Immunogenetic Factors in Autoimmunity

  • Joanne Heward
  • Stephen Gough
Part of the Contemporary Endocrinology book series (COE)


Many genetic loci are likely to contribute to the genetic susceptibility to autoimmune diseases. To date, however, only three genes/gene regions have been consistently associated with multiple autoimmune diseases, namely the human leukocyte antigen (HLA) class II region on chromosome 6p21, the cytotoxic T-lymphocyte-associated antigen (CTLA)-4 gene on chromosome 2q33, and the PTPN22 gene encoding lymphoid tyrosine phosphatase (LYP) on chromosome 1p13. Further genes have been identified that contribute specifically to a particular disease, and many putative genes are awaiting replication in further data sets. Identification of susceptibility loci is confounded by the involvement of environmental factors in many of these conditions and by their complex polygenic nature requiring large data sets to detect genes of small effect. To identify genes that may increase susceptibility to these diseases, it is necessary to understand the role that the immune response plays in such disorders. This chapter aims to provide an overview of this role and how breakdown of complex immune mechanisms may lead to disease presentation. The role of the three common autoimmunity genes above is also discussed along with new developments in the field.


Autoimmune disease HLA CTLA-4 PTPN22 LYP single-nucleotide polymorphism 


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  1. 1.
    Vyse TJ, Todd JA. Genetic analysis of autoimmune disease. Cell 1996;85(3):311–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Sollid LM, McAdam SN, Molberg O, et al. Genes and environment in celiac disease. Acta Odontol Scand 2001;59(3):183–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Koning F, Gilissen L, Wijmenga C. Gluten: a two-edged sword. Immunopathogenesis of celiac disease. Springer Semin Immunopathol 2005;27(2):217–32.PubMedCrossRefGoogle Scholar
  4. 4.
    Heward J, Gough SC. Genetic susceptibility to the development of autoimmune disease. Clin Sci (Lond) 1997;93(6):479–91.Google Scholar
  5. 5.
    Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 2005;102(30):10604–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Vyse TJ, Kotzin BL. Genetic susceptibility to systemic lupus erythematosus. Annu Rev Immunol 1998;16:261–92.PubMedCrossRefGoogle Scholar
  7. 7.
    Becker KG. Comparative genetics of type 1 diabetes and autoimmune disease: common loci, common pathways? Diabetes 1999;48(7):1353–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Tait KF, Marshall T, Berman J, et al. Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository. Diabet Med 2004;21(4):358–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Keir ME, Sharpe AH. The B7/CD28 costimulatory family in autoimmunity. Immunol Rev 2005;204:128–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Pitkanen J, Peterson P. Autoimmune regulator: from loss of function to autoimmunity. Genes Immun 2003;4(1):12–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002;298(5597):1395–401.PubMedCrossRefGoogle Scholar
  12. 12.
    Liston A, Lesage S, Gray DH, Boyd RL, Goodnow CC. Genetic lesions in T-cell tolerance and thresholds for autoimmunity. Immunol Rev 2005;204:87–101.PubMedCrossRefGoogle Scholar
  13. 13.
    Lesage S, Hartley SB, Akkaraju S, Wilson J, Townsend M, Goodnow CC. Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes. J Exp Med 2002;196(9):1175–88.PubMedCrossRefGoogle Scholar
  14. 14.
    Ghosh S, Palmer SM, Rodrigues NR, et al. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet 1993;4(4):404–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nat Rev Immunol 2004;4(9):688–98.PubMedCrossRefGoogle Scholar
  16. 16.
    Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2002;2(1):11–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Alferink J, Tafuri A, Vestweber D, Hallmann R, Hammerling GJ, Arnold B. Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science 1998;282(5392):1338–41.PubMedCrossRefGoogle Scholar
  18. 18.
    Kurts C, Miller JF, Subramaniam RM, Carbone FR, Heath WR. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J Exp Med 1998;188(2):409–14.PubMedCrossRefGoogle Scholar
  19. 19.
    Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 1995;270(5238):985–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192(7):1027–34.PubMedCrossRefGoogle Scholar
  21. 21.
    Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2(3):261–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Kuchroo VK, Das MP, Brown JA, et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995;80(5):707–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Dong C, Juedes AE, Temann UA, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 2001;409(6816):97–101.PubMedCrossRefGoogle Scholar
  24. 24.
    Janeway CA, Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today 1992;13(1):11–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991–1045.PubMedGoogle Scholar
  26. 26.
    Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184(2):387–96.PubMedCrossRefGoogle Scholar
  27. 27.
    O’Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. Nat Med 2004;10(8):801–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000;164(1):183–90.PubMedGoogle Scholar
  29. 29.
    Kuniyasu Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi S. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol 2000;12(8):1145–55.PubMedCrossRefGoogle Scholar
  30. 30.
    Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000;12(4):431–40.PubMedCrossRefGoogle Scholar
  31. 31.
    Ramsdell F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 2003;19(2): 165–8.PubMedCrossRefGoogle Scholar
  32. 32.
    McHugh RS, Shevach EM. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 2002;168(12):5979–83.PubMedGoogle Scholar
  33. 33.
    Groux H, O’Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389(6652):737–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Sundstedt A, O’Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol 2003;170(3):1240–8.PubMedGoogle Scholar
  35. 35.
    Oida T, Zhang X, Goto M, et al. CD4+CD25- T cells that express latency-associated peptide on the surface suppress CD4+CD45RB high-induced colitis by a TGF-beta-dependent mechanism. J Immunol 2003;170(5):2516–22.PubMedGoogle Scholar
  36. 36.
    Christen U, von Herrath MG. Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol 2004;40(14–15):1113–20.PubMedCrossRefGoogle Scholar
  37. 37.
    Schwimmbeck PL, Oldstone MB. Klebsiella pneumoniae and HLA B27-associated diseases of Reiter’s syndrome and ankylosing spondylitis. Curr Top Microbiol Immunol 1989;145:45–56.PubMedGoogle Scholar
  38. 38.
    Panitch HS. Influence of infection on exacerbations of multiple sclerosis. Ann Neurol 1994;36(Suppl):S25–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Yoon JW, Morishima T, McClintock PR, Austin M, Notkins AL. Virus-induced diabetes mellitus: mengovirus infects pancreatic beta cells in strains of mice resistant to the diabetogenic effect of encephalomyocarditis virus. J Virol 1984;50(3):684–90.PubMedGoogle Scholar
  40. 40.
    Fourneau JM, Bach JM, van Endert PM, Bach JF. The elusive case for a role of mimicry in autoimmune diseases. Mol Immunol 2004;40(14–15):1095–102.PubMedCrossRefGoogle Scholar
  41. 41.
    Lanzavecchia A. How can cryptic epitopes trigger autoimmunity? J Exp Med 1995;181(6): 1945–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Salemi S, Caporossi AP, Boffa L, Longobardi MG, Barnaba V. HIVgp120 activates autoreactive CD4-specific T cell responses by unveiling of hidden CD4 peptides during processing. J Exp Med 1995;181(6):2253–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Simitsek PD, Campbell DG, Lanzavecchia A, Fairweather N, Watts C. Modulation of antigen processing by bound antibodies can boost or suppress class II major histocompatibility complex presentation of different T cell determinants. J Exp Med 1995;181(6):1957–63.PubMedCrossRefGoogle Scholar
  44. 44.
    Wucherpfennig KW. Mechanisms for the induction of autoimmunity by infectious agents. J Clin Invest 2001;108(8):1097–104.PubMedCrossRefGoogle Scholar
  45. 45.
    Brocke S, Gaur A, Piercy C, et al. Induction of relapsing paralysis in experimental autoimmune encephalomyelitis by bacterial superantigen. Nature 1993;365(6447):642–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y. Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia 1992;35(5):419–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Badenhoop K, Walfish PG, Rau H, et al. Susceptibility and resistance alleles of human leukocyte antigen (HLA) DQA1 and HLA DQB1 are shared in endocrine autoimmune disease. J Clin Endocrinol Metab 1995;80(7):2112–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Simmonds MJ, Howson JM, Heward JM, et al. Regression mapping of association between the human leukocyte antigen region and Graves disease. Am J Hum Genet 2005;76(1):157–63.PubMedCrossRefGoogle Scholar
  49. 49.
    Vaidya B, Imrie H, Perros P, et al. The cytotoxic T lymphocyte antigen-4 is a major Graves’ disease locus. Hum Mol Genet 1999;8(7):1195–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Ueda H, Howson JM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003;423(6939):506–11.PubMedCrossRefGoogle Scholar
  51. 51.
    Smyth D, Cooper JD, Collins JE, et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004;53(11):3020–3.PubMedCrossRefGoogle Scholar
  52. 52.
    Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005;76(4):561–71.PubMedCrossRefGoogle Scholar
  53. 53.
    Miretti MM, Walsh EC, Ke X, et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 2005;76(4):634–46.PubMedCrossRefGoogle Scholar
  54. 54.
    Nerup J, Platz P, Andersen OO, et al. HL-A antigens and diabetes mellitus. Lancet 1974;2(7885):864–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Giordano M, D’Alfonso S, Momigliano-Richiardi P. Genetics of multiple sclerosis: linkage and association studies. Am J Pharmacogenomics 2002;2(1):37–58.PubMedCrossRefGoogle Scholar
  56. 56.
    Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis. Genes Immun 2004;5(3):151–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Heward JM, Allahabadia A, Daykin J, et al. Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves’ disease: replication using a population case control and family-based study. J Clin Endocrinol Metab 1998;83(10): 3394–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Weetman AP, Zhang L, Tandon N, Edwards OM. HLA associations with autoimmune Addison’s disease. Tissue Antigens 1991;38(1):31–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Graham RR, Ortmann WA, Langefeld CD, et al. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet 2002;71(3):543–53.PubMedCrossRefGoogle Scholar
  60. 60.
    Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 1987;329(6140):599–604.PubMedCrossRefGoogle Scholar
  61. 61.
    Ban Y, Davies TF, Greenberg DA, et al. Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves’ disease. Genes Immun 2004;5(3):203–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Cucca F, Muntoni F, Lampis R, et al. Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia. Hum Immunol 1993;37(2):85–94.PubMedCrossRefGoogle Scholar
  63. 63.
    Cucca F, Lampis R, Frau F, et al. The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci. Hum Immunol 1995;43(4):301–8.PubMedCrossRefGoogle Scholar
  64. 64.
    du Montcel ST, Michou L, Petit-Teixeira E, et al. New classification of HLA-DRB1 alleles supports the shared epitope hypothesis of rheumatoid arthritis susceptibility. Arthritis Rheum 2005;52(4):1063–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Greer JM, Pender MP. The presence of glutamic acid at positions 71 or 74 in pocket 4 of the HLA-DRbeta1 chain is associated with the clinical course of multiple sclerosis. J Neurol Neurosurg Psychiatry 2005;76(5):656–62.PubMedCrossRefGoogle Scholar
  66. 66.
    Kwok WW, Mickelson E, Masewicz S, Milner EC, Hansen J, Nepom GT. Polymorphic DQ alpha and DQ beta interactions dictate HLA class II determinants of allo-recognition. J Exp Med 1990;171(1):85–95.PubMedCrossRefGoogle Scholar
  67. 67.
    Stern LJ, Brown JH, Jardetzky TS, et al. Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 1994;368(6468):215–21.PubMedCrossRefGoogle Scholar
  68. 68.
    Jorgensen JL, Esser U, Fazekas de St Groth B, Reay PA, Davis MM. Mapping T-cell receptor-peptide contacts by variant peptide immunization of single-chain transgenics. Nature 1992;355(6357):224–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Bhayani H, Paterson Y. Analysis of peptide binding patterns in different major histocompatibility complex/T cell receptor complexes using pigeon cytochrome c-specific T cell hybridomas. Evidence that a single peptide binds major histocompatibility complex in different conformations. J Exp Med 1989;170(5):1609–25.PubMedCrossRefGoogle Scholar
  70. 70.
    Cucca F, Lampis R, Congia M, et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum Mol Genet 2001;10(19):2025–37.PubMedCrossRefGoogle Scholar
  71. 71.
    Nanda NK, Arzoo KK, Geysen HM, Sette A, Sercarz EE. Recognition of multiple peptide cores by a single T cell receptor. J Exp Med 1995;182(2):531–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Nepom GT, Kwok WW. Molecular basis for HLA-DQ associations with IDDM. Diabetes 1998;47(8):1177–84.PubMedCrossRefGoogle Scholar
  73. 73.
    Nepom GT. A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes 1990;39(10):1153–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002;16(1):23–35.PubMedCrossRefGoogle Scholar
  75. 75.
    Furugaki K, Shirasawa S, Ishikawa N, et al. Association of the T-cell regulatory gene CTLA4 with Graves’ disease and autoimmune thyroid disease in the Japanese. J Hum Genet 2004;49(3):166–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Heward JM, Allahabadia A, Armitage M, et al. The development of Graves’ disease and the CTLA-4 gene on chromosome 2q33. J Clin Endocrinol Metab 1999;84(7):2398–401.PubMedCrossRefGoogle Scholar
  77. 77.
    Nistico L, Buzzetti R, Pritchard LE, et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet 1996;5(7):1075–80.PubMedCrossRefGoogle Scholar
  78. 78.
    Nithiyananthan R, Heward JM, Allahabadia A, Franklyn JA, Gough SC. Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom. Thyroid 2002;12(1):3–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Vaidya B, Imrie H, Geatch DR, et al. Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison’s disease. J Clin Endocrinol Metab 2000;85(2):688–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Blomhoff A, Lie BA, Myhre AG, et al. Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison’s disease. J Clin Endocrinol Metab 2004;89(7):3474–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Torres B, Aguilar F, Franco E, et al. Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus. Arthritis Rheum 2004;50(7):2211–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Suppiah V, Alloza I, Heggarty S, et al. The CTLA4 +49 A/G* G-CT60* G haplotype is associated with susceptibility to multiple sclerosis in Flanders. J Neuroimmunol 2005;164(1–2):148–53.PubMedCrossRefGoogle Scholar
  83. 83.
    Anjos SM, Shao W, Marchand L, Polychronakos C. Allelic effects on gene regulation at the autoimmunity-predisposing CTLA4 locus: a re-evaluation of the 3′ +6230G>A polymorphism. Genes Immun 2005;6(4):305–11.PubMedCrossRefGoogle Scholar
  84. 84.
    Vijayakrishnan L, Slavik JM, Illes Z, et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 2004;20(5):563–75.PubMedCrossRefGoogle Scholar
  85. 85.
    Marengere LE, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 1996;272(5265):1170–3.PubMedCrossRefGoogle Scholar
  86. 86.
    Masteller EL, Chuang E, Mullen AC, Reiner SL, Thompson CB. Structural analysis of CTLA-4 function in vivo. J Immunol 2000;164(10):5319–27.PubMedGoogle Scholar
  87. 87.
    Lee KM, Chuang E, Griffin M, et al. Molecular basis of T cell inactivation by CTLA-4. Science 1998;282(5397):2263–6.PubMedCrossRefGoogle Scholar
  88. 88.
    Li D, Gal I, Vermes C, et al. Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J Immunol 2004;173(12):7135–9.PubMedGoogle Scholar
  89. 89.
    Duan L, Reddi AL, Ghosh A, Dimri M, Band H. The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling. Immunity 2004;21(1):7–17.PubMedCrossRefGoogle Scholar
  90. 90.
    Bachmaier K, Krawczyk C, Kozieradzki I, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 2000;403(6766):211–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Yokoi N, Komeda K, Wang HY, et al. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 2002;31(4):391–4.PubMedGoogle Scholar
  92. 92.
    Bergholdt R, Taxvig C, Eising S, Nerup J, Pociot F. CBLB variants in type 1 diabetes and their genetic interaction with CTLA4. J Leukoc Biol 2005;77(4):579–85.PubMedCrossRefGoogle Scholar
  93. 93.
    Mustelin T, Alonso A, Bottini N, et al. Protein tyrosine phosphatases in T cell physiology. Mol Immunol 2004;41(6–7):687–700.PubMedCrossRefGoogle Scholar
  94. 94.
    Cohen S, Dadi H, Shaoul E, Sharfe N, Roifman CM. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 1999;93(6):2013–24.PubMedGoogle Scholar
  95. 95.
    Cloutier JF, Veillette A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med 1999;189(1):111–21.PubMedCrossRefGoogle Scholar
  96. 96.
    Hill RJ, Zozulya S, Lu YL, Ward K, Gishizky M, Jallal B. The lymphoid protein tyrosine phosphatase Lyp interacts with the adaptor molecule Grb2 and functions as a negative regulator of T-cell activation. Exp Hematol 2002;30(3):237–44.PubMedCrossRefGoogle Scholar
  97. 97.
    Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004;36(4):337–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Qu H, Tessier MC, Hudson TJ, Polychronakos C. Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. J Med Genet 2005;42(3):266–70.PubMedCrossRefGoogle Scholar
  99. 99.
    Zheng W, She JX. Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes. Diabetes 2005;54(3):906–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Zhernakova A, Eerligh P, Wijmenga C, Barrera P, Roep BO, Koeleman BP. Differential association of the PTPN22 coding variant with autoimmune diseases in a Dutch population. Genes Immun 2005;6(6):459–61.PubMedCrossRefGoogle Scholar
  101. 101.
    Steer S, Lad B, Grumley JA, Kingsley GH, Fisher SA. Association of R602W in a protein tyrosine phosphatase gene with a high risk of rheumatoid arthritis in a British population: evidence for an early onset/disease severity effect. Arthritis Rheum 2005;52(1):358–60.PubMedCrossRefGoogle Scholar
  102. 102.
    Simkins HM, Merriman ME, Highton J, et al. Association of the PTPN22 locus with rheumatoid arthritis in a New Zealand Caucasian cohort. Arthritis Rheum 2005;52(7):2222–5.PubMedCrossRefGoogle Scholar
  103. 103.
    van Oene M, Wintle RF, Liu X, et al. Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn’s disease, in Canadian populations. Arthritis Rheum 2005;52(7):1993–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004;75(3):504–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’ disease. J Clin Endocrinol Metab 2004;89(11):5862–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Skorka A, Bednarczuk T, Bar-Andziak E, Nauman J, Ploski R. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clin Endocrinol (Oxf) 2005;62(6):679–82.CrossRefGoogle Scholar
  107. 107.
    Begovich AB, Caillier SJ, Alexander HC, et al. The R620W polymorphism of the protein tyrosine phosphatase PTPN22 is not associated with multiple sclerosis. Am J Hum Genet 2005;76(1):184–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Matesanz F, Rueda B, Orozco G, et al. Protein tyrosine phosphatase gene (PTPN22) polymorphism in multiple sclerosis. J Neurol 2005;252(8):994–5.PubMedCrossRefGoogle Scholar
  109. 109.
    Carlton VE, Hu X, Chokkalingam AP, et al. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am J Hum Genet 2005;77(4):567–81.PubMedCrossRefGoogle Scholar
  110. 110.
    Chow LM, Fournel M, Davidson D, Veillette A. Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk. Nature 1993;365(6442):156–60.PubMedCrossRefGoogle Scholar
  111. 111.
    Ghose R, Shekhtman A, Goger MJ, Ji H, Cowburn D. A novel, specific interaction involving the Csk SH3 domain and its natural ligand. Nat Struct Biol 2001;8(11):998–1004.PubMedCrossRefGoogle Scholar
  112. 112.
    Gjorloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol 1999;29(12):3845–54.PubMedCrossRefGoogle Scholar
  113. 113.
    Kochi Y, Yamada R, Suzuki A, et al. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet 2005;37(5):478–85.PubMedCrossRefGoogle Scholar
  114. 114.
    Tokuhiro S, Yamada R, Chang X, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 2003;35(4):341–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34(4):395–402.PubMedCrossRefGoogle Scholar
  116. 116.
    Guo D, Li M, Zhang Y, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nat Genet 2004;36(8):837–41.PubMedCrossRefGoogle Scholar
  117. 117.
    Smyth DJ, Howson JM, Lowe CE, et al. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. Nat Genet 2005;37(2):110–1; author reply 2–3.PubMedCrossRefGoogle Scholar
  118. 118.
    Kosoy R, Concannon P. Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes. Genes Immun 2005;6(3):231–5.PubMedCrossRefGoogle Scholar
  119. 119.
    Vella A, Cooper JD, Lowe CE, et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 2005;76(5):773–9.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Joanne Heward
  • Stephen Gough

There are no affiliations available

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