Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients

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"apellidos" => "Kaukinen" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611003235?idApp=UINPBA00004N" "url" => "/03010546/0000004000000001/v1_201304101101/S0301054611003235/v1_201304101101/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Ascorbate-dependent decrease of the mucosal immune inflammatory response to gliadin in coeliac disease patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "3" "paginaFinal" => "8" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "D. Bernardo, B. Martínez-Abad, S. Vallejo-Diez, E. Montalvillo, V. Benito, B. Anta, L. Fernández-Salazar, A. Blanco-Quirós, J.A. Garrote, E. Arranz" "autores" => array:10 [ 0 => array:3 [ "nombre" => "D." "apellidos" => "Bernardo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "B." "apellidos" => "Martínez-Abad" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "S." "apellidos" => "Vallejo-Diez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "E." "apellidos" => "Montalvillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "V." "apellidos" => "Benito" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "B." "apellidos" => "Anta" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "L." "apellidos" => "Fernández-Salazar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 7 => array:3 [ "nombre" => "A." "apellidos" => "Blanco-Quirós" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 8 => array:3 [ "nombre" => "J.A." "apellidos" => "Garrote" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 9 => array:4 [ "nombre" => "E." "apellidos" => "Arranz" "email" => array:1 [ 0 => "earranz@med.uva.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Mucosal Immunology Lab, Department of Paediatrics & Immunology, and IBGM, Universidad de Valladolid-CSIC, Valladolid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Gastroenterology Service, Hospital Clínico Universitario, Valladolid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Research Unit, Hospital Clínico Universitario, Valladolid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 277 "Ancho" => 995 "Tamanyo" => 39242 ] ] "descripcion" => array:1 [ "en" => "Representative western-blot analysis using whole protein biopsy explants of non-CD controls and treated-CD patients, after 24h of basal culture (Basal), and after 3h of gliadin challenge (100μg/ml) with (Gli+Asc) and without (Gli) ascorbate supplementation (20mM) and 21h of basal culture. C: human recombinant IL-15 lane. Basal IL-15 was only detected in one CD patient. Gliadin induced IL-15 production in both non-CD controls (three out of three) and treated CD patients (seven out of eight). Ascorbate inhibited IL-15 production in all cases, even in a patient who had detectable basal levels of IL-15." ] ] ] "textoCompleto" => "IntroductionCoeliac disease (CD) is a common gastro-intestinal disorder caused by a hypersensitivity reaction to wheat gliadin and similar proteins from rye and barley, affecting genetically predisposed individuals (HLA-DQ2/DQ8). The current treatment is a life-long strict gluten-free diet (GFD).<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a>The most accepted model of the CD immunopathogenesis is the two-signal model, which establishes that gliadin has a dual effect on the CD duodenum, triggering the development of an innate immune response in the epithelium, and activating an adaptive immune response controlled by gluten-reactive T cells with a Th1 cytokine profile.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Innate immunity, and specifically interleukin (IL)-15,<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a> plays a key role in the development of CD through a DQ2-independent mechanism.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> The induction of IL-15 seems to be involved in the initial stages of the disease leading to epithelial stress, increase tight-junction permeability, enterocyte apoptosis and dendritic cell (DC) activation,<a class="elsevierStyleCrossRefs" href="#bib0025">5,6,8–12</a> facilitating the development of the secondary adaptive response.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Moreover, the gliadin amplifies the production of inflammatory cytokines through the nuclear factor (NF)-κB<a class="elsevierStyleCrossRef" href="#bib0065">13</a> with a positive feedback by IL-15, which is also a potent NF-κB activator.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Moreover, DCs are important players in the connection between the innate and the subsequent adaptive immune response,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and require NF-κB for their development, survival, function and cytokine production.<a class="elsevierStyleCrossRefs" href="#bib0080">16–18</a> Thus, the IL-15/NF-κB axis is revealed to have an important role in the pathogenesis of CD and may represent a molecular target for strategies of immunomodulation.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>NF-κB is a heterogeneous collection of dimeric proteins subjected to a complex regulatory mechanism,<a class="elsevierStyleCrossRefs" href="#bib0100">20,21</a> involving the inhibitory proteins I-κB that bind to NF-κB subunits which became active after dissociation. This takes place when NF-κB inducers promote I-κB phosphorylation mediated by two I-κB kinases (IKKs), and targets I-κB for its degradation by the 26S proteaseome,<a class="elsevierStyleCrossRefs" href="#bib0110">22,23</a> followed by translocation of NF-κB dimmers to the nucleus and elicit their function. It has been recently proposed that ascorbate, may be able to inhibit IKK activation and, therefore, by blocking I-κB phosphorylation, NF-κB cannot translocate and bind to its DNA targets.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> These inhibitory properties of ascorbate can be elicited at concentrations of 20mM, intracellularly in vivo, without showing toxic effects to cells, or inhibiting other inducible factors.Nitric oxide (NO) is involved in the histological changes produced in coeliac disease. In the mouse monocyte/macrophage cell line RAW 264.7, pre-challenged with IFNγ, the gliadin is able to enhance the NF-κB activity and iNOS protein expression and therefore NO production. Both effects were reduced by NF-κB activation inhibitors, thereby indicating that gliadin should modulate iNOS gene expression through NFKB activation.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>Given the role of the NF-κB pathway in the pathogenesis of CD, we wondered whether ascorbate has an effect on the inhibition of the early/innate immune response triggered by gluten and, therefore, can be used as a supplementary therapeutical strategy to GFD on CD patients. To address this question we have cultured biopsies from treated CD patients stimulated in vitro with gliadin, with and without supplementation of ascorbate. Our data confirm that ascorbate inhibits the gliadin-induced expression of IL-15 in CD biopsy explants.Materials and methodsStudy subjectsWe studied eight CD patients treated on a GFD for a minimum of six months (mean age 41.7yrs, range 23–68yrs, 25.0% males) and three non-CD healthy controls (mean age 63.6yrs, range 61–68yrs, 0.0% males). The diagnosis of CD was based on compatible symptoms, positive serology (IgA antiendomysial or antitransglutaminase antibodies), positive genetic markers (HLA-DQ2/8), and mucosal changes in the duodenum. At the time of sample collection, CD patients had mucosal recovery (Marsh 0-1) and negative serology for at least 1yr. Healthy controls were referred to the gastroenterology clinics due to other intestinal diseases which were later ruled out, and no mucosal alterations were found in the duodenum. All patients were attended in the adult gastroenterology clinics from the “Hospital Clínico Universitario”, Valladolid, Spain, as part of routine diagnostic procedures. Informed consent was obtained from patients, and the study protocol was approved by the Ethics Committee from both “Hospital Clínico Universitario” and Faculty of Medicine, University of Valladolid.Biopsy cultureThree intestinal biopsy explants were collected from each individual and cultured in vitro as previously described.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Briefly, all biopsies were collected in ice-chilled PBS containing 0.1% gentamicine and cultured within 1h in RPMI 1640 supplemented with 10% heat-inactivated FBS, penicillin (100U/ml), streptomycin (100μg/ml) and fungizone (0.25μg/ml) (all from Cambrex Iberia Products, Barcelona, Spain). One sample from each individual antiendomysial cultured in basal medium was used as an internal control. One explant from each patient was challenged in vitro with a gliadin solution (100μg/ml) (Sigma, St Louis, MO, USA) for only 3h, which is considered normal exposure and concentration in the duodenum after a meal. A second explant was co-cultured both with gliadin (100μg/ml) and 20mM of ascorbate (Sigma), a potent non-toxic NF-κB inhibitor.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> After 3h, biopsy explants specimens were washed up in PBS containing 0.1% gentamicine and later cultured for another 21h in new clean culture medium to determine whether gliadin challenge is followed by a secondary response. Tissue culture was carried out in vitro by immersion in culture dishes placed in a cell incubator with 5% CO2 at 37°C. After 24h (3h with stimulus+21h with basal medium), tissue was embedded in RNAlater (Ambion, Applied Bisystems, Austin, TX, USA) and snap-frozen until protein extraction using the TRIZOL® Reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's protocol. Supernatants were collected at both 3 and 24h. All reagents were checked and discarded for lypopolisaccharide (LPS) contamination with Lymulus amebocyte lisate, PYROGENT® Plus (Cambrex) (Detection limit 0.06EU/ml).Effector molecules on culture supernatantsBiopsy culture supernatants after 3h of culture were assayed for the concentration of oxidative stress by applying the Griess reaction following manufacturer's instructions (Molecular Probes, Invitrogen) (detection limit (D.L.) 1μM). The nitric oxide is very unstable, therefore the Griess reaction measures the total amount of nitrites, which are primary metabolites derived from the instantaneous oxidation of NO. Supernatants at 24h of culture were also analysed using a multiplex assay on a Luminex TM platform (BioRad, Hercules, CA, USA), for the concentration of IFNγ [D.L. 3.38pg/ml], tumour necrosis factor α (TNFα) [D.L=4.331pg/ml], IFNα [D.L=89.87pg/ml], IL-17 [D.L=12.98pg/ml], IL-13 [D.L=3.49pg/ml] and IL-6 [D.L=0.19pg/ml].Western-blot analysisFrom whole biopsy explants, 8μg of protein isolated was added per well. They were separated by using a 15% acrilamide/bisacrilamide (37.5:1) gel in a mini-Protean II (BioRad), and later transferred onto PVDF membranes of 0.45 Micron (Pierce Biotechnology Inc. IL, USA). Membranes were incubated with primary specific antibodies to human IL-15 (mouse monoclonal MAB247) (R&D, Minneapolis, MN, USA) at a final dilution of 1/400, performing a second incubation with antibodies to mouse IgG labelled with horseradish peroxidase (Amersham Biosciences Europe, Freiburg, Germany). Chemiluminiscent substrate Lumigen PS-3 (Amersham) and autoradiography film Hyperfilm ECL (Amersham) were used for developing. Recombinant human IL-15 (Peprotech, London, UK) was used as a positive control.Statistical analysisThe Friedman test was applied in all cases to compare different culture conditions from the same patient (non-parametric and paired two-tailed test). The secondary Wilcoxon matched paired test between pairs of conditions was only applied in those cases where the Friedman test was statistically significant. The level of significance was fixed at p<0.05.ResultsAscorbate blocks the secretion of nitrites induced by gliadin challenge in biopsy samples from CD patientsStatistically significant differences were found in nitrites secretion after 3h of culture when explants from the same patient were compared in basal conditions and after gliadin-challenge, both with and without ascorbate supplementation (p<0.001). Gliadin challenge increased the secretion of nitrites, therefore indicating an increase in the production of NO in duodenal explants from treated CD patients (p<0.05) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) compared to non-challenged explants from the same patient as previously described.<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a> The addition of ascorbate, at a non-toxic concentration of 20mM, to gliadin-challenged cultures effectively blocked the induction of nitrite secretion by gliadin (p<0.05) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Because ascorbate is also a strong antioxidant, and given that the Griess reaction is based on the determination of nitrites (mainly derived from the oxidation of NO), these results could reflect an experimental artefact. To confirm that ascorbate really blocks the immune response to gliadin, we have also studied the secretion of cytokines on culture supernatants.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Ascorbate inhibited the secretion of cytokines induced by gliadin challenge in biopsy samples from CD patientsOur findings showed that in the supernatants at 24h (3h of challenge with gliadin plus 21h of basal culture) none of the assayed cytokines were statistically increased compared to the basal culture. However, the addition of ascorbate to culture medium, for those 3h of challenge, clearly decreased the secretion of all cytokines, compared to non-ascorbate supplemented gliadin-challenged supernatants (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The decrease was statistically significant for IFNγ (p=0.0156), TNFα (p=0.0312), IFNα (p=0.0469) and IL-6 (p=0.0312). Moreover, in these cases cytokine secretion was downregulated even to lower values than those observed in basal cultures (IFNγ: p=0.0312; TNFα: p=0.0312; IFNα: p=0.0312; and IL-6: p=0.0078) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), thereby confirming its inhibitory properties.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Ascorbate inhibited duodenal IL-15Basal IL-15 production in biopsy explants was only detectable in one out of eight treated-CD patients and was absent in all three non-CD controls (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). After gliadin-challenge, as previously described,<a class="elsevierStyleCrossRefs" href="#bib0030">6,29,30</a> gliadin induced IL-15 production in treated-CD patients. In this assay it was detected in seven out of eight cases (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Similar results were obtained in non-CD controls, where gliadin was also revealed as an IL-15 inducer in all three non-CD cases compared to basal culture, as previously reported by our group.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> Gliadin-induced IL-15 had detectable levels even 21h after gliadin had been removed from culture medium, given that western-blot was performed at the end of the culture (3h of gliadin challenge and 21h in basal condition). As expected, the addition of ascorbate to culture medium completely inhibited IL-15 production not only by CD biopsy explants but also by those from non-CD controls. Moreover, it is noteworthy that the IL-15 inhibition by ascorbate took place even in the only treated CD-patient who had basal IL-15 production.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionIn this study we have shown, by using a culture model of duodenal explants, that the addition of ascorbate to culture medium decreases the secretion of inflammatory mediators in response to gluten in CD patients. Supplementation of ascorbate, of a non-toxic concentration of 20mM, to gliadin challenged biopsy culture not only inhibits the gliadin-induced production of nitrites, but also downregulates the secretion of proinflammatory cytokines (IFNγ, TNFα, IFNα and IL-6), and completely inhibits that of IL15.Although it has been largely reported that gliadin is a potent cytokine inducer in CD patients by using culture models – especially in the cases of IFNγ and TNFα,<a class="elsevierStyleCrossRefs" href="#bib0020">4,27</a> no statistically significant upregulation of cytokine expression was observed in any of the culture supernatants (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The explanation to this discrepancy probably resides in the experimental design, where the time of challenge in culture (3h, which is considered a normal exposure and concentration in the duodenum after a meal, followed by 21 extra hours in basal conditions) was lower than previous studies in which challenge was performed for 24h. In this situation, it is reasonable to think that the total level of cytokine released should be smaller than previous studies.Gliadin is capable of increasing the production of NO and this is related to the expression of iNOS. Additionally, gliadin increased the binding activity of NF-κB/DNA, the degradation of IκBα and the nuclear translocation of p50 and p65 subunits.<a class="elsevierStyleCrossRef" href="#bib0125">25</a>With these findings we have confirmed that by using a non-toxic (20mM) supplementation of ascorbate to biopsy culture challenged with gliadin, the gliadin-induced production of nitrites is inhibited. The effects of gliadin are probably mediated by iNOS, and ascorbate acts blocking its pathway.<a class="elsevierStyleCrossRefs" href="#bib0125">25,31</a> The expression levels of the cytokines IFNγ, TNFα, IFNα, and IL-6 are decreased to below those levels observed in basal cultures (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). This decrease could be the result of the inhibition of the NF-κB pathway induced by ascorbate.Moreover, ascorbate also affects the IL-15 pathway. This property of ascorbate is very interesting since IL15 is considered to be a central cytokine in CD immunopathogenesis given its capacity to initiate the innate immune response to gliadin<a class="elsevierStyleCrossRefs" href="#bib0030">6,29</a> and to activate dendritic cells,<a class="elsevierStyleCrossRefs" href="#bib0075">15,16,32</a> therefore facilitating the development of the secondary adaptive response.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Ascorbate is capable of inhibiting DC activation, blocking cytokine secretion and the immunostimulatory properties. Moreover, ascorbate-treated DCs are able to generate regulatory T cells with FoxP3+ expression.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> Future studies should address whether ascorbate is also capable of inhibiting DCs maturation in the duodenum of CD patients and even its capacity to generate gliadin specific regulatory T cells.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>It has been recently shown that oral supplementation of ascorbate attenuates several anaphylactic reactions to soybean glycinin-induced hypersensitivity on a swine model.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> In humans, oral supplementation has been reported to delay the progression of transplant-associated coronary arteriosclerosis,<a class="elsevierStyleCrossRef" href="#bib0175">35</a> and of cardiac transplant-associated arteriosclerosis,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> and even reduces xenobiotic-induced T-cell hyperactivation.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> Ascorbate is also capable of inhibit phytohaemagglutinin and concanavalin A mitogen-stimulated peripheral blood mononuclear cells by suppressing both formation and release of IFNγ.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> All together, these results clearly point to the possible therapeutical use of ascorbate in diseases, such as CD. However, further studies are needed to confirm this, including double-blind placebo-controlled trails aiming to characterise not only the optimal dose in vivo of ascorbate, but also the safe amount of gluten intake tolerated by patients on an ascorbate trial.As a final remark, this property of ascorbate of modulating the immunological response to gluten could be used as a supplement to the GFD. Considering the residual amounts of gluten that some “free gluten products” still have, ascorbate could be a necessary supplement to the dietary treatment of CD. Given the relevance of our findings, this effect should be further studied in order to confirm these results, and specifically to analyse how ascorbate exerts its immunomodulatory effects on DCs, given that they are central players in the immune response to gluten in CD.Conflict of interestThe authors have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "xres86063" "titulo" => array:5 [ 0 => "Summary" 1 => "Background" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec74226" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Study subjects" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Biopsy culture" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Effector molecules on culture supernatants" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Western-blot analysis" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 4 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Ascorbate blocks the secretion of nitrites induced by gliadin challenge in biopsy samples from CD patients" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Ascorbate inhibited the secretion of cytokines induced by gliadin challenge in biopsy samples from CD patients" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Ascorbate inhibited duodenal IL-15" ] ] ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 7 => array:2 [ "identificador" => "xack31860" "titulo" => "Acknowledgements" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-08-24" "fechaAceptado" => "2010-11-10" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec74226" "palabras" => array:5 [ 0 => "Ascorbate" 1 => "Coeliac disease" 2 => "Inhibition" 3 => "IL-15" 4 => "Therapy" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Summary" "resumen" => "BackgroundThe IL-15/NF-κB axis has an important role in coeliac disease (CD) and may represent a molecular target for immunomodulation. Ascorbate (vitamin C) is known to show inhibitory effects on NF-κB. Therefore, we studied if ascorbate supplementation to gliadin gliadin-stimulated biopsy culture could down-regulate the mucosal immune response to gliadin in CD. MethodsDuodenal biopsy explants from treated CD patients were gliadin challenged in vitro (100μg/ml) with and without 20mM ascorbate. An extra tissue explant in basal culture was used as internal control. Secretion levels of nitrites (3h), and IFNγ, TNFα, IFNα, IL-17, IL-13, and IL-6 (24h) were measured on the supernatants. IL-15 was assayed by western-blot on whole protein duodenal explants. ResultsThe addition of ascorbate to in vitro culture gliadin-challenged biopsies blocked the secretion of nitrites (p=0.013), IFNγ (p=0.0207), TNFα (p=0.0099), IFNα (p=0.0375), and IL-6 (p=0.0036) compared to samples from non-ascorbate supplemented culture. Cytokine secretion was downregulated by ascorbate even to lower values than those observed in basal cultures (IFNγ: p=0.0312; TNFα: p=0.0312; IFNα: p=0.0312; and IL-6: p=0.0078). Gliadin-challenge induced IL-15 production in biopsies from treated CD patients, while the addition of ascorbate to culture medium completely inhibited IL-15 production. Moreover, the inhibition of IL-15 by ascorbate took place even in the only treated CD-patient who had basal IL-15 production. ConclusionsAscorbate decreases the mucosal inflammatory response to gluten in an intestinal biopsy culture model, so it might have a role in future supplementary therapy in CD." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1102 "Ancho" => 1524 "Tamanyo" => 79179 ] ] "descripcion" => array:1 [ "en" => "Biopsy culture secretion of nitrites in eight treated CD patients after 3h of gliadin challenge (100μg/ml) with (Gli+Ascorb) and without (Gli) ascorbate supplementation (20mM), compared to basal culture (all at 3h). Statistically significant differences are shown (p<0.05, Wilcoxon matched paired test). Horizontal bars indicate median and whiskers maximum and minimum values. IQR: interquartile range." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1602 "Ancho" => 3296 "Tamanyo" => 312998 ] ] "descripcion" => array:1 [ "en" => "Supernatants biopsy culture secretion of IFNγ, TNF-α, IFNα, IL-17, IL-13, and IL-6 in eight treated CD patients after gliadin challenge (100μg/ml) with (Gli+Ascorb) and without (Gli) ascorbate supplementation (20mM) (3h of challenge and 21h of basal culture) compared to the basal culture. Statistically significant differences are shown (p<0.05, Wilcoxon matched paired test). Horizontal bars indicate median and whiskers maximum and minimum values. IQR: interquartile range." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 277 "Ancho" => 995 "Tamanyo" => 39242 ] ] "descripcion" => array:1 [ "en" => "Representative western-blot analysis using whole protein biopsy explants of non-CD controls and treated-CD patients, after 24h of basal culture (Basal), and after 3h of gliadin challenge (100μg/ml) with (Gli+Asc) and without (Gli) ascorbate supplementation (20mM) and 21h of basal culture. C: human recombinant IL-15 lane. Basal IL-15 was only detected in one CD patient. Gliadin induced IL-15 production in both non-CD controls (three out of three) and treated CD patients (seven out of eight). 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We also thank Ms. Alicia Ortega for her technical help." ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004000000001/v1_201304101101/S0301054611000851/v1_201304101101/en/main.assets" "Apartado" => array:4 [ "identificador" => "5554" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004000000001/v1_201304101101/S0301054611000851/v1_201304101101/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611000851?idApp=UINPBA00004N"]

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D. Bernardoa, B. Martínez-Abada, S. Vallejo-Dieza, E. Montalvilloa, V. Benitoa, B. Antaa, L. Fernández-Salazarb, A. Blanco-Quirósa, J.A. Garrotea,c, E. Arranza,

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earranz@med.uva.es

Corresponding author.

a Mucosal Immunology Lab, Department of Paediatrics & Immunology, and IBGM, Universidad de Valladolid-CSIC, Valladolid, Spain

b Gastroenterology Service, Hospital Clínico Universitario, Valladolid, Spain

c Research Unit, Hospital Clínico Universitario, Valladolid, Spain

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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Representative western-blot analysis using whole protein biopsy explants of non-CD controls and treated-CD patients&#44; after 24<span class="elsevierStyleHsp" style=""></span>h of basal culture &#40;Basal&#41;&#44; and after 3<span class="elsevierStyleHsp" style=""></span>h of gliadin challenge &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with &#40;Gli<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Asc&#41; and without &#40;Gli&#41; ascorbate supplementation &#40;20<span class="elsevierStyleHsp" style=""></span>mM&#41; and 21<span class="elsevierStyleHsp" style=""></span>h of basal culture&#46; C&#58; human recombinant IL-15 lane&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Basal IL-15 was only detected in one CD patient&#46; Gliadin induced IL-15 production in both non-CD controls &#40;three out of three&#41; and treated CD patients &#40;seven out of eight&#41;&#46; Ascorbate inhibited IL-15 production in all cases&#44; even in a patient who had detectable basal levels of IL-15&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Coeliac disease &#40;CD&#41; is a common gastro-intestinal disorder caused by a hypersensitivity reaction to wheat gliadin and similar proteins from rye and barley&#44; affecting genetically predisposed individuals &#40;HLA-DQ2&#47;DQ8&#41;&#46; The current treatment is a life-long strict gluten-free diet &#40;GFD&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The most accepted model of the CD immunopathogenesis is the two-signal model&#44; which establishes that gliadin has a dual effect on the CD duodenum&#44; triggering the development of an innate immune response in the epithelium&#44; and activating an adaptive immune response controlled by gluten-reactive T cells with a Th1 cytokine profile&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> Innate immunity&#44; and specifically interleukin &#40;IL&#41;-15&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> plays a key role in the development of CD through a DQ2-independent mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The induction of IL-15 seems to be involved in the initial stages of the disease leading to epithelial stress&#44; increase tight-junction permeability&#44; enterocyte apoptosis and dendritic cell &#40;DC&#41; activation&#44;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6&#44;8&#8211;12</span></a> facilitating the development of the secondary adaptive response&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Moreover&#44; the gliadin amplifies the production of inflammatory cytokines through the nuclear factor &#40;NF&#41;-&#954;B<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> with a positive feedback by IL-15&#44; which is also a potent NF-&#954;B activator&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Moreover&#44; DCs are important players in the connection between the innate and the subsequent adaptive immune response&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and require NF-&#954;B for their development&#44; survival&#44; function and cytokine production&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;18</span></a> Thus&#44; the IL-15&#47;NF-&#954;B axis is revealed to have an important role in the pathogenesis of CD and may represent a molecular target for strategies of immunomodulation&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">NF-&#954;B is a heterogeneous collection of dimeric proteins subjected to a complex regulatory mechanism&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a> involving the inhibitory proteins I-&#954;B that bind to NF-&#954;B subunits which became active after dissociation&#46; This takes place when NF-&#954;B inducers promote I-&#954;B phosphorylation mediated by two I-&#954;B kinases &#40;IKKs&#41;&#44; and targets I-&#954;B for its degradation by the 26S proteaseome&#44;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> followed by translocation of NF-&#954;B dimmers to the nucleus and elicit their function&#46; It has been recently proposed that ascorbate&#44; may be able to inhibit IKK activation and&#44; therefore&#44; by blocking I-&#954;B phosphorylation&#44; NF-&#954;B cannot translocate and bind to its DNA targets&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> These inhibitory properties of ascorbate can be elicited at concentrations of 20<span class="elsevierStyleHsp" style=""></span>mM&#44; intracellularly in vivo&#44; without showing toxic effects to cells&#44; or inhibiting other inducible factors&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Nitric oxide &#40;NO&#41; is involved in the histological changes produced in coeliac disease&#46; In the mouse monocyte&#47;macrophage cell line RAW 264&#46;7&#44; pre-challenged with IFN&#947;&#44; the gliadin is able to enhance the NF-&#954;B activity and iNOS protein expression and therefore NO production&#46; Both effects were reduced by NF-&#954;B activation inhibitors&#44; thereby indicating that gliadin should modulate iNOS gene expression through NFKB activation&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Given the role of the NF-&#954;B pathway in the pathogenesis of CD&#44; we wondered whether ascorbate has an effect on the inhibition of the early&#47;innate immune response triggered by gluten and&#44; therefore&#44; can be used as a supplementary therapeutical strategy to GFD on CD patients&#46; To address this question we have cultured biopsies from treated CD patients stimulated in vitro with gliadin&#44; with and without supplementation of ascorbate&#46; Our data confirm that ascorbate inhibits the gliadin-induced expression of IL-15 in CD biopsy explants&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Study subjects</span><p id="par0030" class="elsevierStylePara elsevierViewall">We studied eight CD patients treated on a GFD for a minimum of six months &#40;mean age 41&#46;7<span class="elsevierStyleHsp" style=""></span>yrs&#44; range 23&#8211;68<span class="elsevierStyleHsp" style=""></span>yrs&#44; 25&#46;0&#37; males&#41; and three non-CD healthy controls &#40;mean age 63&#46;6<span class="elsevierStyleHsp" style=""></span>yrs&#44; range 61&#8211;68<span class="elsevierStyleHsp" style=""></span>yrs&#44; 0&#46;0&#37; males&#41;&#46; The diagnosis of CD was based on compatible symptoms&#44; positive serology &#40;IgA antiendomysial or antitransglutaminase antibodies&#41;&#44; positive genetic markers &#40;HLA-DQ2&#47;8&#41;&#44; and mucosal changes in the duodenum&#46; At the time of sample collection&#44; CD patients had mucosal recovery &#40;Marsh 0-1&#41; and negative serology for at least 1<span class="elsevierStyleHsp" style=""></span>yr&#46; Healthy controls were referred to the gastroenterology clinics due to other intestinal diseases which were later ruled out&#44; and no mucosal alterations were found in the duodenum&#46; All patients were attended in the adult gastroenterology clinics from the &#8220;Hospital Cl&#237;nico Universitario&#8221;&#44; Valladolid&#44; Spain&#44; as part of routine diagnostic procedures&#46; Informed consent was obtained from patients&#44; and the study protocol was approved by the Ethics Committee from both &#8220;Hospital Cl&#237;nico Universitario&#8221; and Faculty of Medicine&#44; University of Valladolid&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Biopsy culture</span><p id="par0035" class="elsevierStylePara elsevierViewall">Three intestinal biopsy explants were collected from each individual and cultured in vitro as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Briefly&#44; all biopsies were collected in ice-chilled PBS containing 0&#46;1&#37; gentamicine and cultured within 1<span class="elsevierStyleHsp" style=""></span>h in RPMI 1640 supplemented with 10&#37; heat-inactivated FBS&#44; penicillin &#40;100<span class="elsevierStyleHsp" style=""></span>U&#47;ml&#41;&#44; streptomycin &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; and fungizone &#40;0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; &#40;all from Cambrex Iberia Products&#44; Barcelona&#44; Spain&#41;&#46; One sample from each individual antiendomysial cultured in basal medium was used as an internal control&#46; One explant from each patient was challenged in vitro with a gliadin solution &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; &#40;Sigma&#44; St Louis&#44; MO&#44; USA&#41; for only 3<span class="elsevierStyleHsp" style=""></span>h&#44; which is considered normal exposure and concentration in the duodenum after a meal&#46; A second explant was co-cultured both with gliadin &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; and 20<span class="elsevierStyleHsp" style=""></span>mM of ascorbate &#40;Sigma&#41;&#44; a potent non-toxic NF-&#954;B inhibitor&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> After 3<span class="elsevierStyleHsp" style=""></span>h&#44; biopsy explants specimens were washed up in PBS containing 0&#46;1&#37; gentamicine and later cultured for another 21<span class="elsevierStyleHsp" style=""></span>h in new clean culture medium to determine whether gliadin challenge is followed by a secondary response&#46; Tissue culture was carried out in vitro by immersion in culture dishes placed in a cell incubator with 5&#37; CO<span class="elsevierStyleInf">2</span> at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; After 24<span class="elsevierStyleHsp" style=""></span>h &#40;3<span class="elsevierStyleHsp" style=""></span>h with stimulus<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>21<span class="elsevierStyleHsp" style=""></span>h with basal medium&#41;&#44; tissue was embedded in RNAlater &#40;Ambion&#44; Applied Bisystems&#44; Austin&#44; TX&#44; USA&#41; and snap-frozen until protein extraction using the TRIZOL<span class="elsevierStyleSup">&#174;</span> Reagent &#40;Invitrogen&#44; Carlsbad&#44; CA&#44; USA&#41; according to the manufacturer&#39;s protocol&#46; Supernatants were collected at both 3 and 24<span class="elsevierStyleHsp" style=""></span>h&#46; All reagents were checked and discarded for lypopolisaccharide &#40;LPS&#41; contamination with <span class="elsevierStyleItalic">Lymulus amebocyte</span> lisate&#44; PYROGENT<span class="elsevierStyleSup">&#174;</span> Plus &#40;Cambrex&#41; &#40;Detection limit 0&#46;06<span class="elsevierStyleHsp" style=""></span>EU&#47;ml&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Effector molecules on culture supernatants</span><p id="par0040" class="elsevierStylePara elsevierViewall">Biopsy culture supernatants after 3<span class="elsevierStyleHsp" style=""></span>h of culture were assayed for the concentration of oxidative stress by applying the Griess reaction following manufacturer&#39;s instructions &#40;Molecular Probes&#44; Invitrogen&#41; &#40;detection limit &#40;D&#46;L&#46;&#41; 1<span class="elsevierStyleHsp" style=""></span>&#956;M&#41;&#46; The nitric oxide is very unstable&#44; therefore the Griess reaction measures the total amount of nitrites&#44; which are primary metabolites derived from the instantaneous oxidation of NO&#46; Supernatants at 24<span class="elsevierStyleHsp" style=""></span>h of culture were also analysed using a multiplex assay on a Luminex TM platform &#40;BioRad&#44; Hercules&#44; CA&#44; USA&#41;&#44; for the concentration of IFN&#947; &#91;D&#46;L&#46; 3&#46;38<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93;&#44; tumour necrosis factor &#945; &#40;TNF&#945;&#41; &#91;D&#46;L<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;331<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93;&#44; IFN&#945; &#91;D&#46;L<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>89&#46;87<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93;&#44; IL-17 &#91;D&#46;L<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#46;98<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93;&#44; IL-13 &#91;D&#46;L<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;49<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93; and IL-6 &#91;D&#46;L<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;19<span class="elsevierStyleHsp" style=""></span>pg&#47;ml&#93;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Western-blot analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">From whole biopsy explants&#44; 8<span class="elsevierStyleHsp" style=""></span>&#956;g of protein isolated was added per well&#46; They were separated by using a 15&#37; acrilamide&#47;bisacrilamide &#40;37&#46;5&#58;1&#41; gel in a mini-Protean II &#40;BioRad&#41;&#44; and later transferred onto PVDF membranes of 0&#46;45 Micron &#40;Pierce Biotechnology Inc&#46; IL&#44; USA&#41;&#46; Membranes were incubated with primary specific antibodies to human IL-15 &#40;mouse monoclonal MAB247&#41; &#40;R&#38;D&#44; Minneapolis&#44; MN&#44; USA&#41; at a final dilution of 1&#47;400&#44; performing a second incubation with antibodies to mouse IgG labelled with horseradish peroxidase &#40;Amersham Biosciences Europe&#44; Freiburg&#44; Germany&#41;&#46; Chemiluminiscent substrate Lumigen PS-3 &#40;Amersham&#41; and autoradiography film Hyperfilm ECL &#40;Amersham&#41; were used for developing&#46; Recombinant human IL-15 &#40;Peprotech&#44; London&#44; UK&#41; was used as a positive control&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">The Friedman test was applied in all cases to compare different culture conditions from the same patient &#40;non-parametric and paired two-tailed test&#41;&#46; The secondary Wilcoxon matched paired test between pairs of conditions was only applied in those cases where the Friedman test was statistically significant&#46; The level of significance was fixed at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ascorbate blocks the secretion of nitrites induced by gliadin challenge in biopsy samples from CD patients</span><p id="par0055" class="elsevierStylePara elsevierViewall">Statistically significant differences were found in nitrites secretion after 3<span class="elsevierStyleHsp" style=""></span>h of culture when explants from the same patient were compared in basal conditions and after gliadin-challenge&#44; both with and without ascorbate supplementation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Gliadin challenge increased the secretion of nitrites&#44; therefore indicating an increase in the production of NO in duodenal explants from treated CD patients &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; compared to non-challenged explants from the same patient as previously described&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> The addition of ascorbate&#44; at a non-toxic concentration of 20<span class="elsevierStyleHsp" style=""></span>mM&#44; to gliadin-challenged cultures effectively blocked the induction of nitrite secretion by gliadin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Because ascorbate is also a strong antioxidant&#44; and given that the Griess reaction is based on the determination of nitrites &#40;mainly derived from the oxidation of NO&#41;&#44; these results could reflect an experimental artefact&#46; To confirm that ascorbate really blocks the immune response to gliadin&#44; we have also studied the secretion of cytokines on culture supernatants&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ascorbate inhibited the secretion of cytokines induced by gliadin challenge in biopsy samples from CD patients</span><p id="par0060" class="elsevierStylePara elsevierViewall">Our findings showed that in the supernatants at 24<span class="elsevierStyleHsp" style=""></span>h &#40;3<span class="elsevierStyleHsp" style=""></span>h of challenge with gliadin plus 21<span class="elsevierStyleHsp" style=""></span>h of basal culture&#41; none of the assayed cytokines were statistically increased compared to the basal culture&#46; However&#44; the addition of ascorbate to culture medium&#44; for those 3<span class="elsevierStyleHsp" style=""></span>h of challenge&#44; clearly decreased the secretion of all cytokines&#44; compared to non-ascorbate supplemented gliadin-challenged supernatants &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The decrease was statistically significant for IFN&#947; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0156&#41;&#44; TNF&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#41;&#44; IFN&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0469&#41; and IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#41;&#46; Moreover&#44; in these cases cytokine secretion was downregulated even to lower values than those observed in basal cultures &#40;IFN&#947;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; TNF&#945;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; IFN&#945;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; and IL-6&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0078&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; thereby confirming its inhibitory properties&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ascorbate inhibited duodenal IL-15</span><p id="par0065" class="elsevierStylePara elsevierViewall">Basal IL-15 production in biopsy explants was only detectable in one out of eight treated-CD patients and was absent in all three non-CD controls &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; After gliadin-challenge&#44; as previously described&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;29&#44;30</span></a> gliadin induced IL-15 production in treated-CD patients&#46; In this assay it was detected in seven out of eight cases &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Similar results were obtained in non-CD controls&#44; where gliadin was also revealed as an IL-15 inducer in all three non-CD cases compared to basal culture&#44; as previously reported by our group&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Gliadin-induced IL-15 had detectable levels even 21<span class="elsevierStyleHsp" style=""></span>h after gliadin had been removed from culture medium&#44; given that western-blot was performed at the end of the culture &#40;3<span class="elsevierStyleHsp" style=""></span>h of gliadin challenge and 21<span class="elsevierStyleHsp" style=""></span>h in basal condition&#41;&#46; As expected&#44; the addition of ascorbate to culture medium completely inhibited IL-15 production not only by CD biopsy explants but also by those from non-CD controls&#46; Moreover&#44; it is noteworthy that the IL-15 inhibition by ascorbate took place even in the only treated CD-patient who had basal IL-15 production&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0070" class="elsevierStylePara elsevierViewall">In this study we have shown&#44; by using a culture model of duodenal explants&#44; that the addition of ascorbate to culture medium decreases the secretion of inflammatory mediators in response to gluten in CD patients&#46; Supplementation of ascorbate&#44; of a non-toxic concentration of 20<span class="elsevierStyleHsp" style=""></span>mM&#44; to gliadin challenged biopsy culture not only inhibits the gliadin-induced production of nitrites&#44; but also downregulates the secretion of proinflammatory cytokines &#40;IFN&#947;&#44; TNF&#945;&#44; IFN&#945; and IL-6&#41;&#44; and completely inhibits that of IL15&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Although it has been largely reported that gliadin is a potent cytokine inducer in CD patients by using culture models &#8211; especially in the cases of IFN&#947; and TNF&#945;&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;27</span></a> no statistically significant upregulation of cytokine expression was observed in any of the culture supernatants &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The explanation to this discrepancy probably resides in the experimental design&#44; where the time of challenge in culture &#40;3<span class="elsevierStyleHsp" style=""></span>h&#44; which is considered a normal exposure and concentration in the duodenum after a meal&#44; followed by 21 extra hours in basal conditions&#41; was lower than previous studies in which challenge was performed for 24<span class="elsevierStyleHsp" style=""></span>h&#46; In this situation&#44; it is reasonable to think that the total level of cytokine released should be smaller than previous studies&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Gliadin is capable of increasing the production of NO and this is related to the expression of iNOS&#46; Additionally&#44; gliadin increased the binding activity of NF-&#954;B&#47;DNA&#44; the degradation of I&#954;B&#945; and the nuclear translocation of p50 and p65 subunits&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">With these findings we have confirmed that by using a non-toxic &#40;20<span class="elsevierStyleHsp" style=""></span>mM&#41; supplementation of ascorbate to biopsy culture challenged with gliadin&#44; the gliadin-induced production of nitrites is inhibited&#46; The effects of gliadin are probably mediated by iNOS&#44; and ascorbate acts blocking its pathway&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;31</span></a> The expression levels of the cytokines IFN&#947;&#44; TNF&#945;&#44; IFN&#945;&#44; and IL-6 are decreased to below those levels observed in basal cultures &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; This decrease could be the result of the inhibition of the NF-&#954;B pathway induced by ascorbate&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Moreover&#44; ascorbate also affects the IL-15 pathway&#46; This property of ascorbate is very interesting since IL15 is considered to be a central cytokine in CD immunopathogenesis given its capacity to initiate the innate immune response to gliadin<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;29</span></a> and to activate dendritic cells&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16&#44;32</span></a> therefore facilitating the development of the secondary adaptive response&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Ascorbate is capable of inhibiting DC activation&#44; blocking cytokine secretion and the immunostimulatory properties&#46; Moreover&#44; ascorbate-treated DCs are able to generate regulatory T cells with FoxP3&#43; expression&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Future studies should address whether ascorbate is also capable of inhibiting DCs maturation in the duodenum of CD patients and even its capacity to generate gliadin specific regulatory T cells&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">It has been recently shown that oral supplementation of ascorbate attenuates several anaphylactic reactions to soybean glycinin-induced hypersensitivity on a swine model&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In humans&#44; oral supplementation has been reported to delay the progression of transplant-associated coronary arteriosclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> and of cardiac transplant-associated arteriosclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> and even reduces xenobiotic-induced T-cell hyperactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> Ascorbate is also capable of inhibit phytohaemagglutinin and concanavalin A mitogen-stimulated peripheral blood mononuclear cells by suppressing both formation and release of IFN&#947;&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> All together&#44; these results clearly point to the possible therapeutical use of ascorbate in diseases&#44; such as CD&#46; However&#44; further studies are needed to confirm this&#44; including double-blind placebo-controlled trails aiming to characterise not only the optimal dose in vivo of ascorbate&#44; but also the safe amount of gluten intake tolerated by patients on an ascorbate trial&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">As a final remark&#44; this property of ascorbate of modulating the immunological response to gluten could be used as a supplement to the GFD&#46; Considering the residual amounts of gluten that some &#8220;free gluten products&#8221; still have&#44; ascorbate could be a necessary supplement to the dietary treatment of CD&#46; Given the relevance of our findings&#44; this effect should be further studied in order to confirm these results&#44; and specifically to analyse how ascorbate exerts its immunomodulatory effects on DCs&#44; given that they are central players in the immune response to gluten in CD&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest&#46;</p></span></span>"
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        0 => array:2 [
          "identificador" => "xres86063"
          "titulo" => array:5 [
            0 => "Summary"
            1 => "Background"
            2 => "Methods"
            3 => "Results"
            4 => "Conclusions"
          ]
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        1 => array:2 [
          "identificador" => "xpalclavsec74226"
          "titulo" => "Keywords"
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        2 => array:2 [
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          "titulo" => "Introduction"
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          "titulo" => "Materials and methods"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Study subjects"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Biopsy culture"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Effector molecules on culture supernatants"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Western-blot analysis"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Statistical analysis"
            ]
          ]
        ]
        4 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Results"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Ascorbate blocks the secretion of nitrites induced by gliadin challenge in biopsy samples from CD patients"
            ]
            1 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Ascorbate inhibited the secretion of cytokines induced by gliadin challenge in biopsy samples from CD patients"
            ]
            2 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Ascorbate inhibited duodenal IL-15"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "Discussion"
        ]
        6 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Conflict of interest"
        ]
        7 => array:2 [
          "identificador" => "xack31860"
          "titulo" => "Acknowledgements"
        ]
        8 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
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    "tienePdf" => true
    "fechaRecibido" => "2010-08-24"
    "fechaAceptado" => "2010-11-10"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec74226"
          "palabras" => array:5 [
            0 => "Ascorbate"
            1 => "Coeliac disease"
            2 => "Inhibition"
            3 => "IL-15"
            4 => "Therapy"
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    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Summary"
        "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The IL-15&#47;NF-&#954;B axis has an important role in coeliac disease &#40;CD&#41; and may represent a molecular target for immunomodulation&#46; Ascorbate &#40;vitamin C&#41; is known to show inhibitory effects on NF-&#954;B&#46; Therefore&#44; we studied if ascorbate supplementation to gliadin gliadin-stimulated biopsy culture could down-regulate the mucosal immune response to gliadin in CD&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Duodenal biopsy explants from treated CD patients were gliadin challenged in vitro &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with and without 20<span class="elsevierStyleHsp" style=""></span>mM ascorbate&#46; An extra tissue explant in basal culture was used as internal control&#46; Secretion levels of nitrites &#40;3<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; and IFN&#947;&#44; TNF&#945;&#44; IFN&#945;&#44; IL-17&#44; IL-13&#44; and IL-6 &#40;24<span class="elsevierStyleHsp" style=""></span>h&#41; were measured on the supernatants&#46; IL-15 was assayed by western-blot on whole protein duodenal explants&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The addition of ascorbate to in vitro culture gliadin-challenged biopsies blocked the secretion of nitrites &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#41;&#44; IFN&#947; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0207&#41;&#44; TNF&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0099&#41;&#44; IFN&#945; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0375&#41;&#44; and IL-6 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0036&#41; compared to samples from non-ascorbate supplemented culture&#46; Cytokine secretion was downregulated by ascorbate even to lower values than those observed in basal cultures &#40;IFN&#947;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; TNF&#945;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; IFN&#945;&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0312&#59; and IL-6&#58; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0078&#41;&#46; Gliadin-challenge induced IL-15 production in biopsies from treated CD patients&#44; while the addition of ascorbate to culture medium completely inhibited IL-15 production&#46; Moreover&#44; the inhibition of IL-15 by ascorbate took place even in the only treated CD-patient who had basal IL-15 production&#46;</p> <span class="elsevierStyleSectionTitle">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Ascorbate decreases the mucosal inflammatory response to gluten in an intestinal biopsy culture model&#44; so it might have a role in future supplementary therapy in CD&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Biopsy culture secretion of nitrites in eight treated CD patients after 3<span class="elsevierStyleHsp" style=""></span>h of gliadin challenge &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with &#40;Gli<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Ascorb&#41; and without &#40;Gli&#41; ascorbate supplementation &#40;20<span class="elsevierStyleHsp" style=""></span>mM&#41;&#44; compared to basal culture &#40;all at 3<span class="elsevierStyleHsp" style=""></span>h&#41;&#46; Statistically significant differences are shown &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; Wilcoxon matched paired test&#41;&#46; Horizontal bars indicate median and whiskers maximum and minimum values&#46; IQR&#58; interquartile range&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Supernatants biopsy culture secretion of IFN&#947;&#44; TNF-&#945;&#44; IFN&#945;&#44; IL-17&#44; IL-13&#44; and IL-6 in eight treated CD patients after gliadin challenge &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with &#40;Gli<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Ascorb&#41; and without &#40;Gli&#41; ascorbate supplementation &#40;20<span class="elsevierStyleHsp" style=""></span>mM&#41; &#40;3<span class="elsevierStyleHsp" style=""></span>h of challenge and 21<span class="elsevierStyleHsp" style=""></span>h of basal culture&#41; compared to the basal culture&#46; Statistically significant differences are shown &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; Wilcoxon matched paired test&#41;&#46; Horizontal bars indicate median and whiskers maximum and minimum values&#46; IQR&#58; interquartile range&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Representative western-blot analysis using whole protein biopsy explants of non-CD controls and treated-CD patients&#44; after 24<span class="elsevierStyleHsp" style=""></span>h of basal culture &#40;Basal&#41;&#44; and after 3<span class="elsevierStyleHsp" style=""></span>h of gliadin challenge &#40;100<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with &#40;Gli<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Asc&#41; and without &#40;Gli&#41; ascorbate supplementation &#40;20<span class="elsevierStyleHsp" style=""></span>mM&#41; and 21<span class="elsevierStyleHsp" style=""></span>h of basal culture&#46; C&#58; human recombinant IL-15 lane&#46;</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Basal IL-15 was only detected in one CD patient&#46; Gliadin induced IL-15 production in both non-CD controls &#40;three out of three&#41; and treated CD patients &#40;seven out of eight&#41;&#46; Ascorbate inhibited IL-15 production in all cases&#44; even in a patient who had detectable basal levels of IL-15&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:38 [
            0 => array:3 [
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              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coeliac disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Maki"
                            1 => "P&#46; Collin"
                          ]
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(96)70237-4"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "1997"
                        "volumen" => "349"
                        "paginaInicial" => "1755"
                        "paginaFinal" => "1759"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9193393"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Coeliac disease&#58; dissecting a complex inflammatory disorder"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "L&#46;M&#46; Sollid"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nri885"
                      "Revista" => array:6 [
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                        "fecha" => "2002"
                        "volumen" => "2"
                        "paginaInicial" => "647"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12209133"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The changing immunological paradigm in coeliac disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Brandtzaeg"
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                      ]
                    ]
                  ]
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        "texto" => "<p id="par0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleGrantSponsor" id="gs0005">Spanish Ministry of Education</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0005">FPU&#44; AP2002-2696</span>&#41;&#44; <span class="elsevierStyleGrantSponsor">Junta de Castilla y Le&#243;n &#40;FPI fellowship&#41;</span>&#44; <span class="elsevierStyleGrantSponsor">Universidad de Valladolid &#40;FPI fellowship&#41;</span>&#44; <span class="elsevierStyleGrantSponsor">Instituto de Salud Carlos III</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0010">Spanish Ministry of Health</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0010">PI 070244</span> and <span class="elsevierStyleGrantNumber" refid="gs0010">CES08&#47;016</span>&#41;&#44; <span class="elsevierStyleGrantSponsor">Fundaci&#243;n IECSCYL</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0015">Junta de Castilla y Le&#243;n</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0015">SAN-GRS232&#47;B&#47;08</span>&#41;&#44; and <span class="elsevierStyleGrantSponsor">Phadia Spain</span>&#46; We also thank Ms&#46; Alicia Ortega for her technical help&#46;</p>"
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]

Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2010.11.003

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	5	1	6
2024 October	34	2	36
2024 September	50	4	54
2024 August	45	4	49
2024 July	40	4	44
2024 June	39	9	48
2024 May	45	8	53
2024 April	45	5	50
2024 March	34	10	44
2024 February	49	6	55
2024 January	36	13	49
2023 December	33	7	40
2023 November	10	27	37
2023 October	15	16	31
2023 September	21	7	28
2023 August	13	5	18
2023 July	27	5	32
2023 June	20	18	38
2023 May	32	6	38
2023 April	8	90	98
2023 March	9	6	15
2023 February	15	5	20
2023 January	12	7	19
2022 December	16	8	24
2022 November	14	7	21
2022 October	17	10	27
2022 September	17	14	31
2022 August	16	13	29
2022 July	9	6	15
2022 June	11	17	28
2022 May	12	5	17
2022 April	9	5	14
2022 March	17	9	26
2022 February	12	5	17
2022 January	28	8	36
2021 December	7	10	17
2021 November	22	9	31
2021 October	20	17	37
2021 September	9	10	19
2021 August	11	11	22
2021 July	9	9	18
2021 June	13	9	22
2021 May	18	9	27
2021 April	44	13	57
2021 March	13	6	19
2021 February	17	9	26
2021 January	76	9	85
2020 December	2	0	2
2020 November	0	1	1
2020 September	0	1	1
2020 July	0	1	1
2020 May	0	3	3
2019 November	0	1	1
2019 October	0	3	3
2019 August	0	1	1
2019 July	0	2	2
2019 June	0	7	7
2019 May	0	22	22
2018 February	11	0	11
2018 January	14	3	17
2017 December	14	6	20
2017 November	16	1	17
2017 October	10	3	13
2017 September	24	10	34
2017 August	17	2	19
2017 July	11	1	12
2017 June	7	5	12
2017 May	30	4	34
2017 April	19	5	24
2017 March	48	32	80
2017 February	21	3	24
2017 January	29	1	30
2016 December	28	7	35
2016 November	15	3	18
2016 October	26	4	30
2016 September	23	6	29
2016 August	16	3	19
2016 July	10	3	13
2016 June	19	4	23
2016 May	8	6	14
2016 April	24	9	33
2016 March	21	9	30
2016 February	18	6	24
2016 January	22	12	34
2015 December	15	6	21
2015 November	16	14	30
2015 October	23	4	27
2015 September	17	3	20
2015 August	20	5	25
2015 July	27	10	37
2015 June	36	1	37
2015 May	58	3	61
2015 April	14	8	22
2015 March	28	3	31
2015 February	14	1	15
2015 January	37	7	44
2014 December	35	5	40
2014 November	22	10	32
2014 October	28	7	35
2014 September	25	4	29
2014 August	9	1	10
2014 July	15	4	19
2014 June	55	2	57
2014 May	13	8	21
2014 April	13	9	22
2014 March	37	10	47
2014 February	72	5	77
2014 January	33	12	45
2013 December	26	10	36
2013 November	27	5	32
2013 October	31	15	46
2013 September	27	8	35
2013 August	43	11	54
2013 July	50	9	59
2013 June	20	4	24
2013 May	28	3	31
2013 April	18	9	27
2013 March	20	6	26
2013 February	15	8	23
2013 January	8	1	9
2012 December	7	2	9
2012 November	0	2	2
2012 October	2	2	4
2012 January	538	0	538

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

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

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