accompanying also chronic inflammatory processes&#44; such as Crohn disease&#46;</p><p class="elsevierStylePara elsevierViewall">Several authors investigated the nature of the gut antigen in AIE&#46; Coletti&#44; et al&#46;<a class="elsevierStyleCrossRef" href="#bib8"><span class="elsevierStyleSup">8</span></a> in 1991&#44; using Western immunoblot&#44; identified a 55<span class="elsevierStyleHsp" style=""></span>kD protein located in gut and renal epithelial cells that reacted with serum autoantibodies&#46; Later&#44; Kobayashi<a class="elsevierStyleCrossRef" href="#bib10"><span class="elsevierStyleSup">10</span></a> detected a 75<span class="elsevierStyleHsp" style=""></span>kD autoantigen&#44; which was distributed through the whole intestine and kidney&#44; and likely implicated in the development of nephropathy&#44; although not present in the thyroid gland&#46; A tryptophan hydroxylase &#40;TH&#41; was identified as the intestinal autoantigen in autoimmune polyendocrine syndrome type 1 which is accompanied by gastrointestinal symptoms in 20&#8211;30&#37; of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib11"><span class="elsevierStyleSup">11</span></a> This antigen is mainly present in enterochromaffin cells of the mucosa&#44; and the search for autoantibodies to TH is also recommended in patients with Crohn disease or ulcerative colitis&#46;</p><p class="elsevierStylePara elsevierViewall">The majority of reported patients with AIE were young boys with the onset of clinical manifestations at a very early stage&#44; within the first 6 months of life&#44; although it has also been observed in older children and female subjects&#44; interestingly with less bowel involvement&#46;<a class="elsevierStyleCrossRef" href="#bib12"><span class="elsevierStyleSup">12</span></a> Several reports describe the involvement of both the small and large bowels&#46; Whether either regions of the gut are simultaneously affected or one region is affected before the other is unclear&#46;<a class="elsevierStyleCrossRef" href="#bib13"><span class="elsevierStyleSup">13</span></a></p><p class="elsevierStylePara elsevierViewall">It was presumed that extra-intestinal involvement was commonly present&#44; but in the absence of a systemic evaluation some histological lesions outside gastrointestinal tract could remain unnoticed&#46; Pancreatic lesions&#44; with endocrine or exocrine insufficiency were usually observed&#44; and diabetes mellitus was frequently the first manifestation of the disease&#44; prior to diarrhoea&#46; Atopic eczema showed the typical clinical and histological findings&#46; During remissions the eczema improves and serum IgE levels decreased&#46; Renal involvement is common and biopsy may show interstitial inflammatory nephritis or membranous glomerulonephritis&#46;<a class="elsevierStyleCrossRefs" href="#bib8"><span class="elsevierStyleSup">8&#44;14</span></a> The liver injury was usually revealed by hepatomegaly and a moderate increase in serum transaminases&#46; Histology shows a periportal fibrosis&#44; which could be more extensive in some cases&#44; associated to a clinical picture of chronic aggressive hepatitis&#46; Thyroid insufficiency was noted in some cases&#44; with lymphoid cell infiltration that could be accompanied by fibrosis&#46;</p><p class="elsevierStylePara elsevierViewall">The mortality of patients with AIE was very high&#44; in spite of new therapies&#46; Nevertheless&#44; the response to treatment was variable&#44; mainly due to the heterogeneity of the disease&#46; Long periods with diet alone have been observed in few cases&#46; On the contrary&#44; other patients were resistant to corticosteroids or immunosuppressive therapy&#46; Cyclosporine induced remission in the majority of cases&#44; and later&#44; the treatment with tacrolimus was reported to be successfully in patients previously resistant to other immunotherapies&#46;</p></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">IPEX syndrome</span><p class="elsevierStylePara elsevierViewall">Powell et al&#46;<a class="elsevierStyleCrossRef" href="#bib15"><span class="elsevierStyleSup">15</span></a> reported the first case of IPEX syndrome&#46; This rare disease is characterized by immune dysfunction&#44; polyendocrinopathy&#44; enteropathy and X-linked inheritance&#44; which seems to be equivalent to the abnormalities expressed by the scurfy mice&#44; also an X-linked abnormality which was accidentally produced in 1949&#46;<a class="elsevierStyleCrossRefs" href="#bib16"><span class="elsevierStyleSup">16&#44;17</span></a> Before the accurate characterization&#44; multiple terms were assigned to IPEX syndrome &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl2"></elsevierMultimedia><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical picture</span><p class="elsevierStylePara elsevierViewall">Symptoms of the IPEX syndrome are different from one patient to another&#59; they can even vary within the same family&#44; especially in severity of symptoms&#46; The most common findings are diabetes mellitus&#44; protracted diarrhoea&#44; failure to thrive&#44; eczema and haemolytic anaemia&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a> Other less common features are thrombocytopenia with platelet-antibodies&#44; autoimmune hypothyroidism and lymphadenopathy with splenomegaly&#46;<ul class="elsevierStyleList"><li class="elsevierStyleListItem"><span class="elsevierStyleLabel">1&#46;</span><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Gastrointestinal disease</span>&#46; It is characterized by a severe watery diarrhoea that could be also mucoid or bloody&#46;<a class="elsevierStyleCrossRef" href="#bib18"><span class="elsevierStyleSup">18</span></a> Generally a worsening occurs when breast-feeding is switched to regular formula&#44; and many patients develop food allergies&#44; frequently associated to atopic eczema&#46;<a class="elsevierStyleCrossRef" href="#bib19"><span class="elsevierStyleSup">19</span></a> The response to dietary manipulation is variable&#44; and symptoms may persist&#44; requiring total parenteral nutrition to reverse the failure to thrive&#46;</p></li><li class="elsevierStyleListItem"><span class="elsevierStyleLabel">2&#46;</span><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Autoimmune endocrinopathies</span>&#46; The onset is very early and the involvement of pancreas and thyroid is the most common feature of IPEX syndrome&#44; whereas the involvement of parathyroids&#44; or adrenals is rare&#46; Insulin-dependent type 1 diabetes begins frequently during the first year of life&#44; although in some cases&#44; glucose intolerance is already present at birth&#46; Thyroiditis is common and can lead to hypothyroidism or hyperthyroidism&#46;</p></li><li class="elsevierStyleListItem"><span class="elsevierStyleLabel">3&#46;</span><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Dermatitis</span>&#46; A mild eczema is the most common finding in the skin and it may onset as an erythematous rash covering all the body&#46;<a class="elsevierStyleCrossRef" href="#bib18"><span class="elsevierStyleSup">18</span></a> Other immune-mediated dermatological diseases described are pemphigoid nodularis&#44;<a class="elsevierStyleCrossRef" href="#bib20"><span class="elsevierStyleSup">20</span></a> psoriasiform dermatitis or alopecia&#46; Patients with lesions resembling onychomycosis were also published&#46;<a class="elsevierStyleCrossRef" href="#bib21"><span class="elsevierStyleSup">21</span></a></p></li><li class="elsevierStyleListItem"><span class="elsevierStyleLabel">4&#46;</span><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Other findings</span>&#46; In addition to the basic triad&#44; other autoimmune alterations were reported in patients with IPEX syndrome&#46; The most common are autoimmune haematological disorders&#44; such as Coombs-positive haemolytic anaemia&#44; thrombocytopenia or neutropenia&#44; which altogether are present in more than 50&#37; of the patients&#46; Renal disease affects about 30&#37; of the cases&#44; mainly as an interstitial nephritis&#44; although membranous glomerulonephritis was also reported&#46;<a class="elsevierStyleCrossRef" href="#bib22"><span class="elsevierStyleSup">22</span></a> The severity of the clinical picture is variable&#59; ranging from mild proteinuria and haematuria to rapidly progressive glomerulonephritis&#44; only reverted by stem cell transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib22"><span class="elsevierStyleSup">22</span></a> Autoimmune hepatitis is also common&#46; Some patients have neurologic abnormalities with developmental delay or seizures&#46;</p></li></ul></p><p class="elsevierStylePara elsevierViewall">A high susceptibility to infections and reactions to vaccines was denoted in many patients without an apparent immunodeficiency&#46; Some authors related infections to alterations of the skin and the gut barrier&#44; or to immunosuppressive therapy&#46; The neutropenia may be another influent factor&#46;</p><p class="elsevierStylePara elsevierViewall">Until now&#44; only cases with typical IPEX syndrome have been easily identified&#44; however cases with mild and uncompleted clinical pictures are increasingly reported&#46; Two unrelated cases with early onset enteropathy and long-term survival&#44; without type 1 diabetes&#44; were recently published&#46; They showed a novel mutation of FOXP3 gene&#46;<a class="elsevierStyleCrossRef" href="#bib23"><span class="elsevierStyleSup">23</span></a></p><p class="elsevierStylePara elsevierViewall">The definitive diagnosis is based on genetic studies and the identification of the mutation&#44; but an easier screening test by immunocytochemical staining of FOXP3 molecule in bowel biopsies has also been proposed&#46;<a class="elsevierStyleCrossRef" href="#bib24"><span class="elsevierStyleSup">24</span></a> The Wiskott-Aldrich syndrome and other X-linked diseases with immune abnormalities have some similarities &#40;<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46; Although previously a common genetic origin was proposed for all these entities&#44; definitively a separate identity has been proven for every syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a></p><elsevierMultimedia ident="tbl3"></elsevierMultimedia></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Immunologic findings</span><p class="elsevierStylePara elsevierViewall">Our knowledge about immune findings is fragmented and incomplete&#44; even contradictory&#44; because infants are frequently studied during serious illness&#44; malnutrition&#44; infections or immunosuppressive therapy No patognomonic abnormalities and consistent changes in number of cells or immune function have been described&#46;<a class="elsevierStyleCrossRef" href="#bib25"><span class="elsevierStyleSup">25</span></a> Nevertheless&#44; IgE serum levels are increased in most patients with IPEX syndrome&#44; and eosinophilia and high IgA are also common&#46; Serum anti-islet&#44; thyroid cell or enterocyte antibodies are present in some patients&#46; Most patients have normal peripheral blood number of CD3&#43; CD4&#43; and CD8&#43; T-cells&#44; with normal proliferative response to mitogens&#46; Some patients showed a low number of NK and B cells&#44; in this case with an associated hypogammaglobulinaemia and recurrent bacterial infections&#46;<a class="elsevierStyleCrossRef" href="#bib26"><span class="elsevierStyleSup">26</span></a> The constant finding is the depletion of naive T-cell &#40;CD4&#43; and CD8&#43;&#41; with increase number of memory T cells&#46;<a class="elsevierStyleCrossRefs" href="#bib26"><span class="elsevierStyleSup">26&#44;27</span></a> A high production of different cytokines&#44; lymphocyte strong response to mitogens and increased expression of MHC class II suggest a global activation of the immune response&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a></p><p class="elsevierStylePara elsevierViewall">A severe villous atrophy accompanied by lymphocytic infiltrates of lamina propria&#44; mucosa and submucosa are characteristic findings of IPEX syndrome&#46; Lymphocytic inflammation of pancreas with complete destruction of islet cells is present in cases with diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a> The typical lymphocytic infiltration may also involve other organs&#44; such as thyroid&#44; skin&#44; liver or brain&#46;</p><p class="elsevierStylePara elsevierViewall">The IPEX syndrome shares features with other X-linked syndromes&#44; such as Wiskott-Aldrich syndrome&#44; X-linked thrombocytopenia or X-linked congenital neutropenia&#46; Genetic studies have clearly defined the IPEX syndrome as a different entity&#46;</p></span></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">FOXP3</span><p class="elsevierStylePara elsevierViewall">The FOXP3 gene is located in the short arm of chromosome X &#40;Xq11&#46;23-Xq13&#46;3&#41;&#46; It has 11 exons which encode a protein of 431 amino acids&#46; It is expressed predominantly&#44; but not exclusively&#44; in CD4&#43;CD25&#43; T-cells&#46; Transcription factors are proteins which bind regulatory regions of DNA and augment or suppress the transcription of particular genes&#46; FOXP3 is a member of subfamily of forkhead box &#40;FOX&#41; transcription factors&#44; which play a predominant role in embryonic pattern&#44; development and metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib28"><span class="elsevierStyleSup">28</span></a></p><p class="elsevierStylePara elsevierViewall">FOXP3 represses the promoter of several cytokine&#44; such as IL-2 or GM-CSF&#46; It interacts with the nuclear factor of activated T cells &#40;NFAT&#41; and perhaps with acute myeloid leukaemia 1&#47;runt related transcription factor &#40;AML1&#47;Runx1&#41; and nuclear factor-kB&#44; forming complexes that repress different cytokines promoters<a class="elsevierStyleCrossRefs" href="#bib29"><span class="elsevierStyleSup">29&#8211;31</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig2">Fig&#46; 2</a>&#41;&#46; The binding of NFAT with FOXP3 occurs specifically in CD4&#43;CD25&#43; Treg cells&#44; whereas in conventional T cells the NFAT exerts the repression function binding through another transcription factor&#44; the activator protein-1 &#40;AP-1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib25"><span class="elsevierStyleSup">25</span></a></p><elsevierMultimedia ident="fig2"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">Three domains are key for the function of FOXP3&#58; a C-terminal region which contains the forkhead domain that directly binds DNA regions&#59; a central domain with a zinc finger and a leucine zipper that promotes the oligomerization of the FOXP3 molecule<a class="elsevierStyleCrossRef" href="#bib32"><span class="elsevierStyleSup">32</span></a>&#59; and a repressor domain located in the N-terminal region which binds the NAFT &#40;nuclear factor of activated T cells&#41; molecule<a class="elsevierStyleCrossRef" href="#bib33"><span class="elsevierStyleSup">33</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig3">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig3"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">Transgenic mice with increased expression of FOXP3 show decreased number of CD4&#43; T cells&#44; a low cellularity in lymphoid tissues and a poor response to antigenic stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib28"><span class="elsevierStyleSup">28</span></a> Some cytokines &#40;TGF-beta and IL-2&#41;&#44; and the stimulation of TCR&#44; have been identified as factors that induce the expression of FOXP3&#44; although their regulation is poorly known yet&#46;</p><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Regulatory T cells &#40;Treg&#41;</span><p class="elsevierStylePara elsevierViewall">Regulatory T cells constitute a small subset &#40;5&#8211;10&#37;&#41; of CD4&#43; T helper cells that develop in the thymus&#46; They are characterized by the expression of IL-2 receptor alpha chain &#40;CD25&#41;&#44; also expressing glucocorticoid-induced TNF receptor &#40;GITR&#41; and cytotoxic T lymphocyte-associated antigen 4 &#40;CTL-4&#41;<a class="elsevierStyleCrossRef" href="#bib25"><span class="elsevierStyleSup">25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig4">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig4"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">Treg cells are of critical importance for the establishment of the self-tolerance and immune homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib34"><span class="elsevierStyleSup">34</span></a> It has been shown that these cells suppress the autoimmune&#44; the antimicrobial and the antitumoral responses<a class="elsevierStyleCrossRef" href="#bib25"><span class="elsevierStyleSup">25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl4">Table 4</a>&#41;&#46; More recently&#44; a novel anti-atherogenic role was claimed for Treg&#46;<a class="elsevierStyleCrossRef" href="#bib35"><span class="elsevierStyleSup">35</span></a> It is noteworthy that antigen simulation is required for the initiation of Treg suppression&#44; but suppressive effects can later occur to bystander cells and systems&#46; They play an important role in controlling exaggerated Th2 response and they are involved in cow&#39;s milk allergy as well as in the allergy to inhalants&#46;<a class="elsevierStyleCrossRefs" href="#bib36"><span class="elsevierStyleSup">36&#44;37</span></a> The capacity of Treg to induced oral antigen tolerance has been proven in mice<a class="elsevierStyleCrossRefs" href="#bib38"><span class="elsevierStyleSup">38&#8211;40</span></a> and is also supposed in man&#46; A defect Treg function was associated to autoimmune&#44; allergic and immunodeficient diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib41"><span class="elsevierStyleSup">41&#44;42</span></a> In contrast&#44; an increased Treg function has been associated to malignancies&#46;<a class="elsevierStyleCrossRefs" href="#bib43"><span class="elsevierStyleSup">43&#8211;46</span></a></p><elsevierMultimedia ident="tbl4"></elsevierMultimedia><p class="elsevierStylePara elsevierViewall">FOXP3 plays a crucial role in the generation of Treg&#44; and when it is absent&#44; these cells do not develop in mice nor in man&#46; Transgenic mice &#40;scurfy&#41; which do not express FOXP3 lack Treg&#46; To date&#44; about 20 mutations of FOXP3 have been identified&#46; The majority are missense mutations that affect the integrity of the forkhead domain&#44; but deletions and substitutions have also been identified in the leucine zipper and in the repressor domain&#46; Nevertheless&#44; the genetic basis o the disease seems to be more heterogeneous than initially presumed&#46;</p><p class="elsevierStylePara elsevierViewall">The forkhead mutations interfere with nuclear import and DNA binding&#46; Mutations located in N terminal region affect the regulation of FOXP3 on the NFAT protein&#46; Other mutations seem to increase the length of the FOXP3 protein&#44; changing the three-dimensional structure and the function&#46;<a class="elsevierStyleCrossRef" href="#bib25"><span class="elsevierStyleSup">25</span></a> In some cases&#44; no mutations in gene FOXP3 are identified and it is supposed that they involve some unknown regulator gene which may be located even outside the X chromosome&#44; because females are affected in some families&#46;<a class="elsevierStyleCrossRefs" href="#bib44"><span class="elsevierStyleSup">44&#44;47&#44;48</span></a> Moreover&#44; a case with gene FOXP3 mutation&#44; normal FOXP3 protein expression and Treg deficient function was published&#44; proving that the complex mechanism of this disorder is yet unclear&#46;<a class="elsevierStyleCrossRefs" href="#bib25"><span class="elsevierStyleSup">25&#44;49</span></a> Some reports support a genotype-phenotype correlation&#46;<a class="elsevierStyleCrossRef" href="#bib50"><span class="elsevierStyleSup">50</span></a></p></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment of IPEX syndrome</span><p class="elsevierStylePara elsevierViewall">Symptomatic treatment includes total parenteral nutrition and insulin injections that are commonly needed&#44; as well as red blood or platelet transfusion&#46; In the early years&#44; the therapy of IPEX syndrome was based on immunosuppressive drugs&#46; Steroids&#44; methotrexate&#44; cyclosporin&#44; FK506 and more recently infliximab and rituximab have been used with unequal results&#44; frequently disappointing&#44; because the response is short and late complications may appear&#46; Sirolimus is the latest drug assayed and seems to be less nephrotoxic and better tolerated&#44; improves diarrhoea and villous histology&#44; and decreases the dosage of corticoids&#46; In addition&#44; it allows the expansion of Treg while the growth of effector T cells is inhibited&#46;<a class="elsevierStyleCrossRefs" href="#bib51"><span class="elsevierStyleSup">51&#44;52</span></a></p><p class="elsevierStylePara elsevierViewall">In spite of new drugs&#44; bone marrow transplantation is the only definitive cure for patients with IPEX syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib53"><span class="elsevierStyleSup">53</span></a> It has been performed in some cases with complete clinical remission&#44; in spite of only a partial engraftment with a chimerical status&#46;<a class="elsevierStyleCrossRef" href="#bib54"><span class="elsevierStyleSup">54</span></a> After transplantation&#44; clinical recovery was associated with the emergence of regulatory T cells&#44; the majority expressing markers of memory phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib53"><span class="elsevierStyleSup">53</span></a> It was remarkable that the conditioning regimen was itself effective in controlling symptoms in some patients and it was recently noticed that a reduced-intensity conditioning regimen prior to the engraftment resulted in more FOXP3<span class="elsevierStyleHsp" style=""></span>T regulatory cells than more aggressive conditioning&#46;<a class="elsevierStyleCrossRef" href="#bib55"><span class="elsevierStyleSup">55</span></a> Correction symptoms were also successfully reached with cord blood donor&#46;<a class="elsevierStyleCrossRef" href="#bib56"><span class="elsevierStyleSup">56</span></a> Unfortunately&#44; the excellent results of bone marrow transplantation are frequently transient&#46;<a class="elsevierStyleCrossRef" href="#bib17"><span class="elsevierStyleSup">17</span></a></p><p class="elsevierStylePara elsevierViewall">The recovery of diabetes mellitus was obtained in some cases&#44; but in most instances the islet damage is already permanent at the time of bone marrow transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib28"><span class="elsevierStyleSup">28</span></a> It is recommended to perform the transplantation in the early phase of the disease in order to avoid irreversible damage and complications&#46;</p><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Complications&#46;</span> Malnutrition is the main complication in infants&#44; and infections in later ages&#44; being the most frequent cause of death&#46; Lymphoproliferative haemophagocytic syndrome is another complication which was also published&#46;<a class="elsevierStyleCrossRefs" href="#bib47"><span class="elsevierStyleSup">47&#44;54</span></a> The immunosuppressive drugs and their dose are one of the most important risk factors of complications&#44; so the type of therapy must be carefully considered&#46; A patient with IPEX syndrome managed with rapamycin who subsequently developed a lymphoma induced by Epstein Barr virus was recently reported&#46;<a class="elsevierStyleCrossRef" href="#bib57"><span class="elsevierStyleSup">57</span></a></p></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">IPEX-like syndromes</span><p class="elsevierStylePara elsevierViewall">Due to the complexity of Treg function it is not surprising to find patients with similar symptoms and different genetic and immune findings&#46;</p><p class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">CD25 deficiency</span>&#46; From the discovery of IL-2R alpha &#40;CD25&#41; defects in 1997&#44;<a class="elsevierStyleCrossRef" href="#bib58"><span class="elsevierStyleSup">58</span></a> at least two families were described with a genetic mutation and a lack expression&#46;<a class="elsevierStyleCrossRef" href="#bib59"><span class="elsevierStyleSup">59</span></a> The main characteristic data was a massive enlargement of peripheral lymphoid organs&#44; with hepatosplenomegaly&#44; enlarged tonsils and lymphadenopathy&#46; All cases show an inflammatory bowel disease with villous atrophy&#46; One case had clear traits of immunodeficiency&#44; with low T cell number and decreased response to mitogens whereas the second patients showed an IPEX typical pattern with several autoantibodies&#46; It was remarkable that the first patient did not develop diabetes or endocrinopathies&#44; and the diabetes showed a late onset&#44; 6 year of age&#44; in the case with IPEX pattern&#46;<a class="elsevierStyleCrossRefs" href="#bib60"><span class="elsevierStyleSup">60&#44;61</span></a></p><p class="elsevierStylePara elsevierViewall">In summary&#44; patients who years ago were diagnosed as AIE may be now considered to have IPEX syndrome&#46; The majority of cases could be confirmed by studying FOXP3 gene mutations&#46; Nevertheless&#44; there are also atypical cases which have appeared with a delayed onset&#44; or affecting female patients&#46; They may be variants of FOXP3 mutation or be related to other molecules also involved in the generation or the function of Treg cells&#44; such as CD25 abnormalities&#46;</p></span></span><span class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:8 [
        0 => array:2 [
          "identificador" => "xres85644"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec73922"
          "titulo" => "Keywords"
        ]
        2 => array:1 [
          "titulo" => "Intractable diarrhoea"
        ]
        3 => array:1 [
          "titulo" => "Autoimmune enteropathy"
        ]
        4 => array:2 [
          "titulo" => "IPEX syndrome"
          "secciones" => array:2 [
            0 => array:1 [
              "titulo" => "Clinical picture"
            ]
            1 => array:1 [
              "titulo" => "Immunologic findings"
            ]
          ]
        ]
        5 => array:2 [
          "titulo" => "FOXP3"
          "secciones" => array:3 [
            0 => array:1 [
              "titulo" => "Regulatory T cells &#40;Treg&#41;"
            ]
            1 => array:1 [
              "titulo" => "Treatment of IPEX syndrome"
            ]
            2 => array:1 [
              "titulo" => "IPEX-like syndromes"
            ]
          ]
        ]
        6 => array:1 [
          "titulo" => "Conflict of interest"
        ]
        7 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2009-04-29"
    "fechaAceptado" => "2009-04-30"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec73922"
          "palabras" => array:4 [
            0 => "Autoimmune enteropathy"
            1 => "IPEX syndrome"
            2 => "FOXP3 molecule"
            3 => "Regulatory T cells"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p class="elsevierStyleSimplePara elsevierViewall">The term autoimmune enteropathy &#40;AIE&#41; was applied to a form of &#8220;intractable diarrhoea&#8221; with serum gut autoantibodies&#44; characterized by male predominance&#44; early onset&#44; poor response to parenteral nutrition and several autoimmune diseases&#44; mainly type 1 diabetes&#46; In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis&#46; The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells &#40;Treg&#41; expressing CD4&#43; and CD25&#43; molecules&#46; Mutations of the FOXP3 gene&#44; located in X chromosome&#44; produce a syndrome with Immune dysfunction&#44; Polyendocrinopathy&#44; Enteropathy and X-linked inheritance &#40;IPEX&#41;&#46; The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome&#44; even in female patients who may have some autosomal genetic variants&#46; Besides FOXP3&#44; other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes&#46; Meanwhile&#44; the important pathogenic role previously ascribed to gut autoantibodies has vanished&#44; with it remaining as having only certain screening usefulness&#46;</p>"
      ]
    ]
    "multimedia" => array:8 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1890
            "Ancho" => 2164
            "Tamanyo" => 390243
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Indirect immunofluorescence pattern putting the patient&#39;s serum on frozen monkey tissue&#46; A&#46; IgA positive antibodies on a longitudinal section of gut &#40;&#215;40&#41;&#44; the staining is stronger at brush-border of crypts&#46; B&#46; IgG positive antibodies on a cross section of gut &#40;&#215;100&#41;&#44; the immunofluorescence is cytoplasmatic with more intensity over apical border and a think linear staining on basolateral border&#46; C&#46; Staining on monkey kidney showing IgG autoantibodies that react with tubular border but avoiding the glomerulus &#40;&#215;40&#41;&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig2"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 970
            "Ancho" => 2917
            "Tamanyo" => 103514
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Representation of human FOXP3 gene&#46; Repressor domain binds NFAT molecule&#44; Zn finger with leucine zipper domain promotes the oligomerization of FOXP3 molecule and its function&#59; Forkhead domain binds DNA sequence&#46; Arrows indicate the location of mutations in patients with IPEX syndrome &#40;Modified from van der Vliet et al&#46; 2007&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig3"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1226
            "Ancho" => 1632
            "Tamanyo" => 96621
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Antigen reaction with T cell receptor &#40;TCR&#41; up-regulates the expression of nuclear factor of activated T cell &#40;NFAT&#41; both&#44; in conventional T cells and CD4&#43; CD25&#43; T cells&#46; However&#44; NFAT binds the activator protein 1 &#40;AP1&#41; in conventional T cells&#44; whereas in Treg &#40;CD4&#43;CD25&#43;&#41; reacts with FOXP3 factor&#46; It produces the transcription of a different set of genes&#44; resulting in a final activation reaction in T conventional cells and suppression in Treg cells&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig4"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 1702
            "Ancho" => 1622
            "Tamanyo" => 137748
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Generation of CD4&#43; subtype cells&#46; Transforming growth factor B-1 promotes the development of Treg cells by signal transducer and activator of transcription 5 &#40;STAT5&#41; and the nuclear factor FOXP3&#46; The early production of IL-4 favours the development of Th2 by STAT 3&#47;6 and GATA3&#59; IL-12 promotes TH-1 by STAT1&#47;4 and t-bet&#59; and IL-21 and IL-23 promotes TH-17 by STAT 3 and RORgt &#40;Modified from Bacchetta et al&#46; 2007&#41;&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; Congenital diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Syndromic or phenotypic diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Microvillous inclusion disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Tufting enteropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Congenital diarrhoea with mutant neurogenin-3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Congenital diarrhoea with disorder of glycosylation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; IPEX and IPEX-like syndromes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; Other autoimmune enteropathies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab164406.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Different forms of intractable diarrhoea of infancy</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46; X-linked Autoimmunity-Allergic Dysregulation Syndrome &#40;XLAAD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46; Insulin-dependent Diabetes Mellitus Diarrhoea Syndrome &#40;DMSD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46; X-linked Autoimmunity-Immunodeficiency Syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46; X-linked Diarrhoea&#44; Polyendocrinopathy&#44; Fatal Infection Syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#46; Autoimmune Enteropathy with Haemolytic Anaemia and Polyendocrinopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46; X-linked Polyendocrinopathy&#44; Immune Dysfunction and Diarrhea &#40;XPID&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#46; Diabetes Mellitus&#44; Congenital Insulin-dependent with Fatal Secretory Diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46; Immunodeficiency&#44; Polyendocrinopathy and Enteropathy&#44; X-linked&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab164407.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Ancient terms assigned to IPEX syndrome &#40;Marabelle et al&#46; 2008&#41;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl3"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p class="elsevierStyleSimplePara elsevierViewall">IPEX&#58; Immunodysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked&#46;</p><p class="elsevierStyleSimplePara elsevierViewall">WAS&#58; Wiskott-Aldrich syndrome&#46;</p><p class="elsevierStyleSimplePara elsevierViewall">XLT&#58; X-linked thrombocytopenia&#46;</p><p class="elsevierStyleSimplePara elsevierViewall">XLN&#58; X-linked neutropenia&#46;</p><p class="elsevierStyleSimplePara elsevierViewall">GATA&#58; is a T-cell transcription factor&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Clinical signs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">IPEX</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">WAS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">XLT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">XLN</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">GATA-1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmune manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diarrhoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atopic eczema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Recurrent infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal bleeding&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thrombocytopenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#177;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">small&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">small&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">large&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T-cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neutropenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-random X-chr&#46; inactivation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8722;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab164408.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Differential characteristics of X-linked syndromes with immune abnormalities &#40;Bennett et al&#46; 2001&#41;</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl4"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Subset</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Characteristic protective activity</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleBold">Main immunopathology</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TH1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intracellular bacteria and some virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Granulomatous disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TH2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Helminths&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Allergic disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TH17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Extracellular bacteria and some fungi&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chronic inflammatory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmune disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolerance against self&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmunity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Control of high response against non-self&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Immunodeficiency&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab164409.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p class="elsevierStyleSimplePara elsevierViewall">Simplified view of protective role and immunopathology involvement of different CD4&#43; T-cell subset &#40;Romagnani 2006&#41;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:61 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intractable diarrhea of early infancy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "G&#46;B&#46; Avery"
                            1 => "O&#46; Villacivencio"
                            2 => "J&#46;R&#46; Lilly"
                            3 => "J&#46;G&#46; Randolph"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "1968"
                        "volumen" => "41"
                        "paginaInicial" => "712"
                        "paginaFinal" => "722"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5643979"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy in a child&#58; Response to Infliximab Therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;A&#46; Vanderhoof"
                            1 => "R&#46;J&#46; Young"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Gastroenterol Nutr"
                        "fecha" => "2002"
                        "volumen" => "34"
                        "paginaInicial" => "312"
                        "paginaFinal" => "316"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11964960"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoantibodies against gut epithelium in a child with small-intestinal enteropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Walker-Smith"
                            1 => "D&#46;J&#46; Unsworth"
                            2 => "P&#46; Hutchins"
                            3 => "P&#46; Hutchins"
                            4 => "A&#46;D&#46; Phillips"
                            5 => "E&#46;J&#46; Holborow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1982"
                        "volumen" => "1"
                        "paginaInicial" => "566"
                        "paginaFinal" => "567"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2564107"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune in diarrhoeal disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;J&#46; Unsworth"
                            1 => "J&#46;A&#46; Walker-Smith"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Gastroenterol Nutr"
                        "fecha" => "1985"
                        "volumen" => "4"
                        "paginaInicial" => "375"
                        "paginaFinal" => "380"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4020570"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Specific autoantibodies to gut epithelium in two infants with severe protracted diarrhea"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;O&#46; Savage"
                            1 => "R&#46; Mirakian"
                            2 => "E&#46;R&#46; Wozniak"
                            3 => "H&#46;R&#46; Jenkins"
                            4 => "M&#46; Malone"
                            5 => "A&#46;D&#46; Phillips"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr Gastroenterol Nutr"
                        "fecha" => "1985"
                        "volumen" => "4"
                        "paginaInicial" => "187"
                        "paginaFinal" => "195"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3886868"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy and villous atrophy in adults"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46;R&#46; Corazza"
                            1 => "F&#46; Biagi"
                            2 => "U&#46; Volta"
                            3 => "M&#46;L&#46; Andreani"
                            4 => "L&#46; de Franceschi"
                            5 => "G&#46; Gasbarrini"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(97)01042-8"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1997"
                        "volumen" => "350"
                        "paginaInicial" => "106"
                        "paginaFinal" => "109"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9228963"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tuftin enteropathy and skeletal dysplasia&#58; is there a link&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "W&#46; El-Matary"
                            1 => "A&#46;M&#46; Dalzell"
                            2 => "G&#46; Kokai"
                            3 => "J&#46;E&#46; Davidson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00431-006-0231-z"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Pediatr"
                        "fecha" => "2007"
                        "volumen" => "166"
                        "paginaInicial" => "265"
                        "paginaFinal" => "268"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16900309"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;B&#46; Colletti"
                            1 => "A&#46;P&#46; Guillot"
                            2 => "S&#46; Rosen"
                            3 => "A&#46;K&#46; Bhan"
                            4 => "C&#46;D&#46; Hobson"
                            5 => "A&#46;B&#46; Collins"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "1991"
                        "volumen" => "118"
                        "paginaInicial" => "858"
                        "paginaFinal" => "864"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2040920"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "T-Lymphocyte dysfunctions occurring together with apical gut epithelial cell autoantibodies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Martin Villa"
                            1 => "J&#46;R&#46; Regueiro"
                            2 => "D&#46; de Juan"
                            3 => "P&#46; Perez Aciego"
                            4 => "M&#46; P&#233;rez Blas"
                            5 => "J&#46; Manzanares"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "1991"
                        "volumen" => "101"
                        "paginaInicial" => "390"
                        "paginaFinal" => "397"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2065915"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A 75-kD autoantigen recognized by sera from patients with X-linked autoimmune enteropathy associated with nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46; Kobayashi"
                            1 => "K&#46; Imamura"
                            2 => "M&#46; Yamada"
                            3 => "M&#46; Okano"
                            4 => "A&#46; Yara"
                            5 => "S&#46; Ikema"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Immunol"
                        "fecha" => "1998"
                        "volumen" => "111"
                        "paginaInicial" => "527"
                        "paginaFinal" => "531"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9528893"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Identification of tryptophan hydroxylase as an intestinal autoantigen"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "O&#46; Enkwall"
                            1 => "H&#46; Hedstrand"
                            2 => "L&#46; Grimelius"
                            3 => "J&#46; Haavik"
                            4 => "J&#46; Perheentupa"
                            5 => "J&#46; Gustafsson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(97)11050-9"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1998"
                        "volumen" => "352"
                        "paginaInicial" => "279"
                        "paginaFinal" => "283"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9690408"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy in infants&#46; Pathological study of the disease in two familial cases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Lachaux"
                            1 => "I&#46; Loras-Duclaux"
                            2 => "R&#46; Bouvier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Virchows Arch"
                        "fecha" => "1998"
                        "volumen" => "433"
                        "paginaInicial" => "481"
                        "paginaFinal" => "485"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9849864"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy and colitis&#58; is there a generalised autoimmune gut disorder&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46;M&#46; Hill"
                            1 => "P&#46;J&#46; Milla"
                            2 => "G&#46;F&#46; Bottazzo"
                            3 => "R&#46; Mirakian"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Gut"
                        "fecha" => "1991"
                        "volumen" => "32"
                        "paginaInicial" => "36"
                        "paginaFinal" => "42"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1991636"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Autoimmune enteropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "P&#46;A&#46; Russo"
                            1 => "P&#46; Brochu"
                            2 => "E&#46;G&#46; Seidman"
                            3 => "C&#46;C&#46; Roy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Dev Pathol"
                        "fecha" => "1999"
                        "volumen" => "2"
                        "paginaInicial" => "65"
                        "paginaFinal" => "71"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9841709"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An X-linked syndrome of diarrhea&#44; polyendocrinopathy and fatal infection in infancy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "B&#46;R&#46; Powell"
                            1 => "N&#46;R&#46; Ruist"
                            2 => "P&#46; Stenzel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "1982"
                        "volumen" => "100"
                        "paginaInicial" => "731"
                        "paginaFinal" => "737"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7040622"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "X-linked lymphorreticular disease in the scurfy &#40;sf&#41; mutant mouse"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "V&#46; Godfrey"
                            1 => "J&#46; Wilkinson"
                            2 => "L&#46; Russell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Pathol"
                        "fecha" => "1991"
                        "volumen" => "138"
                        "paginaInicial" => "1379"
                        "paginaFinal" => "1387"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2053595"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "IPEX is a unique X-linked syndrome characterized by immune disfunction&#44; polyendocrinopathy&#44; enteropathy&#44; and a variety of autoimmune phenomena"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;L&#46; Bennett"
                            1 => "H&#46;D&#46; Ochs"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Pediatr"
                        "fecha" => "2001"
                        "volumen" => "13"
                        "paginaInicial" => "533"
                        "paginaFinal" => "538"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11753102"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "De l&#8217;Ipex &#224; foxp3&#58; une nouvelle contribution de la p&#233;diatrie &#224; la comprehension du systeme immunitaire"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Marabelle"
                            1 => "M&#46; Meyer"
                            2 => "F&#46; Demeocq"
                            3 => "A&#46; Lachaux"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arcped.2007.10.005"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Pediatr"
                        "fecha" => "2008"
                        "volumen" => "15"
                        "paginaInicial" => "55"
                        "paginaFinal" => "63"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18155891"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46;R&#46; Torgerson"
                            1 => "A&#46; Linane"
                            2 => "N&#46; Moes"
                            3 => "S&#46; Anover"
                            4 => "V&#46; Mateo"
                            5 => "F&#46; Rieux-Laucat"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2007.02.044"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2007"
                        "volumen" => "132"
                        "paginaInicial" => "1705"
                        "paginaFinal" => "1717"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17484868"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked syndrome &#40;IPEX&#41; associated with pemphigoid nodularis&#58; a case report and review of the literature"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46;L&#46; McGinness"
                            1 => "M&#46;M&#46; Bivens"
                            2 => "K&#46;E&#46; Greer"
                            3 => "J&#46;W&#46; Patterson"
                            4 => "F&#46;T&#46; Saulsbury"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2005.08.047"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2006"
                        "volumen" => "55"
                        "paginaInicial" => "143"
                        "paginaFinal" => "148"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16781310"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Norwegian scabies mimicking onychomycosis and scalp dermatitis in a child with IPEX syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "P&#46; McLucas"
                            1 => "G&#46;J&#46; Fulchiero Jr"
                            2 => "E&#46; Fernandez"
                            3 => "J&#46;J&#46; Miller"
                            4 => "A&#46;L&#46; Zaenglein"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaad.2006.01.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Acad Dermatol"
                        "fecha" => "2007"
                        "volumen" => "56"
                        "paginaInicial" => "S48"
                        "paginaFinal" => "S49"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17224384"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunodysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked &#40;IPEX&#41; syndrome&#58; an unusual cause of proteinuria in infancy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Moudgil"
                            1 => "P&#46; Perriello"
                            2 => "B&#46; Loechelt"
                            3 => "R&#46; Przygodzki"
                            4 => "W&#46; Fitzerald"
                            5 => "N&#46; Kamani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00467-007-0532-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Nephrol"
                        "fecha" => "2007"
                        "volumen" => "22"
                        "paginaInicial" => "1799"
                        "paginaFinal" => "1802"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17629750"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mechanistic associations of a mild phenotype of immunodysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; x-linked syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; De Benedetti"
                            1 => "A&#46; Insalaco"
                            2 => "A&#46; Diamanti"
                            3 => "E&#46; Cortis"
                            4 => "F&#46; Muratori"
                            5 => "A&#46; Lamioni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cgh.2005.12.014"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Gastroenterol Hepatol"
                        "fecha" => "2006"
                        "volumen" => "4"
                        "paginaInicial" => "653"
                        "paginaFinal" => "659"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16630773"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A potential screening tool for IPEX syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;L&#46; Heltzer"
                            1 => "J&#46;K&#46; Choi"
                            2 => "H&#46;D&#46; Ochs"
                            3 => "K&#46;E&#46; Sullivan"
                            4 => "T&#46;R&#46; Torgerson"
                            5 => "L&#46;M&#46; Ernst"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2350/06-07-0130.1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Dev Pathol"
                        "fecha" => "2007"
                        "volumen" => "10"
                        "paginaInicial" => "98"
                        "paginaFinal" => "105"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17378693"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "IPEX as a result of mutations in FOXP3"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46;J&#46;J&#46; van der Vliet"
                            1 => "E&#46;E&#46; Nieuwenhuis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1155/2007/89017"
                      "Revista" => array:2 [
                        "tituloSerie" => "Clin Dev Immunol"
                        "fecha" => "2007"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Severe FOXP3&#43; and na&#239;ve T lymphopenia in a non-IPEX form of autoimmune enteropathy combined with an immunodeficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Zuber"
                            1 => "M&#46; Viguier"
                            2 => "F&#46; Lemaitre"
                            3 => "V&#46; Sen&#233;e"
                            4 => "N&#46; Patey"
                            5 => "G&#46; Elain"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.gastro.2007.02.034"
                      "Revista" => array:6 [
                        "tituloSerie" => "Gastroenterology"
                        "fecha" => "2007"
                        "volumen" => "132"
                        "paginaInicial" => "1694"
                        "paginaFinal" => "1704"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17484867"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A remarkable depletion of both na&#239;ve CD4&#43; and CD8&#43; with high proportion of memory T cells in an IPEX infant with a FOXP3 mutation in the forkhead domain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;T&#46; Costa-Carvalho"
                            1 => "M&#46;I&#46; de Moraes-Pinto"
                            2 => "L&#46;C&#46; de Almeida"
                            3 => "M&#46;T&#46; de Seixas Alves"
                            4 => "R&#46;P&#46; Maia"
                            5 => "R&#46;L&#46; de Souza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-3083.2008.02055.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Scand J Immunol"
                        "fecha" => "2008"
                        "volumen" => "68"
                        "paginaInicial" => "85"
                        "paginaFinal" => "91"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18489537"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked&#58; Forkhead box protein 3 mutations and lack of regulatory T cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46;R&#46; Torgerson"
                            1 => "H&#46;D&#46; Ochs"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2007.08.044"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2007"
                        "volumen" => "120"
                        "paginaInicial" => "744"
                        "paginaFinal" => "750"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17931557"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expresi&#243;n and effector functions of T helper cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "E&#46; Bettelli"
                            1 => "M&#46; Dastrange"
                            2 => "M&#46; Oukka"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.0501675102"
                      "Revista" => array:6 [
                        "tituloSerie" => "Proc Natl Acad Sci U S A"
                        "fecha" => "2005"
                        "volumen" => "102"
                        "paginaInicial" => "5138"
                        "paginaFinal" => "5143"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15790681"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "FOXP3 controls regulatory T cell function through cooperation with NFAT"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Wu"
                            1 => "M&#46; Borde"
                            2 => "V&#46; Heissmeyer"
                            3 => "M&#46; Feuerer"
                            4 => "A&#46;D&#46; Lapan"
                            5 => "J&#46;C&#46; Stroud"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cell.2006.05.042"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell"
                        "fecha" => "2006"
                        "volumen" => "126"
                        "paginaInicial" => "375"
                        "paginaFinal" => "387"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16873067"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Foxp3 controls regulatory T-cell function by interacting with AML1&#47;Runx1"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Ono"
                            1 => "H&#46; Yaguchi"
                            2 => "N&#46; Ohkura"
                            3 => "I&#46; Kitabayashi"
                            4 => "Y&#46; Nagamura"
                            5 => "T&#46; Nomura"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nature05673"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2007"
                        "volumen" => "446"
                        "paginaInicial" => "685"
                        "paginaFinal" => "689"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17377532"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD&#47;IPEX autoimmune disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Li"
                            1 => "A&#46; Samanta"
                            2 => "X&#46; Song"
                            3 => "K&#46;T&#46; Iacono"
                            4 => "P&#46; Brennan"
                            5 => "T&#46;A&#46; Chatila"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/intimm/dxm043"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int Immunol"
                        "fecha" => "2007"
                        "volumen" => "19"
                        "paginaInicial" => "825"
                        "paginaFinal" => "835"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17586580"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;E&#46; Lopes"
                            1 => "T&#46;R&#46; Torgerson"
                            2 => "L&#46;A&#46; Schubert"
                            3 => "S&#46;D&#46; Anover"
                            4 => "E&#46;L&#46; Ocheltree"
                            5 => "H&#46;D&#46; Ochs"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2006"
                        "volumen" => "177"
                        "paginaInicial" => "3133"
                        "paginaFinal" => "3142"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16920951"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A well adapted regulatory contrivance&#58; regulatory T cell development and the forkhead family transcription factor Foxp3"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;D&#46; Fontenot"
                            1 => "A&#46;Y&#46; Rudensky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/ni1179"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Immunol"
                        "fecha" => "2005"
                        "volumen" => "6"
                        "paginaInicial" => "331"
                        "paginaFinal" => "337"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15785758"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Nik Tavakoli N&#44; Hambly BD&#44; Sullivan DR&#44; Bao S&#46; Forkhead box protein 3&#58; Essential immune regulatory role&#46; Int J Biochem Cell Biol&#46; 2007 Oct 10 &#91;Epub ahead of print&#93;"
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Inhibition of the allergic response by regulatory T cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "P&#46; Stock"
                            1 => "R&#46;H&#46; DeKruyff"
                            2 => "D&#46;T&#46; Umetsu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/01.all.0000200502.69672.44"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Allergy Clin Immunol"
                        "fecha" => "2006"
                        "volumen" => "6"
                        "paginaInicial" => "12"
                        "paginaFinal" => "16"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16505606"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relation of CD4 CD25 regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;M&#46; Ling"
                            1 => "T&#46; Smith"
                            2 => "X&#46;D&#46; Nguyen"
                            3 => "C&#46; Pridgeon"
                            4 => "M&#46; Dallman"
                            5 => "J&#46; Arbery"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2004"
                        "volumen" => "63"
                        "paginaInicial" => "608"
                        "paginaFinal" => "615"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Innate CD4 CD25 regulatory T cells are required for oral tolerance and inhibition of CD8T cells mediating skin inflammation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "B&#46; Dubois"
                            1 => "L&#46; Chapat"
                            2 => "A&#46; Goubier"
                            3 => "M&#46; Papiernik"
                            4 => "J&#46;F&#46; Nicolas"
                            5 => "D&#46; Kaiserlian"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2003-03-0727"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2003"
                        "volumen" => "102"
                        "paginaInicial" => "3295"
                        "paginaFinal" => "3301"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12855551"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional CD25- and CD25 mucosal regulatory T cells are induced in gut-draining lymphoid tissue within 48<span class="elsevierStyleHsp" style=""></span>h after oral antigen application"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "F&#46; Hauet-Broere"
                            1 => "W&#46;W&#46; Unger"
                            2 => "J&#46; Garssen"
                            3 => "M&#46;A&#46; Hoijer"
                            4 => "G&#46; Kraal"
                            5 => "J&#46;N&#46; Samsom"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/eji.200324115"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Immunol"
                        "fecha" => "2003"
                        "volumen" => "33"
                        "paginaInicial" => "2801"
                        "paginaFinal" => "2810"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14515264"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Activation of CD25&#43;CD4&#43; regulatory T cells by oral antigen administration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "X&#46; Zhang"
                            1 => "L&#46; Izikson"
                            2 => "L&#46; Liu"
                            3 => "H&#46;L&#46; Weiner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2001"
                        "volumen" => "167"
                        "paginaInicial" => "4245"
                        "paginaFinal" => "4253"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11591746"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Role of regulatory T cells and FOXP3 in human disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Bacchetta"
                            1 => "E&#46; Gambineri"
                            2 => "M&#46;-G&#46; Roncarolo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2007.06.023"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2007"
                        "volumen" => "120"
                        "paginaInicial" => "227"
                        "paginaFinal" => "235"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17666212"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulation of the T cell response"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46; Romagnani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2222.2006.02606.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Allergy"
                        "fecha" => "2006"
                        "volumen" => "36"
                        "paginaInicial" => "1357"
                        "paginaFinal" => "1366"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17083345"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expression of FoxP3&#44; a key molecule in CD4CD25 regulatory T cells&#44; in adult T-cell leukaemia&#47;lymphoma cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Karube"
                            1 => "K&#46; Ohshima"
                            2 => "T&#46; Tsuchiya"
                            3 => "T&#46; Yamaguchi"
                            4 => "R&#46; Kawano"
                            5 => "J&#46; Suzumiya"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2141.2004.04999.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Haematol"
                        "fecha" => "2004"
                        "volumen" => "126"
                        "paginaInicial" => "81"
                        "paginaFinal" => "84"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15198736"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Foxp3 expressing CD4 CD25 &#40;high&#41; regulatory T cells are overrep-resented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Viguier"
                            1 => "F&#46; Lemaitre"
                            2 => "O&#46; Verola"
                            3 => "M&#46;S&#46; Cho"
                            4 => "G&#46; Gorochov"
                            5 => "L&#46; Dubertret"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Immunol"
                        "fecha" => "2004"
                        "volumen" => "173"
                        "paginaInicial" => "1444"
                        "paginaFinal" => "1453"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15240741"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cutaneous T-cell lymphoma&#58; malignant proliferation of T-regulatory cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;L&#46; Berger"
                            1 => "R&#46; Tigelaar"
                            2 => "J&#46; Cohen"
                            3 => "K&#46; Mariwalla"
                            4 => "J&#46; Trinh"
                            5 => "N&#46; Wang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2004-06-2181"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2005"
                        "volumen" => "105"
                        "paginaInicial" => "1640"
                        "paginaFinal" => "1647"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15514008"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "L&#46;A&#46; Ormandy"
                            1 => "T&#46; Hillemann"
                            2 => "H&#46; Wedemeyer"
                            3 => "M&#46;P&#46; Manns"
                            4 => "T&#46;F&#46; Greten"
                            5 => "F&#46; Ko-rangy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/0008-5472.CAN-04-3232"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Res"
                        "fecha" => "2005"
                        "volumen" => "65"
                        "paginaInicial" => "2457"
                        "paginaFinal" => "2464"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15781662"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical and molecular features of the immunodysregulation&#44; polyen-docrinopathy&#44; enteropathy&#44; X linked &#40;IPEX&#41; s&#237;ndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;S&#46; Wildin"
                            1 => "S&#46; Smyk-Pearson"
                            2 => "A&#46;H&#46; Filipovich"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Med Genet"
                        "fecha" => "2002"
                        "volumen" => "39"
                        "paginaInicial" => "537"
                        "paginaFinal" => "545"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12161590"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutational an&#225;lisis of the FOXP 3 gene and evidence for genetic hetero-geneity in the immunodysregulation&#44; polyendocrinopathy&#44; en-teropathy syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46;J&#46; Owen"
                            1 => "C&#46;E&#46; Jennings"
                            2 => "H&#46; Imrie"
                            3 => "A&#46; Lachaux"
                            4 => "N&#46;A&#46; Bridges"
                            5 => "T&#46;D&#46; Cheetham"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Endocrinol Metabol"
                        "fecha" => "2003"
                        "volumen" => "88"
                        "paginaInicial" => "6034"
                        "paginaFinal" => "6039"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "IPEX and the role of FOXP 3 in the development and function of human Tregs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "S&#46; Le Bras"
                            1 => "R&#46;S&#46; Geha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI28880"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "2006"
                        "volumen" => "116"
                        "paginaInicial" => "1473"
                        "paginaFinal" => "1475"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16741571"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Developmental changes of FOXP3-expressing CD4&#43;CD25&#43; regulatory T cells and their impairment in patients with FOXP3 gene mutations"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Fuchizawa"
                            1 => "Y&#46; Adachi"
                            2 => "Y&#46; Ito"
                            3 => "H&#46; Higashiyama"
                            4 => "H&#46; Kanegane"
                            5 => "T&#46; Futatani"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.clim.2007.08.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Immunol"
                        "fecha" => "2007"
                        "volumen" => "125"
                        "paginaInicial" => "237"
                        "paginaFinal" => "246"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17916446"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib51"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful use of the new immune-suppressor sirolimus in IPEX &#40;immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked syndrome&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Bindl"
                            1 => "T&#46; Torgerson"
                            2 => "L&#46; Perroni"
                            3 => "N&#46; Youssef"
                            4 => "H&#46;D&#46; Ochs"
                            5 => "O&#46; Goulet"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jpeds.2005.04.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pediatr"
                        "fecha" => "2005"
                        "volumen" => "147"
                        "paginaInicial" => "256"
                        "paginaFinal" => "259"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16126062"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib52"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Yong PL&#44; Russo P&#44; Sullivan KE&#46; Use of Sirolimus in IPEX and IPEX-Like Children&#46; J Clin Immunol&#46; 2008 May 15&#46; &#91;Epub ahead of print&#93;"
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib53"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune reconstitution and recovery of FOXP3 &#40;forkhead box P3&#41;-expressing T cells after transplantation for IPEX &#40;immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked&#41; syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Zhan"
                            1 => "J&#46; Sinclair"
                            2 => "S&#46; Adams"
                            3 => "C&#46;M&#46; Cale"
                            4 => "S&#46; Murch"
                            5 => "L&#46; Perroni"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1542/peds.2007-1863"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatrics"
                        "fecha" => "2008"
                        "volumen" => "121"
                        "paginaInicial" => "e998"
                        "paginaFinal" => "e1002"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18316354"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib54"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked syndrome &#40;IPEX&#41; by allogeneic bone marrow transplantation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "O&#46; Baud"
                            1 => "O&#46; Goulet"
                            2 => "D&#46; Canioni"
                            3 => "F&#46; LeDeist"
                            4 => "I&#46; Radford"
                            5 => "D&#46; Riev"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJM200106073442304"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2001"
                        "volumen" => "344"
                        "paginaInicial" => "1758"
                        "paginaFinal" => "1762"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11396442"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib55"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Rao"
                            1 => "N&#46; Kamani"
                            2 => "A&#46; Filipovich"
                            3 => "S&#46;M&#46; Lee"
                            4 => "S&#46;M&#46; Davies"
                            5 => "J&#46; Dalal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1182/blood-2006-05-025072"
                      "Revista" => array:6 [
                        "tituloSerie" => "Blood"
                        "fecha" => "2007"
                        "volumen" => "109"
                        "paginaInicial" => "383"
                        "paginaFinal" => "385"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16990602"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib56"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "K&#46;G&#46; Lucas"
                            1 => "D&#46; Ungar"
                            2 => "M&#46; Comito"
                            3 => "M&#46; Bayerl"
                            4 => "B&#46; Groh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bmt.1705542"
                      "Revista" => array:6 [
                        "tituloSerie" => "Bone Marrow Transplant"
                        "fecha" => "2007"
                        "volumen" => "39"
                        "paginaInicial" => "55"
                        "paginaFinal" => "56"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17115064"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib57"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epstein Barr virus induced lymphoma in a child with IPEX syndrome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "K&#46;G&#46; Lucas"
                            1 => "D&#46; Ungar"
                            2 => "M&#46; Comito"
                            3 => "B&#46; Groh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/pbc.21341"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Blood Cancer"
                        "fecha" => "2008"
                        "volumen" => "50"
                        "paginaInicial" => "1056"
                        "paginaFinal" => "1057"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17828748"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib58"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Sharfe N&#44; Dadi HK&#44; Shahar M&#44; Roifman CM&#46; Proc Natl Acad Sci USA 1997&#59; 94&#58; 3168&#8211;71"
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib59"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Regulatory T cells in human autoimmune diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "T&#46;R&#46; Torgerson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Springer Semin Immun"
                        "fecha" => "2006"
                        "volumen" => "28"
                        "paginaInicial" => "63"
                        "paginaFinal" => "76"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib60"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human IL-2 receptor alpha chain deficiency"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "C&#46;M&#46; Roifman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1203/00006450-200007000-00004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Pediatr Res"
                        "fecha" => "2000"
                        "volumen" => "48"
                        "paginaInicial" => "6"
                        "paginaFinal" => "11"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10879793"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib61"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CD25 deficiency causes an immune dysregulation&#44; polyendocrinopathy&#44; enteropathy&#44; X-linked-like syndrome&#44; and defective IL-10 expression from CD4 lymphocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "A&#46;A&#46; Caudy"
                            1 => "S&#46;T&#46; Reddy"
                            2 => "T&#46; Chatila"
                            3 => "J&#46;P&#46; Atkinson"
                            4 => "J&#46;W&#46; Verbsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jaci.2006.10.007"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Allergy Clin Immunol"
                        "fecha" => "2007"
                        "volumen" => "119"
                        "paginaInicial" => "482"
                        "paginaFinal" => "487"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17196245"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/03010546/0000003700000004/v1_201304101017/S0301054609000238/v1_201304101017/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "5555"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Review"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/03010546/0000003700000004/v1_201304101017/S0301054609000238/v1_201304101017/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054609000238?idApp=UINPBA00004N"
]

Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2009.04.002

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	29	13	42
2024 September	47	21	68
2024 August	53	8	61
2024 July	69	15	84
2024 June	38	11	49
2024 May	66	10	76
2024 April	56	9	65
2024 March	71	14	85
2024 February	46	17	63
2024 January	68	12	80
2023 December	93	29	122
2023 November	69	19	88
2023 October	90	23	113
2023 September	69	9	78
2023 August	82	5	87
2023 July	64	6	70
2023 June	58	6	64
2023 May	92	8	100
2023 April	111	5	116
2023 March	100	1	101
2023 February	99	11	110
2023 January	61	18	79
2022 December	52	10	62
2022 November	66	18	84
2022 October	56	18	74
2022 September	63	16	79
2022 August	58	11	69
2022 July	40	11	51
2022 June	37	10	47
2022 May	57	21	78
2022 April	56	17	73
2022 March	95	15	110
2022 February	64	12	76
2022 January	56	9	65
2021 December	38	10	48
2021 November	47	7	54
2021 October	75	10	85
2021 September	107	13	120
2021 August	71	7	78
2021 July	53	17	70
2021 June	61	21	82
2021 May	53	7	60
2021 April	172	31	203
2021 March	52	15	67
2021 February	35	16	51
2021 January	58	8	66
2020 December	3	0	3
2020 January	0	1	1
2018 March	1	0	1
2018 February	25	10	35
2018 January	35	5	40
2017 December	27	5	32
2017 November	28	2	30
2017 October	35	5	40
2017 September	43	17	60
2017 August	39	18	57
2017 July	27	7	34
2017 June	56	26	82
2017 May	59	12	71
2017 April	38	6	44
2017 March	37	23	60
2017 February	32	34	66
2017 January	32	7	39
2016 December	42	9	51
2016 November	68	15	83
2016 October	59	8	67
2016 September	72	14	86
2016 August	58	12	70
2016 July	36	8	44
2016 June	43	18	61
2016 May	31	23	54
2016 April	56	31	87
2016 March	41	17	58
2016 February	45	32	77
2016 January	33	21	54
2015 December	38	22	60
2015 November	54	22	76
2015 October	61	30	91
2015 September	45	10	55
2015 August	58	10	68
2015 July	90	13	103
2015 June	47	10	57
2015 May	60	11	71
2015 April	71	19	90
2015 March	78	12	90
2015 February	43	12	55
2015 January	39	9	48
2014 December	41	13	54
2014 November	34	15	49
2014 October	36	23	59
2014 September	40	19	59
2014 August	27	9	36
2014 July	24	10	34
2014 June	19	10	29
2014 May	20	14	34
2014 April	18	9	27
2014 March	146	24	170
2014 February	121	23	144
2014 January	158	29	187
2013 December	138	18	156
2013 November	142	10	152
2013 October	157	19	176
2013 September	159	25	184
2013 August	88	25	113
2013 July	93	27	120
2013 June	60	6	66
2013 May	65	14	79
2013 April	62	11	73
2013 March	45	7	52
2013 February	18	5	23
2013 January	16	2	18
2012 December	6	5	11
2012 November	0	2	2
2012 October	2	1	3
2009 June	6137	0	6137

Show all

Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

Indexed in:

Follow us:

Statistics

Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter