Search tips
Search criteria 


Logo of molmedLink to Publisher's site
Mol Med. 1998 April; 4(4): 231–239.
PMCID: PMC2230363

T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents.


The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes. The dominant epitope, VIVMLTPLVEDGVKQC (aa 805-820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75-45% identity and 88-64% similarity over 8-14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71-100% similar over 7-12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80-82% similar over 10-11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate beta-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Rabin DU, Pleasic SM, Shapiro JA, Yoo-Warren H, Oles J, Hicks JM, Goldstein DE, Rae PM. Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. J Immunol. 1994 Mar 15;152(6):3183–3188. [PubMed]
  • 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 May;13(5):505–514. [PubMed]
  • Solimena M, Dirkx R, Jr, Hermel JM, Pleasic-Williams S, Shapiro JA, Caron L, Rabin DU. ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J. 1996 May 1;15(9):2102–2114. [PubMed]
  • Bonifacio E, Lampasona V, Genovese S, Ferrari M, Bosi E. Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. J Immunol. 1995 Dec 1;155(11):5419–5426. [PubMed]
  • Cui L, Yu WP, DeAizpurua HJ, Schmidli RS, Pallen CJ. Cloning and characterization of islet cell antigen-related protein-tyrosine phosphatase (PTP), a novel receptor-like PTP and autoantigen in insulin-dependent diabetes. J Biol Chem. 1996 Oct 4;271(40):24817–24823. [PubMed]
  • Notkins AL, Lu J, Li Q, VanderVegt FP, Wasserfall C, Maclaren NK, Lan MS. 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 Oct;9(5):677–682. [PubMed]
  • Hawkes CJ, Wasmeier C, Christie MR, Hutton JC. Identification of the 37-kDa antigen in IDDM as a tyrosine phosphatase-like protein (phogrin) related to IA-2. Diabetes. 1996 Sep;45(9):1187–1192. [PubMed]
  • Durinovic-Bellò I, Hummel M, Ziegler AG. Cellular immune response to diverse islet cell antigens in IDDM. Diabetes. 1996 Jun;45(6):795–800. [PubMed]
  • Hammer J, Bono E, Gallazzi F, Belunis C, Nagy Z, Sinigaglia F. Precise prediction of major histocompatibility complex class II-peptide interaction based on peptide side chain scanning. J Exp Med. 1994 Dec 1;180(6):2353–2358. [PMC free article] [PubMed]
  • Sinigaglia F, Romagnoli P, Guttinger M, Takacs B, Pink JR. Selection of T cell epitopes and vaccine engineering. Methods Enzymol. 1991;203:370–386. [PubMed]
  • Jones DB, Crosby I. Proliferative lymphocyte responses to virus antigens homologous to GAD65 in IDDM. Diabetologia. 1996 Nov;39(11):1318–1324. [PubMed]
  • Rudy G, Stone N, Harrison LC, Colman PG, McNair P, Brusic V, French MB, Honeyman MC, Tait B, Lew AM. Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes. Mol Med. 1995 Sep;1(6):625–633. [PMC free article] [PubMed]
  • Van Eden W, Anderton SM, Van Der Zee R, Prakken BJ, Broeren CP, Wauben MH. (Altered) self peptides and the regulation of self reactivity in the peripheral T cell pool. Immunol Rev. 1996 Feb;149:55–73. [PubMed]
  • Schloot NC, Roep BO, Wegmann DR, Yu L, Wang TB, Eisenbarth GS. T-cell reactivity to GAD65 peptide sequences shared with coxsackie virus protein in recent-onset IDDM, post-onset IDDM patients and control subjects. Diabetologia. 1997 Mar;40(3):332–338. [PubMed]
  • Kumar D, Gemayel NS, Deapen D, Kapadia D, Yamashita PH, Lee M, Dwyer JH, Roy-Burman P, Bray GA, Mack TM. North-American twins with IDDM. Genetic, etiological, and clinical significance of disease concordance according to age, zygosity, and the interval after diagnosis in first twin. Diabetes. 1993 Sep;42(9):1351–1363. [PubMed]
  • Yoon JW, Austin M, Onodera T, Notkins AL. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med. 1979 May 24;300(21):1173–1179. [PubMed]
  • Forrest JM, Menser MA, Burgess JA. High frequency of diabetes mellitus in young adults with congenital rubella. Lancet. 1971 Aug 14;2(7720):332–334. [PubMed]
  • Karam JH, Lewitt PA, Young CW, Nowlain RE, Frankel BJ, Fujiya H, Freedman ZR, Grodsky GM. Insulinopenic diabetes after rodenticide (Vacor) ingestion: a unique model of acquired diabetes in man. Diabetes. 1980 Dec;29(12):971–978. [PubMed]
  • Foulis AK, McGill M, Farquharson MA, Hilton DA. A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia. 1997 Jan;40(1):53–61. [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]
  • 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]
  • Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. [PubMed]
  • Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. [PubMed]
  • Hyöty H, Hiltunen M, Knip M, Laakkonen M, Vähäsalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes. 1995 Jun;44(6):652–657. [PubMed]
  • Brusic V, Rudy G, Kyne AP, Harrison LC. MHCPEP--a database of MHC-binding peptides: update 1995. Nucleic Acids Res. 1996 Jan 1;24(1):242–244. [PMC free article] [PubMed]
  • Patel SD, Cope AP, Congia M, Chen TT, Kim E, Fugger L, Wherrett D, Sonderstrup-McDevitt G. Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(alpha1*0101,beta1*0401) transgenic mice. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8082–8087. [PubMed]
  • Heath RR, Stagg S, Xu F, McCrae MA. Mapping of the target antigens of the rotavirus-specific cytotoxic T cell response. J Gen Virol. 1997 May;78(Pt 5):1065–1075. [PubMed]
  • Verge CF, Howard NJ, Irwig L, Simpson JM, Mackerras D, Silink M. Environmental factors in childhood IDDM. A population-based, case-control study. Diabetes Care. 1994 Dec;17(12):1381–1389. [PubMed]
  • Bishop RF, Unicomb LE, Barnes GL. Epidemiology of rotavirus serotypes in Melbourne, Australia, from 1973 to 1989. J Clin Microbiol. 1991 May;29(5):862–868. [PMC free article] [PubMed]
  • Rott LS, Rosé JR, Bass D, Williams MB, Greenberg HB, Butcher EC. Expression of mucosal homing receptor alpha4beta7 by circulating CD4+ cells with memory for intestinal rotavirus. J Clin Invest. 1997 Sep 1;100(5):1204–1208. [PMC free article] [PubMed]
  • Paronen J, Klemetti P, Kantele JM, Savilahti E, Perheentupa J, Akerblom HK, Vaarala O. Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gut-specific homing receptor alpha4beta7-integrin. Diabetes. 1997 Apr;46(4):583–588. [PubMed]
  • Hänninen A, Salmi M, Simell O, Jalkanen S. Mucosa-associated (beta 7-integrinhigh) lymphocytes accumulate early in the pancreas of NOD mice and show aberrant recirculation behavior. Diabetes. 1996 Sep;45(9):1173–1180. [PubMed]
  • Harrison LC. Cow's milk and IDDM. Lancet. 1996 Oct 5;348(9032):905–906. [PubMed]
  • Cavallo MG, Fava D, Monetini L, Barone F, Pozzilli P. Cell-mediated immune response to beta casein in recent-onset insulin-dependent diabetes: implications for disease pathogenesis. Lancet. 1996 Oct 5;348(9032):926–928. [PubMed]
  • Hoorfar J, Buschard K, Dagnaes-Hansen F. Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice. Br J Nutr. 1993 Mar;69(2):597–607. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ