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Mol Med. 1995 September; 1(6): 625–633.
PMCID: PMC2229979

Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes.


BACKGROUND: Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM. MATERIALS AND METHODS: Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay. RESULTS: Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects. CONCLUSIONS: This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

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  • Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK, Paquette TL. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 1983 Dec 23;222(4630):1337–1339. [PubMed]
  • Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P, Camilli PD. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. [PubMed]
  • Honeyman MC, Harrison LC. The immunologic insult in type 1 diabetes. Springer Semin Immunopathol. 1993;14(3):253–274. [PubMed]
  • Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR. In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med. 1985 Aug 8;313(6):353–360. [PubMed]
  • Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man--macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991 Oct;165(2):97–103. [PubMed]
  • Hänninen A, Jalkanen S, Salmi M, Toikkanen S, Nikolakaros G, Simell O. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest. 1992 Nov;90(5):1901–1910. [PMC free article] [PubMed]
  • Hanafusa T, Miyazaki A, Miyagawa J, Tamura S, Inada M, Yamada K, Shinji Y, Katsura H, Yamagata K, Itoh N, et al. Examination of islets in the pancreas biopsy specimens from newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia. 1990 Feb;33(2):105–111. [PubMed]
  • Itoh N, Hanafusa T, Miyazaki A, Miyagawa J, Yamagata K, Yamamoto K, Waguri M, Imagawa A, Tamura S, Inada M, et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest. 1993 Nov;92(5):2313–2322. [PMC free article] [PubMed]
  • Sibley RK, Sutherland DE, Goetz F, Michael AF. Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest. 1985 Aug;53(2):132–144. [PubMed]
  • Harrison LC. Islet cell antigens in insulin-dependent diabetes: Pandora's box revisited. Immunol Today. 1992 Sep;13(9):348–352. [PubMed]
  • Böhmer K, Keilacker H, Kuglin B, Hübinger A, Bertrams J, Gries FA, Kolb H. Proinsulin autoantibodies are more closely associated with type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies. Diabetologia. 1991 Nov;34(11):830–834. [PubMed]
  • Ziegler AG, Hillebrand B, Rabl W, Mayrhofer M, Hummel M, Mollenhauer U, Vordemann J, Lenz A, Standl E. On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia. 1993 May;36(5):402–408. [PubMed]
  • Harrison LC, De Aizpurua H, Loudovaris T, Campbell IL, Cebon JS, Tait BD, Colman PG. Reactivity to human islets and fetal pig proislets by peripheral blood mononuclear cells from subjects with preclinical and clinical insulin-dependent diabetes. Diabetes. 1991 Sep;40(9):1128–1133. [PubMed]
  • Harrison LC, Chu SX, DeAizpurua HJ, Graham M, Honeyman MC, Colman PG. Islet-reactive T cells are a marker of preclinical insulin-dependent diabetes. J Clin Invest. 1992 Apr;89(4):1161–1165. [PMC free article] [PubMed]
  • Honeyman MC, Cram DS, Harrison LC. Glutamic acid decarboxylase 67-reactive T cells: a marker of insulin-dependent diabetes. J Exp Med. 1993 Feb 1;177(2):535–540. [PMC free article] [PubMed]
  • 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 Nov;94(5):2125–2129. [PMC free article] [PubMed]
  • Lohmann T, Leslie RD, Hawa M, Geysen M, Rodda S, Londei M. Immunodominant epitopes of glutamic acid decarboxylase 65 and 67 in insulin-dependent diabetes mellitus. Lancet. 1994 Jun 25;343(8913):1607–1608. [PubMed]
  • Wegmann DR, Norbury-Glaser M, Daniel D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol. 1994 Aug;24(8):1853–1857. [PubMed]
  • Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. [PubMed]
  • Davidson HW, Rhodes CJ, Hutton JC. Intraorganellar calcium and pH control proinsulin cleavage in the pancreatic beta cell via two distinct site-specific endopeptidases. Nature. 1988 May 5;333(6168):93–96. [PubMed]
  • Schmidli RS, DeAizpurua HJ, Harrison LC, Colman PG. Antibodies to glutamic acid decarboxylase in at-risk and clinical insulin-dependent diabetic subjects: relationship to age, sex and islet cell antibody status, and temporal profile. J Autoimmun. 1994 Feb;7(1):55–66. [PubMed]
  • Snorgaard O, Hartling SG, Binder C. Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990 Jan;33(1):36–42. [PubMed]
  • Heaton DA, Millward BA, Gray IP, Tun Y, Hales CN, Pyke DA, Leslie RD. Increased proinsulin levels as an early indicator of B-cell dysfunction in non-diabetic twins of type 1 (insulin-dependent) diabetic patients. Diabetologia. 1988 Mar;31(3):182–184. [PubMed]
  • Hartling SG, Lindgren F, Dahlqvist G, Persson B, Binder C. Elevated proinsulin in healthy siblings of IDDM patients independent of HLA identity. Diabetes. 1989 Oct;38(10):1271–1274. [PubMed]
  • Lindgren FA, Hartling SG, Persson BE, Röder ME, Snellman K, Binder C, Dahlquist G. Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers. Diabetologia. 1993 Jun;36(6):560–563. [PubMed]
  • Spinas GA, Snorgaard O, Hartling SG, Oberholzer M, Berger W. Elevated proinsulin levels related to islet cell antibodies in first-degree relatives of IDDM patients. Diabetes Care. 1992 May;15(5):632–637. [PubMed]
  • Kuglin B, Gries FA, Kolb H. Evidence of IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment. Diabetes. 1988 Jan;37(1):130–132. [PubMed]
  • Kuglin B, Halder B, Bertrams J, Grüneklee D, Gries FA, Kolb H. Proinsulin autoantibodies: association with type I diabetes but not with islet cell antibodies, insulin autoantibodies or HLA-DR type. J Autoimmun. 1990 Oct;3(5):573–577. [PubMed]
  • Luo AM, Garza KM, Hunt D, Tung KS. Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation. J Clin Invest. 1993 Nov;92(5):2117–2123. [PMC free article] [PubMed]
  • Hurtenbach U, Lier E, Adorini L, Nagy ZA. Prevention of autoimmune diabetes in non-obese diabetic mice by treatment with a class II major histocompatibility complex-blocking peptide. J Exp Med. 1993 May 1;177(5):1499–1504. [PMC free article] [PubMed]
  • Taki T, Nagata M, Ogawa W, Hatamori N, Hayakawa M, Hari J, Shii K, Baba S, Yokono K. Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD/Shi/Kbe mice by anti-MHC class I Kd monoclonal antibody. Diabetes. 1991 Sep;40(9):1203–1209. [PubMed]
  • Romero P, Corradin G, Luescher IF, Maryanski JL. H-2Kd-restricted antigenic peptides share a simple binding motif. J Exp Med. 1991 Sep 1;174(3):603–612. [PMC free article] [PubMed]
  • Reich EP, von Grafenstein H, Barlow A, Swenson KE, Williams K, Janeway CA., Jr Self peptides isolated from MHC glycoproteins of non-obese diabetic mice. J Immunol. 1994 Mar 1;152(5):2279–2288. [PubMed]
  • Deng H, Apple R, Clare-Salzler M, Trembleau S, Mathis D, Adorini L, Sercarz E. Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease. J Exp Med. 1993 Nov 1;178(5):1675–1680. [PMC free article] [PubMed]
  • Tian J, Lehmann PV, Kaufman DL. T cell cross-reactivity between coxsackievirus and glutamate decarboxylase is associated with a murine diabetes susceptibility allele. J Exp Med. 1994 Nov 1;180(5):1979–1984. [PMC free article] [PubMed]
  • Butler MH, Solimena M, Dirkx R, Jr, Hayday A, De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med. 1993 Dec 1;178(6):2097–2106. [PMC free article] [PubMed]
  • Richter W, Shi Y, Baekkeskov S. Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2832–2836. [PubMed]
  • Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med. 1995 May 1;181(5):1835–1845. [PMC free article] [PubMed]
  • Graham S, Wang EC, Jenkins O, Borysiewicz LK. Analysis of the human T-cell response to picornaviruses: identification of T-cell epitopes close to B-cell epitopes in poliovirus. J Virol. 1993 Mar;67(3):1627–1637. [PMC free article] [PubMed]
  • Lin RH, Mamula MJ, Hardin JA, Janeway CA., Jr Induction of autoreactive B cells allows priming of autoreactive T cells. J Exp Med. 1991 Jun 1;173(6):1433–1439. [PMC free article] [PubMed]
  • Campbell IL, Oxbrow L, West J, Harrison LC. Regulation of MHC protein expression in pancreatic beta-cells by interferon-gamma and tumor necrosis factor-alpha. Mol Endocrinol. 1988 Feb;2(2):101–107. [PubMed]
  • Campbell IL, Cutri A, Wilkinson D, Boyd AW, Harrison LC. Intercellular adhesion molecule 1 is induced on isolated endocrine islet cells by cytokines but not by reovirus infection. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4282–4286. [PubMed]
  • 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 Nov 4;366(6450):72–75. [PubMed]

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