Molecular Targets of the Autoimmunity of Type I Diabetes

  • Massimo Pietropaolo
  • George S. Eisenbarth


One feature of many autoimmune diseases is a humoral autoimmune response against multiple antigens of a given tissue. Although the pathogenic significance of autoantibodies in type I diabetes is unclear, they serve both as essential markers that an autoimmune response has been initiated and as probes to identify their target autoantigens (1–5).


Influenza Trypsin Oligosaccharide Glucagon Hypoglycemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Eisenbarth GS: Type I diabetes mellitus: a chronic autoimmune disease. N Engl J Med 314:1360–1368, 1986.CrossRefGoogle Scholar
  2. 2.
    Bottazzo GF, Genovese S, Bosi E, Dean BM, Christie MR, Bonifacio E: Novel considerations on the antibody/autoantigen system in type I (insulin-dependent) diabetes mellitus. Ann Med 23:453–461, 1991.CrossRefGoogle Scholar
  3. 3.
    Harrison LC: Islet cell antigens in insulin-dependent diabetes: Pandora’s box revisited. Immunol Today 13:348–352, 1992.CrossRefGoogle Scholar
  4. 4.
    Maclaren N, Lafferty K: Perspectives in diabetes: The 12th international immunology and diabetes workshop. Diabetes 42:1099–1104, 1993.CrossRefGoogle Scholar
  5. 5.
    Tan EM: Autoantibodies in pathology and cell biology. Cell 67:841–842, 1991.CrossRefGoogle Scholar
  6. 6.
    Palmer JP, Asplin CM, Clemons P, et al.: Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337–1339, 1983.CrossRefGoogle Scholar
  7. 7.
    Ziegler AG, Ziegler R, Vardi P, Jackson RA, Soeldner JS, Eisenbarth GS: Life table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes. Diabetes 38:1320–1325, 1989.CrossRefGoogle Scholar
  8. 8a.
    Wegmann D, Norbury-Glaser M, and Daniel D: Insulin specific T cells are a predominant component of islet-specific T cells isolated from islet infiltrates of pre-diabetic NOD mice. Eur J Immunol, in press.Google Scholar
  9. 8.
    Castaño L, Ziegler A, Ziegler R, Shoelson S, Eisenbarth GS: Characterization of insulin autoantibodies in relatives of patients with insulin-dependent diabetes mellitus. Diabetes 42:1202–1209, 1993.CrossRefGoogle Scholar
  10. 9.
    Zhang JZ, Davidson L, Eisenbarth GS, Weiner HL: Suppression of diabetes in non-obese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 88:10252–10256, 1991.CrossRefGoogle Scholar
  11. 10.
    Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL: Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor B after antigen-specific triggering. Proc Natl Acad Sci USA 421:425,1992.Google Scholar
  12. 11.
    Todd JA, Mijovic C, Fletcher J, Jenkins D, Bradwell AR, Barnett AH: Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338:587–589, 1989.CrossRefGoogle Scholar
  13. 12.
    Baekkeskov S, Aanstoot H, Christgau S, et al.: Identification of the 64K autoantigen in insulin dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156, 1990.CrossRefGoogle Scholar
  14. 13.
    Christgau S, Aanstoot HJ, Schierbeck H, et al.: Membrane anchoring of the autoantigen GAD65 to micro vesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol 118(2):309–320, 1992.CrossRefGoogle Scholar
  15. 14.
    Karlsen AE, Hagopian WA, Grubin CE, et al.: Cloning and primary structure of a human isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci USA 88:8337–8341, 1991.CrossRefGoogle Scholar
  16. 15.
    Solimena M, Folli F, Denis-Donini S, et al.: Autoantibodies to glutamic acid decarboxylase in a patient with stiffman syndrome, epilepsy, and type I diabetes mellitus. N Eng J Med 318:1012–1020, 1988.CrossRefGoogle Scholar
  17. 16.
    Harrison LC, Honeyman MC, DeAizpurua HJ, et al.: Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 341: 1365–1369, 1993.CrossRefGoogle Scholar
  18. 17.
    Gianani R, Pugliese A, Bonner-Weir S, et al.: Prognostically significant heterogeneity of cytoplasmic islet cell antibodies in relatives of patients with type I diabetes. Diabetes 41:347–353, 1992.CrossRefGoogle Scholar
  19. 18.
    Rorsman P, Berggren PO, Bokvist K, et al.: Glucose-inhibition of glucagon secretion involves activation of GABA-receptor chloride channels. Nature 341:233,234, 1989.CrossRefGoogle Scholar
  20. 19.
    Petersen JS, Russel S, Marshall MO, et al.: Differential expression of glutamic acid decarboxylase in rat and human islets. Diabetes 42:484–495, 1993.CrossRefGoogle Scholar
  21. 20.
    Velloso LA, Kampe O, Hallberg A, Christmanson L, Betsholtz C, Karlsson FA: Demonstration of GAD-65 as the main immunogenic isoform of glutamate decarboxylase in type I diabetes and determination of autoantibodies using a radiogland produced by eukaryotic expression. J Clin Invest 91:2084–2090, 1993.CrossRefGoogle Scholar
  22. 21.
    Deres K, Schild H, Wiesmuller KH, Jung G, Rammensee HG: In vivo priming of virus-specific cytotoxic T lymphocytes with lipopeptide vaccine. Nature 342:561–564, 1989.CrossRefGoogle Scholar
  23. 22.
    Gianani R, Jackson R, Eisenbarth GS: Evidence that the autoantigen of restricted ICA is GAD. Diabetes Res Clin Prac 14(suppl 1):S13 (abstract), 1991.Google Scholar
  24. 23.
    Pietropaolo M, Castaño 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; 92:359–371.CrossRefGoogle Scholar
  25. 24.
    Karjalainen J, Martin JM, Knip M, et al.: A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 327:302–307, 1992.CrossRefGoogle Scholar
  26. 25.
    Karjalainen J, Cheung R, Vandermeulen J, Martin JM, Knip M: T cell proliferation response against bovine albumin (BSA) follows the natural course and is restricted to the linear ABBOS sequence in insulin-dependent diabetes mellitus (IDDM). Autoimmunity (suppl):62 (abstract), 1993.Google Scholar
  27. 26.
    Luo A-M, Garza KM, Hunt D, Tung KSK: Antigen mimicry in autoimmune disease. Sharing of amino acid residues critical for pathogenic T cell activation. J Clin Invest 92:2117–2123, 1993.CrossRefGoogle Scholar
  28. 27.
    Freimer ML, Mclnstosh K, Adams RA, Alving CR, Drachman DB: Ganglio-sides elicit a T-cell independent antibody response. J Autoimmun 6:281–289, 1993.CrossRefGoogle Scholar
  29. 28.
    Dotta F, Colman PG, Nayak RC, et al.: Ganglioside expression in human pancreatic islets. Diabetes 38:1478–1483, 1989.CrossRefGoogle Scholar
  30. 29.
    Dotta F, Gianani R, Dionisi S, Tiberti C, Eisenbarth GS, DiMario U: Expression of anti-GM2-l islet ganglioside antibodies in ICA+ relatives of type I diabetics. Autoimmunity (suppl):70 (abstract), 1993.Google Scholar
  31. 30.
    Davidson HW, Rhodes CJ, Hutton JC: Intraorganellar calcium and pH control proinsulin cleavage in the pancreatic A cell via two distinct site-specific endopeptidases. Nature 333:93–96, 1988.CrossRefGoogle Scholar
  32. 31.
    Castano L, Russo E, Zhou L, Lipes MA, Eisenbarth GS: Identification and cloning of a granule autoantigen (carboxypeptidase H) associated with type I diabetes. J Clin Endocrinol Metab 73:1197–1201, 1991.CrossRefGoogle Scholar
  33. 32.
    Davidson HW, Hutton JC: The insulin-secretory-granule carboxypeptidase H. Biochem J 245:575–582, 1993.Google Scholar
  34. 33.
    Christie MR, Hollands JA, Brown TJ, Michelsen BK, Delovitch TL: Detection of pancreatic islet 64,000 Mr autoantigens in insulin-dependent diabetes distinct from glutamate decarboxylase. J Clin Invest 92:240–248, 1993.CrossRefGoogle Scholar
  35. 34.
    Christie MR, Richard YM, Tun RYM, et al.: Antibodies to GAD and tryptic fragments of islet 64K antigen as distinct markers for development of IDDM: Studies with identical twins. Diabetes 41:782–787, 1992.CrossRefGoogle Scholar
  36. 35.
    Honeyman MC, Cram DS, Harrison LC: Transcription factor jun-B is target of autoreactive T-cells in IDDM. Diabetes 1993 (in press).Google Scholar
  37. 36.
    Pak CY, Cha CY, Rajotte RV, McArthur RG, Yoon YW: Human pancreatic islet cell specific 38 kilodalton autoantigen identified by cytomegalovirus-induced monoclonal islet cell autoantibody. Diabetologia 33:569–572, 1990.CrossRefGoogle Scholar
  38. 37.
    Karounos DG, Simmerman L, Hickman SL, Jacob RJ: Identification of the p52-Rubella related autoantigen as an insulin secretory granule protein. Diabetes 42(Suppl 1):221A (abstract), 1993.Google Scholar
  39. 38.
    Thomas NM, Ginsberg-Fellner F, McEvoy RC: Strong association between diabetes and displacement of mouse anti-rat insulinoma cell monoclonal antibody by human serum in vitro. Diabetes 39:1203–1211, 1990.CrossRefGoogle Scholar
  40. 39.
    Pan Y-X, Thomas NM, McEvoy RC: Purification and partial characterization of 160 kD and 155 kD B cell membrane antigens detected by MAb 1A2. Autoimmunity (suppl):77 (abstract), 1993.Google Scholar
  41. 40.
    Buschard K, Josefsen K, Horn T, Larsen S, Fredman P: Sulphatide and anti-sulphatide antibodies in type I diabetes mellitus. Diabetes 42(Suppl 1): 5A (abstract), 1993.Google Scholar
  42. 41.
    Johnson JH, Crider BP, McCorkle K, Alford M, Unger RH: Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. N Engl J Med 322:653–659, 1990.CrossRefGoogle Scholar
  43. 42.
    Trucco M, Ricordi C, Weidman E, Rodriquez-Rilo H, Trucco G, Finegold D: Involvement of superantigens in the etiology of IDDM. Diabetes 42(Suppl 1):4A, 1993.Google Scholar
  44. 43.
    Elias D, Reshef T, Birk OS, Zee R, Walker MD, Cohen IR: Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kD heat shock protein. Proc Natl Acad Sci USA 88:3088–3091, 1991.CrossRefGoogle Scholar
  45. 44.
    Jones DB, Hunter NR, Duff GW: Heat-shock protein 65 as a B cell antigen of insulin-dependent diabetes. Lancet 336:583–585, 1990.CrossRefGoogle Scholar
  46. 45.
    Kaufman SHE: Heat shock proteins and the immune response. Immunol Today 11:129–136, 1990.CrossRefGoogle Scholar
  47. 46.
    Boitard C, Villa MC, Becourt C, et al.: Peripherin: An islet antigen that is cross-reactive with non-obese diabetic mouse class II gene products. Proc Natl Acad Sci USA 89:172–176, 1992.CrossRefGoogle Scholar
  48. 47.
    Pietropaolo M, Buelow R, Gianani R, Yu L, Eisenbarth GS: Independent assortment of biochemically defined autoantibodies in prediabetic relatives. J Immunol 150:166A (abstract), 1993.Google Scholar
  49. 48.
    Bingley PJ, Christie MR, Bonfanti R, et al.: Combined analysis of autoantibodies enhances prediction of IDDM in islet cell antibody (ICA) positive relatives. Autoimmunity (suppl):67 (abstract), 1993.Google Scholar
  50. 49.
    Eisenbarth GS, Verge CF, Allen H, Rewers MJ: Perspectives in diabetes: The design of trials for the prevention of IDDM. Diabetes 42:941–947, 1993.CrossRefGoogle Scholar
  51. 50.
    Maul GG, French BT, van Venrooij WJ, Jimenez SA: Topoisomerase I identified by scleroderma 70 antisera: enrichment of topoisomerase I at the centromere in mouse mitotic cells before anaphase. Proc Natl Acad Sci USA 83:5245–5149, 1986.CrossRefGoogle Scholar
  52. 51.
    Boitard C: The differentiation of the immune system towards anti-islet autoimmunity. Clinical aspects. Diabetologia 35:1101–1112, 1992.CrossRefGoogle Scholar
  53. 52.
    Haskins K, McDuffie M: Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science 249:1433–1436, 1990.CrossRefGoogle Scholar
  54. 53.
    Roep BO, Kalian AA, Hazenbos WLW, et al.: T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes. Lancet 337:1439–1441, 1991.CrossRefGoogle Scholar
  55. 54.
    Atkinson MA, Kaufman DL, Campbell L, et al.: Response of peripheralblood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339:458,459, 1992.CrossRefGoogle Scholar
  56. 55.
    Latchman D: No diabetes link to hsp65? Nature 356:114, 1992.CrossRefGoogle Scholar
  57. 56.
    Calcinaro F, Hao L, Chase HP, Klingensmith G, Lafferty KJ: Detection of cell-mediated immunity in type I diabetes mellitus. J Autoimmun 5:137–147, 1992.CrossRefGoogle Scholar
  58. 57.
    Erlich HA, Griffith RL, Bugawan TL, Ziegler R, Alper C, Eisenbarth GS: Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Diabetes 40:478–481, 1991.CrossRefGoogle Scholar
  59. 58.
    Atkinson MA, Maclaren NK: What causes diabetes? Sci Am 263:62–71, 1990.CrossRefGoogle Scholar
  60. 59.
    Nishimoto H, Kikutani H, Yamamura K, Kishimoto T: Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. Nature 328:432–434, 1987.CrossRefGoogle Scholar
  61. 60.
    Reich EP, Janeway C, Rath S, Sherwin RS: Islet specific T cell clones from diabetes NOD mice can cause histological insulitis. Diabetes 38(Suppl 2): 13 A, 1989.Google Scholar
  62. 61.
    Lipes MA, Rosenzweig A, Tan K, et al.: Progression to diabetes in nonobese diabetic (NOD) mice with transgenic T cell receptors. Science 259:1165–1169, 1993.CrossRefGoogle Scholar
  63. 62.
    Strominger JL: Biology of the human histocompatibility leukocyte antigen (HLA) system and a hypothesis regarding the generation of autoimmune disease. J Clin Invest 77:1411–1415, 1986.CrossRefGoogle Scholar
  64. 63.
    Wicker LS, Miller BJ, Mullen Y: Transfer of autoimmune diabetes mellitus with splenocytes from non-obese diabetic (NOD) mice. Diabetes 35(8): 855–860, 1986.CrossRefGoogle Scholar
  65. 64.
    Bendelac A, Carnaud C, Boitard C, Bach JF: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T-cells. J Exp Med 166:823–832, 1987.CrossRefGoogle Scholar
  66. 65.
    Miller BJ, Appel MC, O’Neil JJ, Wicker LS: Both the LYT-2+ and L3T4+ T cell subsets are required for the transfer of diabetes in non-obese diabetic mice. J Immunol 140:52–58, 1992.Google Scholar
  67. 66.
    Hutchings P, Simpson E, O’Reilly LA, Lund T, Waldmann H, Cooke A: The involvment of Lyt2+ T cells in beta cell destruction. J Autoimmun 3:101–109, 1990.CrossRefGoogle Scholar
  68. 67.
    Bendelac A, Boitard C, Bedossa P, Bazin H, Bach JF, Carnaud C: Adoptive T cell transfer does not require recruitment of host B lymphocytes. J Immunol 141:2625–2628, 1988.Google Scholar
  69. 68.
    Candeias S, Katz J, Benoist C, Mathis D, Haskins K: Islet-specific T cell clones from non-obese diabetic mice express heterogenous T cell receptors. Proc Natl Acad Sci USA 88:6167, 1991.CrossRefGoogle Scholar
  70. 69.
    Nomikos IN, Wang Y, Lafferty KJ: Involvement of O2 radicals in “autoimmune” diabetes. Immun Cell Biol 67:85–87, 1989.CrossRefGoogle Scholar
  71. 70.
    Stewart TA, Hultgren B, Huang X, Pitts-Meek S, Hully J, Maclachlan NJ: Induction of type I diabetes by interferon-a in transgenic mice. Science 260:1942–1946, 1993.CrossRefGoogle Scholar
  72. 71.
    Debray-Sachs M, Carnaud C, Boitard C, et al.: Prevention of diabetes in NOD mice treated with antibody to murine IFN-g. J Autoimmun 4:237–248, 1991.CrossRefGoogle Scholar
  73. 72.
    Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA: Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-g. Cell 52:773–782, 1988.CrossRefGoogle Scholar
  74. 73.
    Shehadeh NN, LaRosa F, Lafferty KJ: Altered cytokine activity in adjuvant inhibition of autoimmune diabetes. J Autoimmun 6:291–300, 1993.CrossRefGoogle Scholar
  75. 74.
    Foulis AK, McGill M, Farquharson MA: Insulitis in type I (insulin-dependent) diabetes mellitus in man-macrophages, and interferon-g containing cells. J Pathol 165:97–103, 1991.CrossRefGoogle Scholar
  76. 75.
    Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M: Cytotoxicity of human pl7 interleukin-1 for pancreatic islets of Langerhans. Science 232:1545–1547, 1986.CrossRefGoogle Scholar
  77. 76.
    Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH: Affinity-purified human interleukin-1 is cytotoxic to isolated islets of Langerhans. Diabetologia 29:63–67, 1986.CrossRefGoogle Scholar
  78. 77.
    Sutton R, Gray DWR, McShane P, Dallman P, Morris PJ: The specificity of rejection and the absence of susceptibility of pancreatic islet beta cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat. J Exp Med 170:751–762, 1989.CrossRefGoogle Scholar
  79. 78.
    Campbell IL, Oxbrow L, Harrison LC: Reduction in insulitis following administration of IFN-g and TNF-alpha in the NOD mouse. J Autoimmun 4:249–262, 1991.CrossRefGoogle Scholar
  80. 79.
    Jacob CO, Also S, Michie S, McDevitt HO, Acha-Orbea H: Prevention of diabetes in non-obese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha interleukin 1. Proc Natl Acad Sci USA 87:968–972, 1990.CrossRefGoogle Scholar
  81. 80.
    Weiner HL, Mackin GA, Matsui M, et al.: Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 1321: 1324, 1993.Google Scholar
  82. 81.
    Gaur A, Wiers B, Liu A, Rothbard J, Fathman CG: Amelioration of autoimmune encephalitis by myelin basic protein synthetic peptide-induced anergy. Science 258:1491–1494, 1992.CrossRefGoogle Scholar
  83. 82.
    Nussenblatt RB, Caspi R, Mahdi R, et al.: Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol 144:1689–1695. 1990.Google Scholar
  84. 83.
    Zhang JZ, Lee CS, Lider O, Weiner HL: Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. J Immunol 145:2489–2493, 1990.Google Scholar
  85. 84.
    Gottsfredsen CF, Buschard K, Frandsen EK: Reduction of diabetes incidence of BB Wistar rats by early prophylactic insulin treatment of diabetes-prone animals. Diabetologia 28:933–935, 1985.CrossRefGoogle Scholar
  86. 85.
    Keller RJ, Eisenbarth GS, Jackson RA: Insulin prophylaxis in individuals at high risk of type I diabetes. Lancet 341:927–928, 1993.CrossRefGoogle Scholar
  87. 86.
    Appel MC, Dotta F, O’Neill J, Eisenbarth GS: Beta cell activity regulates the expression of islet antigen determinant. Diabetologia 32:461A (abstract), 1989.Google Scholar
  88. 87.
    Anderson GD, Banerjee S, Luthra HS, David CS: Role of Mls-1 locus and clonal deletion of T cells in susceptibility to collagen-induced arthritis in mice. J Immunol 147:1189–1193, 1991.Google Scholar
  89. 88.
    Guberski DL, Thomas VA, Shek WR, et al.: Induction of type 1 diabetes by Kilham’s rat virus in diabetes-resistant BB/Wor rats. Science 254:1010–1013, 1991.CrossRefGoogle Scholar
  90. 89.
    Oldstone C: Prevention of type I diabetes in non-obese diabetic mice by virus infection. Science 239:500–502, 1987.CrossRefGoogle Scholar
  91. 90.
    Horn GT, Bugawan TL, Long CM, Erlich HA: Allelic sequence variation of the HLA-DQ loci: Relationship to serology and to insulin-dependent diabetes mellitus susceptibility. Proc Natl Acad Sci USA 85:6012–6016, 1988.CrossRefGoogle Scholar
  92. 91.
    Yoon JW, Austin M, Onodera T, Notkins AL: Isolation of a virus from the pancreas of achild with diabetic ketoacidosis. N Engl J Med 300(21): 1173–1179, 1979.CrossRefGoogle Scholar
  93. 92.
    Howard M, O’Garra A: Biological properties of interleukin 10. Immunol Today 13:198–200, 1992.CrossRefGoogle Scholar
  94. 93.
    Elliott RB, Martin JM: Dietary protein: a trigger of insulin dependent diabetes in the BB rat. Diabetologia 26:297–299, 1984.CrossRefGoogle Scholar
  95. 94.
    Martin JM, Trink B, Daneman D, Dosch H, Robinson B: Milk proteins in the etiology of insulin-dependent diabetes mellitus (IDDM). Ann Med 23:447–452, 1991.CrossRefGoogle Scholar
  96. 95.
    Kostraba JN, Cruickshanks KJ, Lawler-Heavner J, et al.: Early exposure to cow’s milk and solid foods in infancy, genetic predisposition and risk of IDDM. Diabetes 42:288–295, 1993.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Massimo Pietropaolo
  • George S. Eisenbarth

There are no affiliations available

Personalised recommendations