Skip to main content
SpringerLink
Log in
Book cover

Autoimmune Diseases in Endocrinology pp 243–274Cite as

Islet Cell Autoantigens

  • Chapter

  • 1360 Accesses

Part of the book series: Contemporary Endocrinology ((COE))

Summary

Type 1 diabetes (T1D) appears after autoimmune processes have eradicated a large majority of the pancreatic islet β cells. Although patients may also have other organ-specific autoimmune diseases such as thyroiditis or celiac disease (CD), most T1D patients suffer from life-long insulin dependence because only the β cells have been eradicated. The genetic etiology is strongly associated with certain HLA-DQ class II heterodimers, which in part may explain the cell-specific loss as these proteins control antigen processing and presentation. Other etiologies include environmental factors such as virus and environmental or dietary toxins. The pathogenesis is closely associated with a number of autoimmune abnormalities, among them are autoantibodies and T cells to specific autoantigens. Autoantibody assays, standardized in international efforts, are used to identify autoantibodies against the islet autoantigens insulin, GAD65 and islet antigen-2 (IA-2). The presence of autoantibodies to these autoantigens predicts T1D. Other β-cell autoantigens have been reported but have failed confirmation especially because such antigens have failed to predict disease. The possible pathogenic importance of minor candidate autoantigens is typically not pursued. Reproducible and standardized T-cell tests of either CD4- or CD8-positive T cells are yet to be developed. Immunomodulating therapies with insulin and GAD65 are in progress, and preliminary data indicate that it may be possible to alter the T1D pathogenic process.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   269.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia 1983;24(5):366–71.

    PubMed  CAS  Google Scholar 

  2. Greenbaum CJ, Sears KL, Kahn SE, Palmer JP. Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study. Diabetes 1999;48(1):170–5.

    PubMed  CAS  Google Scholar 

  3. Sosenko JM, Palmer JP, Greenbaum CJ, et al. Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1. Diabetes Care 2006;29(3):643–9.

    PubMed  Google Scholar 

  4. DPT-1. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346(22):1685–91.

    Google Scholar 

  5. Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004;363(9413):925–31.

    PubMed  CAS  Google Scholar 

  6. Bingley PJ, Gale EA. Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk. Diabetologia 2006;49(5):881–90.

    PubMed  CAS  Google Scholar 

  7. Lernmark A. Type 1 diabetes as a model for prediction and diagnosis. Autoimmunity 2004;37(4):341–5.

    PubMed  CAS  Google Scholar 

  8. Notkins AL. Type 1 diabetes as a model for autoantibodies as predictors of autoimmune diseases. Autoimmun Rev 2004;3(Suppl 1):S7–9.

    PubMed  Google Scholar 

  9. Notkins AL, Lernmark A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 2001;108(9):1247–52.

    PubMed  CAS  Google Scholar 

  10. Lernmark A. Type 1 diabetes as a model for prediction and diagnosis. Autoimmunity 2004;37(4):341–5.

    PubMed  CAS  Google Scholar 

  11. Gianani R, Eisenbarth GS. The stages of type 1A diabetes: 2005. Immunol Rev 2005;204:232–49.

    PubMed  CAS  Google Scholar 

  12. Tsai EB, Sherry NA, Palmer JP, Herold KC. The rise and fall of insulin secretion in type 1 diabetes mellitus. Diabetologia 2006;49(2):261–70.

    PubMed  CAS  Google Scholar 

  13. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965;14(10):619–33.

    PubMed  CAS  Google Scholar 

  14. Nerup J, Bendixen G, Binder C. Autoimmunity in diabetes mellitus. Lancet 1970;2(7673):610–1.

    PubMed  CAS  Google Scholar 

  15. Nerup J, Andersen OO, Bendixen G, Egeberg J, Poulsen JE. Anti-pancreatic cellular hypersensitivity in diabetes mellitus. Diabetes 1971;20(6):424–7.

    PubMed  CAS  Google Scholar 

  16. Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 1973;22(6):429–32.

    PubMed  CAS  Google Scholar 

  17. Nerup J, Platz P, Andersen OO, et al. HL-A antigens and diabetes mellitus. Lancet 1974;2(7885):864–6.

    PubMed  CAS  Google Scholar 

  18. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 1974;2(7892):1279–83.

    PubMed  CAS  Google Scholar 

  19. MacCuish AC, Irvine WJ, Barnes EW, Duncan LJ. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet 1974;2(7896):1529–31.

    PubMed  CAS  Google Scholar 

  20. Lendrum R, Walker G, Gamble DR. Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Lancet 1975;1(7912):880–2.

    PubMed  CAS  Google Scholar 

  21. Gorsuch AN, Spencer KM, Lister J, et al. Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus. Lancet 1981;2(8260–61):1363–5.

    PubMed  CAS  Google Scholar 

  22. Lernmark A, Sehlin J, Taljedal IB, Kromann H, Nerup J. Possible toxic effects of normal and diabetic patient serum on pancreatic B-cells. Diabetologia 1978;14(1):25–31.

    PubMed  CAS  Google Scholar 

  23. Lernmark A, Freedman ZR, Hofmann C, et al. Islet-cell-surface antibodies in juvenile diabetes mellitus. N Engl J Med 1978;299(8):375–80.

    PubMed  CAS  Google Scholar 

  24. Dobersen MJ, Scharff JE, Ginsberg-Fellner F, Notkins AL. Cytotoxic autoantibodies to beta cells in the serum of patients with insulin-dependent diabetes mellitus. N Engl J Med 1980;303(26):1493–8.

    PubMed  CAS  Google Scholar 

  25. Lernmark A, Baekkeskov S. Islet cell antibodies-theoretical and practical implications. Diabetologia 1981;21(5):431–5.

    PubMed  CAS  Google Scholar 

  26. Baekkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982;298(5870):167–9.

    PubMed  CAS  Google Scholar 

  27. Gerling I, Baekkeskov S, Lernmark A. Islet cell and 64K autoantibodies are associated with plasma IgG in newly diagnosed insulin-dependent diabetic children. J Immunol 1986;137(12):3782–5.

    PubMed  CAS  Google Scholar 

  28. Christie M, Landin-Olsson M, Sundkvist G, Dahlquist G, Lernmark A, Baekkeskov S. Antibodies to a Mr-64,000 islet cell protein in Swedish children with newly diagnosed type 1 (insulin-dependent) diabetes. Diabetologia 1988;31(8):597–602.

    PubMed  CAS  Google Scholar 

  29. Palmer JP, Asplin CM, Clemons P, et al. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 1983;222(4630):1337–9.

    PubMed  CAS  Google Scholar 

  30. Kuglin B, Gries FA, Kolb H. Evidence of IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment. Diabetes 1988;37(1):130–2.

    PubMed  CAS  Google Scholar 

  31. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990;347(6289):151–6.

    PubMed  CAS  Google Scholar 

  32. Karlsen AE, Hagopian WA, Grubin CE, et al. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci USA 1991;88(19): 8337–41.

    PubMed  CAS  Google Scholar 

  33. Hagopian WA, Michelsen B, Karlsen AE, et al. Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase. Diabetes 1993;42(4):631–6.

    PubMed  CAS  Google Scholar 

  34. Kim J, Richter W, Aanstoot HJ, et al. Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes 1993;42(12):1799–808.

    PubMed  CAS  Google Scholar 

  35. Lan MS, Lu J, Goto Y, Notkins AL. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol 1994;13(5):505–14.

    PubMed  CAS  Google Scholar 

  36. Lan MS, Wasserfall C, Maclaren NK, Notkins AL. IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1996;93(13):6367–70.

    PubMed  CAS  Google Scholar 

  37. Payton MA, Hawkes CJ, Christie MR. Relationship of the 37,000- and 40,000-M(r) tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512). J Clin Invest 1995;96(3):1506–11.

    PubMed  CAS  Google Scholar 

  38. Wasmeier C, Hutton JC. Molecular cloning of phogrin, a protein-tyrosine phosphatase homologue localized to insulin secretory granule membranes. J Biol Chem 1996;271(30):18161–70.

    PubMed  CAS  Google Scholar 

  39. Bingley PJ, Bonifacio E, Mueller PW. Diabetes Antibody Standardization Program: first assay proficiency evaluation. Diabetes 2003;52(5):1128–36.

    PubMed  CAS  Google Scholar 

  40. Mire-Sluis AR, Gaines Das R, Lernmark A. The World Health Organization International Collaborative Study for islet cell antibodies. Diabetologia 2000;43(10):1282–92.

    PubMed  CAS  Google Scholar 

  41. Greenbaum CJ, Wilkin TJ, Palmer JP. Fifth International Serum Exchange Workshop for Insulin Autoantibody (IAA) Standardization. The Immunology and Diabetes Workshops and participating laboratories. Diabetologia 1992;35(8):798–800.

    PubMed  CAS  Google Scholar 

  42. Karlsson Faresjo M, Vaarala O, Thuswaldner S, Ilonen J, Hinkkanen A, Ludvigsson J. Diminished IFN-gamma response to diabetes-associated autoantigens in children at diagnosis and during follow up of type 1 diabetes. Diabetes Metab Res Rev 2006.

    Google Scholar 

  43. Toma A, Haddouk S, Briand JP, et al. Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients. Proc Natl Acad Sci USA 2005;102(30):10581–6.

    PubMed  CAS  Google Scholar 

  44. Tree TI, Duinkerken G, Willemen S, de Vries RR, Roep BO. HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65. Diabetes 2004;53(7):1692–9.

    PubMed  CAS  Google Scholar 

  45. Kent SC, Chen Y, Bregoli L, et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005;435(7039):224–8.

    PubMed  CAS  Google Scholar 

  46. Chatenoud L, Bach JF. Regulatory T cells in the control of autoimmune diabetes: the case of the NOD mouse. Int Rev Immunol 2005;24(3–4):247–67.

    PubMed  CAS  Google Scholar 

  47. Mathis D, Vence L, Benoist C. beta-Cell death during progression to diabetes. Nature 2001;414(6865):792–8.

    PubMed  CAS  Google Scholar 

  48. Leiter EH, von Herrath M. Animal models have little to teach us about type 1 diabetes: 2. In opposition to this proposal. Diabetologia 2004;47(10):1657–60.

    PubMed  CAS  Google Scholar 

  49. Keskinen P, Korhonen S, Kupila A, et al. First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes. Diabetologia 2002;45(12):1639–48.

    PubMed  CAS  Google Scholar 

  50. Krischer JP, Cuthbertson DD, Greenbaum C. Male sex increases the risk of autoimmunity but not type 1 diabetes. Diabetes Care 2004;27(8):1985–90.

    PubMed  Google Scholar 

  51. Roep BO, Arden SD, de Vries RR, Hutton JC. T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature 1990;345(6276):632–4.

    PubMed  CAS  Google Scholar 

  52. Vafiadis P, Ounissi-Benkalha H, Palumbo M, et al. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 2001;86(8):3705–10.

    PubMed  CAS  Google Scholar 

  53. Pugliese A, Brown D, Garza D, et al. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J Clin Invest 2001;107(5): 555–64.

    PubMed  CAS  Google Scholar 

  54. Ueno H. Enzymatic and structural aspects on glutamate decarboxylase. J Mol Catal B: Enzymatic 2000;10:67–79.

    CAS  Google Scholar 

  55. Bu DF, Erlander MG, Hitz BC, et al. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci USA 1992;89(6):2115–9.

    PubMed  CAS  Google Scholar 

  56. Bosma PT, Blazquez M, Collins MA, et al. Multiplicity of glutamic acid decarboxylases (GAD) in vertebrates: molecular phylogeny and evidence for a new GAD paralog. Mol Biol Evol 1999;16(3):397–404.

    PubMed  CAS  Google Scholar 

  57. Bu DF, Tobin AJ. The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD67 and GAD65) suggests that they derive from a common ancestral GAD. Genomics 1994;21(1):222–8.

    PubMed  CAS  Google Scholar 

  58. Strausbauch PH, Fischer EHB. Structure of the binding site of pyridoxal 5’-phosphate to Escherichia coli glutamate decarboxylase. Biochemistry 1970;20:233–8.

    Google Scholar 

  59. Dutyshev DI, Darii EL, Fomenkova NP, et al. Structure of Escherichia coli glutamate decarboxylase (GADalpha) in complex with glutarate at 2.05 angstroms resolution. Acta Crystallogr D Biol Crystallogr 2005;61(Pt 3):230–5.

    PubMed  CAS  Google Scholar 

  60. Capitani G, De Biase D, Aurizi C, Gut H, Bossa F, Grutter MG. Crystal structure and functional analysis of Escherichia coli glutamate decarboxylase. EMBO J 2003;22(16):4027–37.

    PubMed  CAS  Google Scholar 

  61. Schwartz HL, Chandonia JM, Kash SF, et al. High-resolution autoreactive epitope mapping and structural modeling of the 65 kDa form of human glutamic acid decarboxylase. J Mol Biol 1999;287(5):983–99.

    PubMed  CAS  Google Scholar 

  62. Padoa CJ, Banga JP, Madec AM, et al. Recombinant Fabs of human monoclonal antibodies specific to the middle epitope of GAD65 inhibit type 1 diabetes-specific GAD65Abs. Diabetes 2003;52(11):2689–95.

    PubMed  CAS  Google Scholar 

  63. Chen CH, Battaglioli G, Martin DL, Hobart SA, Colon W. Distinctive interactions in the holoenzyme formation for two isoforms of glutamate decarboxylase. Biochim Biophys Acta 2003;1645(1):63–71.

    PubMed  CAS  Google Scholar 

  64. Kanaani J, Lissin D, Kash SF, Baekkeskov S. The hydrophilic isoform of glutamate decarboxylase, GAD67, is targeted to membranes and nerve terminals independent of dimerization with the hydrophobic membrane-anchored isoform, GAD65. J Biol Chem 1999;274(52):37200–9.

    PubMed  CAS  Google Scholar 

  65. Namchuk M, Lindsay L, Turck CW, Kanaani J, Baekkeskov S. Phosphorylation of serine residues 3, 6, 10, and 13 distinguishes membrane anchored from soluble glutamic acid decarboxylase 65 and is restricted to glutamic acid decarboxylase 65alpha. J Biol Chem 1997;272(3):1548–57.

    PubMed  CAS  Google Scholar 

  66. Dirkx R, Jr., Thomas A, Li L, et al. Targeting of the 67-kDa isoform of glutamic acid decarboxylase to intracellular organelles is mediated by its interaction with the NH2-terminal region of the 65-kDa isoform of glutamic acid decarboxylase. J Biol Chem 1995;270(5):2241–6.

    PubMed  CAS  Google Scholar 

  67. Shi Y, Veit B, Baekkeskov S. Amino acid residues 24–31 but not palmitoylation of cysteines 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase, GAD65. J Cell Biol 1994;124(6):927–34.

    PubMed  CAS  Google Scholar 

  68. Rorsman P, Berggren PO, Bokvist K, et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 1989;341(6239):233–6.

    PubMed  CAS  Google Scholar 

  69. Wendt A, Birnir B, Buschard K, et al. Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes 2004;53(4):1038–45.

    PubMed  CAS  Google Scholar 

  70. Wang C, Kerckhofs K, Van de Casteele M, Smolders I, Pipeleers D, Ling Z. Glucose inhibits GABA release by pancreatic beta-cells through an increase in GABA shunt activity. Am J Physiol Endocrinol Metab 2006;290(3):E494–9.

    PubMed  CAS  Google Scholar 

  71. Hawa MI, Leslie RD. GAD antigen and its significance in type I diabetes. J Endocrinol Invest 2002;25(7):576.

    PubMed  CAS  Google Scholar 

  72. Pihoker C, Gilliam LK, Hampe CS, Lernmark A. Autoantibodies in diabetes. Diabetes 2005;54(Suppl 2):S52–61.

    PubMed  CAS  Google Scholar 

  73. Graham J, Hagopian WA, Kockum I, et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002;51(5):1346–55.

    PubMed  CAS  Google Scholar 

  74. Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 1999;42(1):3–14.

    PubMed  CAS  Google Scholar 

  75. Rolandsson O, Hagg E, Hampe C, et al. Glutamate decarboxylase (GAD65) and tyrosine phosphatase-like protein (IA-2) autoantibodies index in a regional population is related to glucose intolerance and body mass index. Diabetologia 1999;42(5):555–9.

    PubMed  CAS  Google Scholar 

  76. Weets I, Van Autreve J, Van der Auwera BJ, et al. Male-to-female excess in diabetes diagnosed in early adulthood is not specific for the immune-mediated form nor is it HLA-DQ restricted: possible relation to increased body mass index. Diabetologia 2001;44(1):40–7.

    PubMed  CAS  Google Scholar 

  77. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322(22):1555–60.

    PubMed  CAS  Google Scholar 

  78. Murinson BB. Stiff-person syndrome. Neurologist 2004;10(3):131–7.

    PubMed  Google Scholar 

  79. Lernmark A. Glutamic acid decarboxylase–gene to antigen to disease. J Intern Med 1996;240(5):259–77.

    PubMed  CAS  Google Scholar 

  80. Raju R, Foote J, Banga JP, et al. Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients. J Immunol 2005;175(11):7755–62.

    PubMed  CAS  Google Scholar 

  81. Kim J, Namchuk M, Bugawan T, et al. Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. J Exp Med 1994;180(2):595–606.

    PubMed  CAS  Google Scholar 

  82. Grubin CE, Daniels T, Toivola B, et al. A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 1994;37(4):344–50.

    PubMed  CAS  Google Scholar 

  83. Akamine H, Komiya I, Shimabukuro T, et al. High prevalence of GAD65 (and IA-2) antibodies in Japanese IDDM patients by a new immunoprecipitation assay based on recombinant human GAD65. Diabet Med 1997;14(9):778–84.

    PubMed  CAS  Google Scholar 

  84. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 1993;42(2):359–62.

    PubMed  CAS  Google Scholar 

  85. Hagopian WA, Karlsen AE, Gottsater A, et al. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest 1993;91(1):368–74.

    PubMed  CAS  Google Scholar 

  86. Brooking H, Ananieva-Jordanova R, Arnold C, et al. A sensitive non-isotopic assay for GAD65 autoantibodies. Clin Chim Acta 2003;331(1–2):55–9.

    PubMed  CAS  Google Scholar 

  87. Chen S, Willis J, Maclean C, et al. Sensitive non-isotopic assays for autoantibodies to IA-2 and to a combination of both IA-2 and GAD65. Clin Chim Acta 2005;357(1):74–83.

    PubMed  CAS  Google Scholar 

  88. Verge CF, Stenger D, Bonifacio E, et al. Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in type 1 diabetes: Combinatorial Islet Autoantibody Workshop. Diabetes 1998;47(12):1857–66.

    PubMed  CAS  Google Scholar 

  89. Atkinson MA, Bowman MA, Campbell L, Darrow BL, Kaufman DL, Maclaren NK. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest 1994;94(5):2125–9.

    PubMed  CAS  Google Scholar 

  90. Bergholdt R, Heding P, Nielsen K, et al. Type 1 database mellitus: an inflammatory disease of the islet. Adv Exp Med Biol 2004;552:129–53.

    PubMed  CAS  Google Scholar 

  91. Hampe CS, Hammerle LP, Bekris L, et al. Recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different GAD antibody-positive phenotypes. J Clin Endocrinol Metab 2000;85(12):4671–9.

    PubMed  CAS  Google Scholar 

  92. Ronkainen MS, Savola K, Knip M. Antibodies to GAD65 epitopes at diagnosis and over the first 10 years of clinical type 1 diabetes mellitus. Scand J Immunol 2004;59(3):334–40.

    PubMed  CAS  Google Scholar 

  93. Sanjeevi CB, Falorni A, Kockum I, Hagopian WA, Lernmark A. HLA and glutamic acid decarboxylase in human insulin-dependent diabetes mellitus. Diabet Med 1996;13(3):209–17.

    PubMed  CAS  Google Scholar 

  94. Borg H, Gottsater A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 2002;51(6):1754–62.

    PubMed  CAS  Google Scholar 

  95. Vandewalle CL, Falorni A, Svanholm S, Lernmark A, Pipeleers DG, Gorus FK. High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. The Belgian Diabetes Registry. J Clin Endocrinol Metab 1995;80(3):846–51.

    PubMed  CAS  Google Scholar 

  96. Hallengren B, Falorni A, Landin-Olsson M, Lernmark A, Papadopoulos KI, Sundkvist G. Islet cell and glutamic acid decarboxylase antibodies in hyperthyroid patients: at diagnosis and following treatment. J Intern Med 1996;239(1):63–8.

    PubMed  CAS  Google Scholar 

  97. Ou D, Jonsen LA, Metzger DL, Tingle AJ. CD4+ and CD8+ T-cell clones from congenital rubella syndrome patients with IDDM recognize overlapping GAD65 protein epitopes. Implications for HLA class I and II allelic linkage to disease susceptibility. Hum Immunol 1999;60(8):652–64.

    PubMed  CAS  Google Scholar 

  98. Kallan AA, Roep BO, Arden SD, Hutton JC, de Vries RR. Beta-cell reactive T-cell clones from type I diabetes patients are not beta cell specific and recognize multiple antigens. J Autoimmun 1995;8(6):887–99.

    PubMed  CAS  Google Scholar 

  99. Reijonen H, Daniels TL, Lernmark A, Nepom GT. GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65. Diabetes 2000;49(10):1621–6.

    PubMed  CAS  Google Scholar 

  100. Jaume JC, Parry SL, Madec AM, Sonderstrup G, Baekkeskov S. Suppressive effect of glutamic acid decarboxylase 65-specific autoimmune B lymphocytes on processing of T cell determinants located within the antibody epitope. J Immunol 2002;169(2):665–72.

    PubMed  CAS  Google Scholar 

  101. Reijonen H, Novak EJ, Kochik S, et al. Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes 2002;51(5):1375–82.

    PubMed  CAS  Google Scholar 

  102. Oling V, Marttila J, Ilonen J, et al. GAD65- and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects. J Autoimmun 2005;25(3):235–43.

    PubMed  Google Scholar 

  103. Schloot NC, Meierhoff G, Karlsson Faresjo M, et al. Comparison of cytokine ELISpot assay formats for the detection of islet antigen autoreactive T cells. Report of the third immunology of diabetes society T-cell workshop. J Autoimmun 2003;21(4):365–76.

    PubMed  CAS  Google Scholar 

  104. Nagata M, Kotani R, Moriyama H, Yokono K, Roep BO, Peakman M. Detection of autoreactive T cells in type 1 diabetes using coded autoantigens and an immunoglobulin-free cytokine ELISPOT assay: report from the fourth immunology of diabetes society T cell workshop. Ann N Y Acad Sci 2004;1037:10–5.

    PubMed  CAS  Google Scholar 

  105. Kaufman DL, Clare-Salzler M, Tian J, et al. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 1993;366(6450):69–72.

    PubMed  CAS  Google Scholar 

  106. Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 1993;366(6450):72–5.

    PubMed  CAS  Google Scholar 

  107. McDevitt H. Specific antigen vaccination to treat autoimmune disease. Proc Natl Acad Sci USA 2004;101(Suppl 2):14627–30.

    PubMed  CAS  Google Scholar 

  108. Li A, Ojogho O, Franco E, Baron P, Iwaki Y, Escher A. Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro. Vaccine 2006;24(23):5036–46.

    PubMed  CAS  Google Scholar 

  109. Lernmark A, Agardh CD. Immunomodulation with human recombinant autoantigens. Trends Immunol 2005;26(11):608–12.

    PubMed  CAS  Google Scholar 

  110. Agardh CD, Cilio CM, Lethagen A, et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J Diabetes Complications 2005;19(4):238–46.

    PubMed  Google Scholar 

  111. Rabin DU, Pleasic SM, Palmer-Crocker R, Shapiro JA. Cloning and expression of IDDM-specific human autoantigens. Diabetes 1992;41(2):183–6.

    PubMed  CAS  Google Scholar 

  112. Lan MS, Modi WS, Xie H, Notkins AL. Assignment of the IA-2 gene encoding an autoantigen in IDDM to chromosome 2q35. Diabetologia 1996;39(8):1001–2.

    PubMed  CAS  Google Scholar 

  113. Dirkx R, Jr., Hermel JM, Rabin DU, Solimena M. ICA 512, a receptor tyrosine phosphatase-like protein, is concentrated in neurosecretory granule membranes. Adv Pharmacol 1998;42:243–6.

    PubMed  CAS  Google Scholar 

  114. Notkins AL, Lu J, Li Q, et al. IA-2 and IA-2 beta are major autoantigens in IDDM and the precursors of the 40 kDa and 37 kDa tryptic fragments. J Autoimmun 1996;9(5):677–82.

    PubMed  CAS  Google Scholar 

  115. Xie H, Notkins AL, Lan MS. IA-2, a transmembrane protein tyrosine phosphatase, is expressed in human lung cancer cell lines with neuroendocrine phenotype. Cancer Res 1996;56(12):2742–4.

    PubMed  CAS  Google Scholar 

  116. Magistrelli G, Toma S, Isacchi A. Substitution of two variant residues in the protein tyrosine phosphatase-like PTP35/IA-2 sequence reconstitutes catalytic activity. Biochem Biophys Res Commun 1996;227(2):581–8.

    PubMed  CAS  Google Scholar 

  117. Verge CF, Gianani R, Yu L, et al. Late progression to diabetes and evidence for chronic beta-cell autoimmunity in identical twins of patients with type I diabetes. Diabetes 1995;44(10):1176–9.

    PubMed  CAS  Google Scholar 

  118. Morgenthaler NG, Lobner K, Morgenthaler UY, Christie MR, Seissler J, Scherbaum WA. Recombinant IA-2 expressed in E. coli can be used for the routine detection of autoantibodies in type-I diabetes. Horm Metab Res 1998;30(9):559–64.

    PubMed  CAS  Google Scholar 

  119. Westerlund A, Ankelo M, Ilonen J, Knip M, Simell O, Hinkkanen AE. Absence of avidity maturation of autoantibodies to the protein tyrosine phosphatase-like IA-2 molecule and glutamic acid decarboxylase (GAD65) during progression to type 1 diabetes. J Autoimmun 2005;24(2):153–67.

    PubMed  CAS  Google Scholar 

  120. Zhang B, Lan MS, Notkins AL. Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. Diabetes 1997;46(1):40–3.

    PubMed  Google Scholar 

  121. Bearzatto M, Lampasona V, Belloni C, Bonifacio E. Fine mapping of diabetes-associated IA-2 specific autoantibodies. J Autoimmun 2003;21(4):377–82.

    PubMed  CAS  Google Scholar 

  122. Vandewalle CL, Falorni A, Lernmark A, et al. Associations of GAD65- and IA-2-autoantibodies with genetic risk markers in new-onset IDDM patients and their siblings. The Belgian Diabetes Registry. Diabetes Care 1997;20(10):1547–52.

    PubMed  CAS  Google Scholar 

  123. Genovese S, Bonfanti R, Bazzigaluppi E, et al. Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM. Diabetologia 1996;39(10):1223–6.

    PubMed  CAS  Google Scholar 

  124. Hawkes CJ, Schloot NC, Marks J, et al. T-cell lines reactive to an immunodominant epitope of the tyrosine phosphatase-like autoantigen IA-2 in type 1 diabetes. Diabetes 2000;49(3):356–66.

    PubMed  CAS  Google Scholar 

  125. Honeyman MC, Stone NL, Harrison LC. T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-(2): potential for mimicry with rotavirus and other environmental agents. Mol Med 1998;4(4):231–9.

    PubMed  CAS  Google Scholar 

  126. Herzog BA, Ott PA, Dittrich MT, et al. Increased in vivo frequency of IA-2 peptide-reactive IFNgamma+/IL-4- T cells in type 1 diabetic subjects. J Autoimmun 2004;23(1):45–54.

    PubMed  CAS  Google Scholar 

  127. Williams AJ, Bingley PJ, Chance RE, Gale EA. Insulin autoantibodies: more specific than proinsulin autoantibodies for prediction of type 1 diabetes. J Autoimmun 1999;13(3):357–63.

    PubMed  CAS  Google Scholar 

  128. Uchigata Y, Hirata Y. Insulin autoimmune syndrome (IAS, Hirata disease). Ann Med Interne (Paris) 1999;150(3):245–53.

    CAS  Google Scholar 

  129. Hagopian WA, Sanjeevi CB, Kockum I, et al. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J Clin Invest 1995;95(4):1505–11.

    PubMed  CAS  Google Scholar 

  130. Castano L, Ziegler AG, Ziegler R, Shoelson S, Eisenbarth GS. Characterization of insulin autoantibodies in relatives of patients with type I diabetes. Diabetes 1993;42(8):1202–9.

    PubMed  CAS  Google Scholar 

  131. Williams AJ, Bingley PJ, Moore WP, Gale EA. Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes. Diabetologia 2002;45(2):217–23.

    PubMed  CAS  Google Scholar 

  132. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005;435(7039):220–3.

    PubMed  CAS  Google Scholar 

  133. Alleva DG, Crowe PD, Jin L, et al. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. J Clin Invest 2001;107(2):173–80.

    PubMed  CAS  Google Scholar 

  134. Lee KH, Wucherpfennig KW, Wiley DC. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2001;2(6):501–7.

    PubMed  CAS  Google Scholar 

  135. Kimura K, Kawamura T, Kadotani S, Inada H, Niihira S, Yamano T. Peptide-specific cytotoxicity of T lymphocytes against glutamic acid decarboxylase and insulin in type 1 diabetes mellitus. Diabetes Res Clin Pract 2001;51(3):173–9.

    PubMed  CAS  Google Scholar 

  136. Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial–Type 1. Diabetes Care 2005;28(5):1068–76.

    PubMed  CAS  Google Scholar 

  137. Roep BO, Atkinson MA, van Endert PM, Gottlieb PA, Wilson SB, Sachs JA. Autoreactive T cell responses in insulin-dependent (Type 1) diabetes mellitus. Report of the first international workshop for standardization of T cell assays. J Autoimmun 1999;13(2):267–82.

    PubMed  CAS  Google Scholar 

  138. Peakman M, Tree TI, Endl J, van Endert P, Atkinson MA, Roep BO. Characterization of preparations of GAD65, proinsulin, and the islet tyrosine phosphatase IA-2 for use in detection of autoreactive T-cells in type 1 diabetes: report of phase II of the Second International Immunology of Diabetes Society Workshop for Standardization of T-cell assays in type 1 diabetes. Diabetes 2001;50(8):1749–54.

    PubMed  CAS  Google Scholar 

  139. Pietropaolo M, Castano L, Babu S, et al. Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen. J Clin Invest 1993;92(1):359–71.

    PubMed  CAS  Google Scholar 

  140. Mally MI, Cirulli V, Hayek A, Otonkoski T. ICA69 is expressed equally in the human endocrine and exocrine pancreas. Diabetologia 1996;39(4):474–80.

    PubMed  CAS  Google Scholar 

  141. Pilon M, Peng XR, Spence AM, Plasterk RH, Dosch HM. The diabetes autoantigen ICA69 and its Caenorhabditis elegans homologue, ric-19, are conserved regulators of neuroendocrine secretion. Mol Biol Cell 2000;11(10):3277–88.

    PubMed  CAS  Google Scholar 

  142. Kasimiotis H, Fida S, Rowley MJ, et al. Antibodies to SOX13 (ICA12) are associated with type 1 diabetes. Autoimmunity 2001;33(2):95–101.

    PubMed  CAS  Google Scholar 

  143. Fida S, Myers MA, Whittingham S, Rowley MJ, Ozaki S, Mackay IR. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. J Autoimmun 2002;19(4):251–7.

    PubMed  Google Scholar 

  144. Davis TM, Mehta Z, Mackay IR, et al. Autoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetes. Diabet Med 2003;20(3):198–204.

    PubMed  CAS  Google Scholar 

  145. Alcalde L, Tonacchera M, Costagliola S, Jaraquemada D, Pujol-Borrell R, Ludgate M. Cloning of candidate autoantigen carboxypeptidase H from a human islet library: sequence identity with human brain CPH. J Autoimmun 1996;9(4):525–8.

    PubMed  CAS  Google Scholar 

  146. Zhou ZG, Yang L, Huang G. Diagnostic value of carboxypeptidase-H autoantibodies in detecting latent autoimmune diabetes in adults. Hunan Yi Ke Da Xue Xue Bao 2003;28(6):549–52.

    PubMed  CAS  Google Scholar 

  147. Buschard K, Blomqvist M, Osterbye T, Fredman P. Involvement of sulfatide in beta cells and type 1 and type 2 diabetes. Diabetologia 2005;48(10):1957–62.

    PubMed  CAS  Google Scholar 

  148. Andersson K, Buschard K, Fredman P, et al. Patients with insulin-dependent diabetes but not those with non-insulin-dependent diabetes have anti-sulfatide antibodies as determined with a new ELISA assay. Autoimmunity 2002;35(7):463–8.

    PubMed  Google Scholar 

  149. Ilyas AA, Mithen FA, Dalakas MC, et al. Antibodies to sulfated glycolipids in Guillain-Barre syndrome. J Neurol Sci 1991;105(1):108–17.

    PubMed  CAS  Google Scholar 

  150. Pestronk A, Li F, Griffin J, et al. Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein. Neurology 1991;41(3):357–62.

    PubMed  CAS  Google Scholar 

  151. Dotta F, Previti M, Neerman-Arbez M, et al. The GM2–1 ganglioside islet autoantigen in insulin-dependent diabetes mellitus is expressed in secretory granules and is not beta-cell specific. Endocrinology 1998;139(1):316–9.

    PubMed  CAS  Google Scholar 

  152. Dotta F, Falorni A, Tiberti C, et al. Autoantibodies to the GM2–1 islet ganglioside and to GAD-65 at type 1 diabetes onset. J Autoimmun 1997;10(6):585–8.

    PubMed  CAS  Google Scholar 

  153. Geluk A, van Meijgaarden KE, Roep BO, Ottenhoff TH. Altered peptide ligands of islet autoantigen Imogen 38 inhibit antigen specific T cell reactivity in human type-1 diabetes. J Autoimmun 1998;11(4):353–61.

    PubMed  CAS  Google Scholar 

  154. Arden SD, Roep BO, Neophytou PI, et al. Imogen 3(8): a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient. J Clin Invest 1996;97(2): 551–61.

    PubMed  CAS  Google Scholar 

  155. Aanstoot HJ, Kang SM, Kim J, et al. Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes. J Clin Invest 1996;97(12):2772–83.

    PubMed  CAS  Google Scholar 

  156. Winnock F, Christie MR, Batstra MR, et al. Autoantibodies to a 38-kDa glycosylated islet cell membrane-associated antigen in (pre)type 1 diabetes: association with IA-2 and islet cell autoantibodies. Diabetes Care 2001;24(7):1181–6.

    PubMed  CAS  Google Scholar 

  157. Arden SD, Zahn T, Steegers S, et al. Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein. Diabetes 1999;48(3):531–42.

    PubMed  CAS  Google Scholar 

  158. Lieberman SM, Evans AM, Han B, et al. Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA 2003;100(14):8384–8.

    PubMed  CAS  Google Scholar 

  159. Yang J, Danke NA, Berger D, et al. Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol 2006;176(5):2781–9.

    PubMed  CAS  Google Scholar 

  160. Li M, Fisher WE, Kim HJ, et al. Somatostatin, somatostatin receptors, and pancreatic cancer. World J Surg 2005;29(3):293–6.

    PubMed  Google Scholar 

  161. Patel YC, Greenwood MT, Panetta R, Demchyshyn L, Niznik H, Srikant CB. The somatostatin receptor family. Life Sci 1995;57(13):1249–65.

    PubMed  CAS  Google Scholar 

  162. Krantic S. Peptides as regulators of the immune system: emphasis on somatostatin. Peptides 2000;21(12):1941–64.

    PubMed  CAS  Google Scholar 

  163. Wang XP, Norman MA, Brunicardi FC. Somatostatin receptors and autoimmune-mediated diabetes. Diabetes Metab Res Rev 2005;21(1):15–30.

    PubMed  Google Scholar 

  164. Haskins K. Pathogenic T-cell clones in autoimmune diabetes: more lessons from the NOD mouse. Adv Immunol 2005;87:123–62.

    PubMed  Google Scholar 

  165. Tisch R, Wang B, Atkinson MA, Serreze DV, Friedline R. A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice. J Immunol 2001;166(11):6925–36.

    PubMed  CAS  Google Scholar 

  166. Achenbach P, Kelemen K, Wegmann DR, Hutton JC. Spontaneous peripheral T-cell responses to the IA-2beta (phogrin) autoantigen in young nonobese diabetic mice. J Autoimmun 2002;19(3):111–6.

    PubMed  Google Scholar 

  167. Kelemen K, Wegmann DR, Hutton JC. T-cell epitope analysis on the autoantigen phogrin (IA-2beta) in the nonobese diabetic mouse. Diabetes 2001;50(8):1729–34.

    PubMed  CAS  Google Scholar 

  168. Trigwell SM, Radford PM, Page SR, et al. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin Exp Immunol 2001;126(2):242–9.

    PubMed  CAS  Google Scholar 

  169. van Gaalen F, Ioan-Facsinay A, Huizinga TW, Toes RE. The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis. J Immunol 2005;175(9):5575–80.

    PubMed  Google Scholar 

  170. Westman E, Harris HE. Alteration of an autoantigen by chlorination, a process occurring during inflammation, can overcome adaptive immune tolerance. Scand J Immunol 2004;59(5):458–63.

    PubMed  CAS  Google Scholar 

  171. Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002;2(9):647–55.

    PubMed  CAS  Google Scholar 

  172. Binder CJ, Shaw PX, Chang MK, et al. The role of natural antibodies in atherogenesis. J Lipid Res 2005;46(7):1353–63.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. Anastasia Katsarou MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbro Holm PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristian Lynch MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Åke Lernmark PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Anthony P. Weetman MD,DSc

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this chapter

Cite this chapter

Katsarou, A., Holm, B., Lynch, K., Lernmark, Å. (2007). Islet Cell Autoantigens. In: Weetman, A.P. (eds) Autoimmune Diseases in Endocrinology. Contemporary Endocrinology. Humana Press. https://doi.org/10.1007/978-1-59745-517-6_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-517-6_11

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-733-4

  • Online ISBN: 978-1-59745-517-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation