Article information
Resumen
La expresión anormal de moléculas claves en señalización y la función defectuosa de los linfocitos T cumplen un papel significativo en la patogénesis de la enfermedad autoinmune. Las células T muestran numerosas anormalidades en la señalización del complejo TCRζ1, estas aberraciones resultan en la alteración de la expresión de citoquinas. Mientras algunas de estas anormalidades explican el aumento de la actividad de células B por células T con incremento de los anticuerpos, la disminución en la producción de IL-2 resulta en un aumento en la susceptibilidad a las infecciones, reducción en la activación de las células T, inducción de la muerte celular y prolongada sobrevida de las células T autorreactivas2.
Palabras clave:
lupus
TCRζ
CTLA-4
Elf-1
FcγR
LES
ITAM
UTR
CaMKIV
Summary
The abnormal expression of key molecules in signaling and the malfunction of the T cell T have a significant activity in the pathogenesis of the autoimmune disease. The cells T exhibit numerous abnormalities in the signaling of the complex TCR1, these aberrations result in the alteration of the citoquines. While some of these abnormalities explain the increase of the activity of cells B for cells T with increment of the antibodies production, the decrease in the production of IL-2 induces an increase in the susceptibility to the infections, diminishing in the activation of the cells T, and expansion of the lifespan of the autorreactive cells2.
Key words:
lupus
TCRζ
CTLA-4
Elf-1
FcγR
LES
ITAM
UTR
CaMKIV
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Referencias
[1.]
A.G. Iliopoulos, C.G. Tsokos.
Immunopathogenesis and spectrumof infections in systemic lupus erythematosus. Semin.
Arthritis Rheum, 25 (1996), pp. 318-336
[2.]
C.G. Tsokos, M.P. Nambiar, K. Tenbrock, Y.T. Juang.
Rewiring the T-cell: signaling defects and novel prospects for the treatment of SLE.
Trends Immunol, 24 (2003), pp. 259-263
[3.]
C.T. Ravirajan, M.A. Rahman, L. Papadaki.
Genetic, structural and functional properties of an IgG DNAbinding monoclonal antibody from a lupus patient with nephritis.
Eur J Immunol, 28 (1998), pp. 339-350
[4.]
M.R. Ehrenstein, D.R. Katz, M.H. Griffiths.
Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice.
Kidney Int, 48 (1995), pp. 705-711
[5.]
M. Okamura, Y. Kanayama, K. Amastu.
Significance of enzyme linked immunosorbent assay (ELISA) for antibodies to double stranded and single stranded DNA in patients with lupus nephritis: correlation with severity of renal histology.
Ann Rheum Dis, 52 (1993), pp. 14-20
[6.]
A. Davidson, B. Diamond, D. Wofsy, D. Daikh.
Block and tackle: CTLA4 Ig takes on lupus.
Lupus, 14 (2005), pp. 197-203
[7.]
D. Isenberg, A. Rahman.
Systemic lupus erythematosus 2005 annuls mirabilis?.
Nat Clin Pract Rheumatol, 2 (2006), pp. 145-152
[8.]
T. Dörner, P.E. Lipsky.
Immunoglobulin variable-region gene usage in systemic autoimmune diseases.
Arthritis Rheum, 44 (2001), pp. 2715-2727
[9.]
M.E. Call, K.W. Wucherpfennig.
The T cell receptor: critical role of the membrane environment in receptor assembly and function.
Annu Rev Immunol, 23 (2005), pp. 101-125
[10.]
M.E. Call, K.W. Wucherpfennig.
Molecular mechanisms for the assembly of the T cell receptor-CD3complex.
Mol. Immunol, 40 (2004), pp. 1295-1305
[11.]
M.L. Ford, B.D. Evavold.
Degenerate recognition of T cell epitopes: impact of T cell receptor reserve and stability of peptide: MHC complexes.
Mol Immunol, 40 (2004), pp. 1019-1025
[12.]
M.S. Jordan, A.L. Singer, G.A. Koretzky.
Adaptors as central mediators of signal transduction in immune cells.
Nat Immunol, 4 (2000), pp. 110-116
[14.]
M. Rincon.
MAP-kinase signaling pathways in T cells.
Curr Opin. Immunol, 13 (2001), pp. 339-345
[15.]
J.P. Northrop, S.N. Ho, L. Chen.
NF-AT components define a family of transcription factors targeted in T-cell activation.
Nature, 369 (1994), pp. 497-502
[16.]
J.P. Jensen, P.W. Bates, M. Yang, R.D. Vierstra, A.M. Weissman.
Identification of a family of closely related human ubiquitin conjugating enzymes.
J Biol Chem, 270 (1995), pp. 30408-30414
[17.]
K.L. Moser, et al.
Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees.
Proc Natl Acad Sci USA, 95 (1998), pp. 14869-14874
[18.]
P.M. Gaffney, G.M. Kearns, SharkKB, W.A. Ortmann, S.A. Selby, M.L. Malmgren, K.E. Rohlf, T.C. Ockenden, R.P. Messner, R.A. King, S.S. Rich, T.W. Behrens.
A genomewide search for susceptibility genes in human systemic lupus erythematosus sib-pair families.
Proc Natl Acad Sci USA, 95 (1998), pp. 14875-14879
[19.]
R. Shai, F.P. Quismorio, et al.
Genomewide screen for systemic lupus erythematosus susceptibility genes in multiplex families.
Hum Mol Genet 1999, 8 (1999), pp. 639-644
[20.]
B. Chowdhury, S. Krishnan, C.G. Tsokos, et al.
Stability and translation of TCR zeta mRNA are regulated by the adenosine-uridine-rich elements in splice-deleted 3′untranslated region of zeta-chain.
J Immunol, 177 (2006), pp. 8248-8257
[21.]
G.C. Tsokos, S.N. Liossis.
Immune cell signaling defects in lupus: activation, anergy and death.
Immunol. Today, 20 (1999), pp. 119-124
[22.]
J.H. Finke, A.H. Zea, J. Stanley, D.L. Longo, H. Mizoguchi, R.R. Tubbs, R.H. Wiltrout, J.J. O'Shea, S. Kudoh, E. Klein.
Loss of T-cell receptor zeta chain and p561ck in T-cells infiltrating human renal cell carcinoma.
Cancer Res, 53 (1993), pp. 5613-5616
[23.]
A.M. Weissman, M. Baniyash, D. Hou, L.E. Samelson, W.H. Burgess, R.D. Klausner.
Molecular cloning of the zeta chain of the T cell antigen receptor.
Science, 239 (1988), pp. 1018-1021
[24.]
M. Stacey, A. Barlow, M. Hulten.
Human T-cell receptor zeta chain gene Map Q7 position 1q23.1.
Chromosome Res, 5 (1997), pp. 279
[25.]
K.L. Moser, B.R. Neas, J.E. Salmon, H. Yu, C. Gray-McGurie, N. Asundi, G.R. Bruner, J. Fox, J. Kelly, S. Henshall, D. Bacino, et al.
Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees.
Proc Natl Acad, 95 (1998), pp. 14869-14874
[26.]
J.P. Jensen, D. Hou, M.A. Ramsburg, D.M. Taylor, A.M. Weissman.
Organization of the human T cell receptor zeta-eta gene and its genetic linkage to the Fc gamma RII-Fc gamma RIII gene cluster.
J Immunol, 148 (1992), pp. 2563-2571
[27.]
S.N. Liossis, D.Z. Ding, G.J. Dennis, G.C. Tsokos.
Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T-cell receptor zeta chain.
J Clin Invest, 101 (1998), pp. 1448-1457
[28.]
T. Takeuchi, Tsuzaka k, M. Pang, K. Amano, J. Koide, T. Abe.
TCR zeta chain lacking exon 7 in two patients with systemic lupus erythematosus.
Int Immunol, 10 (1998), pp. 911-921
[29.]
V. Brundula, L.J. Rivas, A.M. Blasini, M. Paris, S. Salazar, I.L. Stekman, M.A. Rodriguez.
Diminshed levels of T cell receptor zeta chains in peripheral blood T lymphocytes from patients with systemic lupus erythematosus.
Arthritis Rheum, 42 (1999), pp. 1908-1916
[30.]
M.P. Nambiar, et al.
Abnormal expression of various molecular forms and distribution of T cell receptor z chain in patients with systemic lupus erythematosus.
Arthritis Rheum, 46 (2002), pp. 163-174
[31.]
D. Vassilopoulos, B. Kovacs, G.C. Tsokos.
TCR/CD3 complex mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus.
J Immunol, 155 (1995), pp. 2269-2281
[32.]
S. Krishnan, M.P. Nambiar, V.G. Warke, et al.
Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus.
J Immunol, 172 (2004), pp. 7821-7831
[33.]
M.P. Nambiar, C.U. Fisher, V.G. Warke, et al.
Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus.
Arthritis Rheum, 48 (2003), pp. 1948-1955
[34.]
R. Vaishali, C. Vasileios, T.J. Yuang, G.C. Tsokos.
Post-Transcriptional Regulation of T Cell Receptor zeta Chain in Systemic Lupus Erythematosus.
Clinical Immunology, 123 (2007), pp. 66
[35.]
M.P. Nambiar, E.J. Enyedy, V.G. Warke, S. Krishnan, G. Dennis, H.K. Wong, G.M. Kammer, G.C. Tsokos.
T cell signaling abnormalities in systemic lupus erythematosus are associated with increased mutations/polymorphisms and splice variants of T cell receptor chain messenger RNA.
Arthritis Rheum, 44 (2001), pp. 1336-1350
[36.]
B. Chowdhury, C.G. Tsokos, S. Krishnan, J. Robertson, C. Fisher, et al.
Decreased Stability and Translation of T Cell receptor mRNA with an Alternatively Spliced 3 Untranslated Region Contribute to Chain Downregulation in Patients with Systemic Lupus Erythematosus.
The journal of biological chemistry, 280 (2005), pp. 18959-18966
[37.]
M.P. Nambiar, E.J. Enyedy, V.G. Warke, S. Krishnan, G. Dennis, G.M. Kammer, G.C. Tsokos.
Polymorphisms mutations of TCR-zeta-chain promoter and 3′ untranslated region and selective expression of TCR zeta-chain with an alternatively spliced 30 untranslated region in patients with systemic lupus erythematosus.
J Autoimmun, 16 (2001), pp. 133-142
[38.]
V.C. Kyttaris, et al.
Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus.
J Immunol, 178 (2007), pp. 1960-1966
[39.]
A. Desai-Mehta, L. Lu, R. Ramsey-Goldman, S.K. Datta.
Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.
J Clin Invest, 97 (1996), pp. 2063-2073
[40.]
R.D. Fritsch, X. Shen, G.G. Illei, et al.
Abnormal differentiation of memory T cells in systemic lupus erythematosus.
Arthritis Rheum, 54 (2006), pp. 2184-2197
[41.]
Y. Amasaki, S. Kobayashi, T. Takeda, et al.
Up-regulated expression of Fas antigen (CD95) by peripheral naive and memory T cell subsets in patients with systemic lupus erythematosus (SLE): a possible mechanism for lymphopenia.
Clin Exp Immunol, 99 (1995), pp. 245-250
[42.]
P.A. Mudd, B.N. Teague, A.D. Farris.
Regulatory T cells and systemic lupus erythematosus.
Scand J Immunol, 64 (2006), pp. 211-218
[43.]
B.A. Irving, A.C. Chan, A. Weiss.
Functional characterization of a signal transducing motif present in the T cell antigen receptor zeta chain.
J Exp Med, 177 (1993), pp. 1093-1103
[44.]
M.M. Maurice, A.C. Lankester, A.C. Bezemer, et al.
Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis.
J Immunol, 159 (1997), pp. 2973-2978
[45.]
Y.T. Juang, E.E. Solomou, B. Rellahan, G.C. Tsokos.
Phosphorylation and O-linked glycosylation of Elf-1 leads to its translocation to the nucleus and binding to the promoter of the TCR zeta-chain.
J Immunol, 168 (2002), pp. 2865-2871
[46.]
Y.T. Juang, K. Tenbrock, M.P. Nambiar, M.F. Gourley, G.C. Tsokos.
Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR zeta-chain in patients with systemic lupus erythematosus.
J Immunol, 169 (2002), pp. 6048-6055
[47.]
E.J. Enyedy, M.P. Nambiar, S.N. Liossis, G. Dennis, G.M. Kammer, G.C. Tsokos.
Fc epsilon receptor type I gamma chain replaces the deficient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus.
Arthritis Rheum, 44 (2001), pp. 1114-1121
[48.]
S. Krishnan, V.G. Warke, M.P. Nambiar, G.C. Tsokos, D.L. Farber.
The FcR gamma subunit and Syk kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4T cells.
J Immunol, 170 (2003), pp. 4189-4195
[49.]
M. Lovatt, A. Filby, V. Parravicini, G. Werlen, E. Palmer, R. Zamoyska.
Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response.
Mol Cell Biol, 26 (2006), pp. 8655-8665
[50.]
E.C. Jury, P.S. Kabouridis, F. Flores-Borja, R.A. Mageed, D.A. Isenberg.
Altered lipid raft associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus.
J Clin Invest, 113 (2004), pp. 1176-1187
[51.]
M. Koshy, D. Berger, M.K. Crow.
Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes.
J Clin Invest, 98 (1996), pp. 826-837
[52.]
V.C. Kyttaris, Y. Wang, Y.T. Juang, A. Weinstein, G.C. Tsokos.
Increased Levels of NFATc2 Differentially Regulate CD154 and IL-2 Genes in T Cells from Patients with Systemic Lupus Erythematosus.
J Immunol, 178 (2007), pp. 1960-1966
[53.]
V.C. Kyttaris, Y.T. Juang, K. Tenbrock, A. Weinstein, G.C. Tsokos.
Cyclic adenosine 5′-monophosphate response element modulator is responsible for the decreased expression of c-fos and activator protein-1 binding in T cells from patients with systemic lupus erythematosus.
J Immunol, 173 (2004), pp. 3557-3563
[54.]
Y.T. Juang, Y. Wang, E.E. Solomou, et al.
Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV.
J Clin Invest, 115 (2005), pp. 996-1005
[55.]
E.K. Heist, M. Srinivasan, H. Schulman.
Phosphorylation at the nuclear localization signal of Ca2þ/calmodulin- dependent protein kinase II blocks its nuclear targeting.
J Biol Chem, 273 (1998), pp. 19763-19771
[56.]
K.A. Anderson, C.D. Kane.
Ca2þ/calmodulin-dependent protein kinase IV and calcium signaling.
Biometals, 11 (1998), pp. 331-343
[57.]
J.D. Powell, C.G. Lerner, G.R. Ewoldt, R.H. Schwartz.
The _180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy.
J Immunol, 163 (1999), pp. 6631-6639
[58.]
A. Rahman, D.S. Isenberg.
Systemic lupus erythematosus.
N Engl J Med, 358 (2008), pp. 929-939
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