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. 1996 Jun 15;97(12):2772–2783. doi: 10.1172/JCI118732

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.

H J Aanstoot 1, S M Kang 1, J Kim 1, L A Lindsay 1, U Roll 1, M Knip 1, M Atkinson 1, P Mose-Larsen 1, S Fey 1, J Ludvigsson 1, et al.
PMCID: PMC507370  PMID: 8675688

Abstract

Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 M(r). Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD65, glima 38, and IA2 antibodies in the same groups was 91 and 84%, respectively. GAD65, IA2, and glima 38 represent three distinct targets of immunoprecipitating IgG autoantibodies associated with beta cell destruction and type 1 diabetes.

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Selected References

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  1. Aanstoot H. J., Sigurdsson E., Jaffe M., Shi Y., Christgau S., Grobbee D., Bruining G. J., Molenaar J. L., Hofman A., Baekkeskov S. Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. Diabetologia. 1994 Sep;37(9):917–924. doi: 10.1007/BF00400948. [DOI] [PubMed] [Google Scholar]
  2. Arden S. D., Roep B. O., Neophytou P. I., Usac E. F., Duinkerken G., de Vries R. R., Hutton J. C. Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient. J Clin Invest. 1996 Jan 15;97(2):551–561. doi: 10.1172/JCI118448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Atkinson M. A., Maclaren N. K., Scharp D. W., Lacy P. E., Riley W. J. 64,000 Mr autoantibodies as predictors of insulin-dependent diabetes. Lancet. 1990 Jun 9;335(8702):1357–1360. doi: 10.1016/0140-6736(90)91241-2. [DOI] [PubMed] [Google Scholar]
  4. Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. 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. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
  5. Baekkeskov S., Landin M., Kristensen J. K., Srikanta S., Bruining G. J., Mandrup-Poulsen T., de Beaufort C., Soeldner J. S., Eisenbarth G., Lindgren F. Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes. J Clin Invest. 1987 Mar;79(3):926–934. doi: 10.1172/JCI112903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Baekkeskov S., Nielsen J. H., Marner B., Bilde T., Ludvigsson J., Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature. 1982 Jul 8;298(5870):167–169. doi: 10.1038/298167a0. [DOI] [PubMed] [Google Scholar]
  7. Baekkeskov S., Warnock G., Christie M., Rajotte R. V., Larsen P. M., Fey S. Revelation of specificity of 64K autoantibodies in IDDM serums by high-resolution 2-D gel electrophoresis. Unambiguous identification of 64K target antigen. Diabetes. 1989 Sep;38(9):1133–1141. doi: 10.2337/diab.38.9.1133. [DOI] [PubMed] [Google Scholar]
  8. Bruining G. J., Molenaar J. L., Grobbee D. E., Hofman A., Scheffer G. J., Bruining H. A., de Bruyn A. M., Valkenburg H. A. Ten-year follow-up study of islet-cell antibodies and childhood diabetes mellitus. Lancet. 1989 May 20;1(8647):1100–1103. doi: 10.1016/s0140-6736(89)92383-0. [DOI] [PubMed] [Google Scholar]
  9. Castaño L., Russo E., Zhou L., Lipes M. A., Eisenbarth G. S. Identification and cloning of a granule autoantigen (carboxypeptidase-H) associated with type I diabetes. J Clin Endocrinol Metab. 1991 Dec;73(6):1197–1201. doi: 10.1210/jcem-73-6-1197. [DOI] [PubMed] [Google Scholar]
  10. Christgau S., Aanstoot H. J., Schierbeck H., Begley K., Tullin S., Hejnaes K., Baekkeskov S. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol. 1992 Jul;118(2):309–320. doi: 10.1083/jcb.118.2.309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Christgau S., Schierbeck H., Aanstoot H. J., Aagaard L., Begley K., Kofod H., Hejnaes K., Baekkeskov S. Pancreatic beta cells express two autoantigenic forms of glutamic acid decarboxylase, a 65-kDa hydrophilic form and a 64-kDa amphiphilic form which can be both membrane-bound and soluble. J Biol Chem. 1991 Nov 5;266(31):21257–21264. [PubMed] [Google Scholar]
  12. Christie M. R., Vohra G., Champagne P., Daneman D., Delovitch T. L. Distinct antibody specificities to a 64-kD islet cell antigen in type 1 diabetes as revealed by trypsin treatment. J Exp Med. 1990 Sep 1;172(3):789–794. doi: 10.1084/jem.172.3.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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 Aug;31(8):597–602. doi: 10.1007/BF00264766. [DOI] [PubMed] [Google Scholar]
  14. Cooke A. An overview on possible mechanisms of destruction of the insulin-producing beta cell. Curr Top Microbiol Immunol. 1990;164:125–142. doi: 10.1007/978-3-642-75741-9_7. [DOI] [PubMed] [Google Scholar]
  15. Efrat S., Linde S., Kofod H., Spector D., Delannoy M., Grant S., Hanahan D., Baekkeskov S. Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9037–9041. doi: 10.1073/pnas.85.23.9037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gorsuch A. N., Spencer K. M., Lister J., McNally J. M., Dean B. M., Bottazzo G. F., Cudworth A. G. Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus. Lancet. 1981 Dec 19;2(8260-61):1363–1365. doi: 10.1016/s0140-6736(81)92795-1. [DOI] [PubMed] [Google Scholar]
  17. Greenbaum C. J., Palmer J. P., Nagataki S., Yamaguchi Y., Molenaar J. L., Van Beers W. A., MacLaren N. K., Lernmark A. Improved specificity of ICA assays in the Fourth International Immunology of Diabetes Serum Exchange Workshop. Diabetes. 1992 Dec;41(12):1570–1574. doi: 10.2337/diab.41.12.1570. [DOI] [PubMed] [Google Scholar]
  18. Honeyman M. C., Cram D. S., Harrison L. C. Transcription factor jun-B is target of autoreactive T-cells in IDDM. Diabetes. 1993 Apr;42(4):626–630. doi: 10.2337/diab.42.4.626. [DOI] [PubMed] [Google Scholar]
  19. Karjalainen J. K. Islet cell antibodies as predictive markers for IDDM in children with high background incidence of disease. Diabetes. 1990 Sep;39(9):1144–1150. doi: 10.2337/diab.39.9.1144. [DOI] [PubMed] [Google Scholar]
  20. Karjalainen J., Martin J. M., Knip M., Ilonen J., Robinson B. H., Savilahti E., Akerblom H. K., Dosch H. M. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med. 1992 Jul 30;327(5):302–307. doi: 10.1056/NEJM199207303270502. [DOI] [PubMed] [Google Scholar]
  21. Karounos D. G., Thomas J. W. Recognition of common islet antigen by autoantibodies from NOD mice and humans with IDDM. Diabetes. 1990 Sep;39(9):1085–1090. doi: 10.2337/diab.39.9.1085. [DOI] [PubMed] [Google Scholar]
  22. Ko I. Y., Ihm S. H., Yoon J. W. Studies on autoimmunity for initiation of beta-cell destruction. VIII. Pancreatic beta-cell dependent autoantibody to a 38 kilodalton protein precedes the clinical onset of diabetes in BB rats. Diabetologia. 1991 Aug;34(8):548–554. doi: 10.1007/BF00400271. [DOI] [PubMed] [Google Scholar]
  23. Landin-Olsson M., Nilsson K. O., Lernmark A., Sundkvist G. Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus. Diabetologia. 1990 Sep;33(9):561–568. doi: 10.1007/BF00404145. [DOI] [PubMed] [Google Scholar]
  24. Lernmark A., Molenaar J. L., van Beers W. A., Yamaguchi Y., Nagataki S., Ludvigsson J., Maclaren N. K. The Fourth International Serum Exchange Workshop to standardize cytoplasmic islet cell antibodies. The Immunology and Diabetes Workshops and Participating Laboratories. Diabetologia. 1991 Jul;34(7):534–535. doi: 10.1007/BF00403293. [DOI] [PubMed] [Google Scholar]
  25. Martínez de la Escalera G., Choi A. L., Weiner R. I. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1852–1855. doi: 10.1073/pnas.89.5.1852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mauch L., Abney C. C., Berg H., Scherbaum W. A., Liedvogel B., Northemann W. Characterization of a linear epitope within the human pancreatic 64-kDa glutamic acid decarboxylase and its autoimmune recognition by sera from insulin-dependent diabetes mellitus patients. Eur J Biochem. 1993 Mar 1;212(2):597–603. doi: 10.1111/j.1432-1033.1993.tb17698.x. [DOI] [PubMed] [Google Scholar]
  27. Nayak R. C., Omar M. A., Rabizadeh A., Srikanta S., Eisenbarth G. S. "Cytoplasmic" islet cell antibodies. Evidence that the target antigen is a sialoglycoconjugate. Diabetes. 1985 Jun;34(6):617–619. doi: 10.2337/diab.34.6.617. [DOI] [PubMed] [Google Scholar]
  28. Okada Y., Taniguchi H., Schimada C. High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma. Science. 1976 Nov 5;194(4265):620–622. doi: 10.1126/science.185693. [DOI] [PubMed] [Google Scholar]
  29. Okey A. B., Bondy G. P., Mason M. E., Nebert D. W., Forster-Gibson C. J., Muncan J., Dufresne M. J. Temperature-dependent cytosol-to-nucleus translocation of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in continuous cell culture lines. J Biol Chem. 1980 Dec 10;255(23):11415–11422. [PubMed] [Google Scholar]
  30. Palmer J. P., Asplin C. M., Clemons P., Lyen K., Tatpati O., Raghu P. K., Paquette T. L. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 1983 Dec 23;222(4630):1337–1339. doi: 10.1126/science.6362005. [DOI] [PubMed] [Google Scholar]
  31. Passini N., Larigan J. D., Genovese S., Appella E., Sinigaglia F., Rogge L. The 37/40-kilodalton autoantigen in insulin-dependent diabetes mellitus is the putative tyrosine phosphatase IA-2. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9412–9416. doi: 10.1073/pnas.92.20.9412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Payton M. A., Hawkes C. J., Christie M. R. 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 Sep;96(3):1506–1511. doi: 10.1172/JCI118188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Powers A. C., Efrat S., Mojsov S., Spector D., Habener J. F., Hanahan D. Proglucagon processing similar to normal islets in pancreatic alpha-like cell line derived from transgenic mouse tumor. Diabetes. 1990 Apr;39(4):406–414. doi: 10.2337/diab.39.4.406. [DOI] [PubMed] [Google Scholar]
  34. Preis P. N., Saya H., Nádasdi L., Hochhaus G., Levin V., Sadée W. Neuronal cell differentiation of human neuroblastoma cells by retinoic acid plus herbimycin A. Cancer Res. 1988 Nov 15;48(22):6530–6534. [PubMed] [Google Scholar]
  35. Rabin D. U., Pleasic S. M., Palmer-Crocker R., Shapiro J. A. Cloning and expression of IDDM-specific human autoantigens. Diabetes. 1992 Feb;41(2):183–186. doi: 10.2337/diab.41.2.183. [DOI] [PubMed] [Google Scholar]
  36. Radvanyi F., Christgau S., Baekkeskov S., Jolicoeur C., Hanahan D. Pancreatic beta cells cultured from individual preneoplastic foci in a multistage tumorigenesis pathway: a potentially general technique for isolating physiologically representative cell lines. Mol Cell Biol. 1993 Jul;13(7):4223–4232. doi: 10.1128/mcb.13.7.4223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Richter W., Jury K. M., Loeffler D., Manfras B. J., Eiermann T. H., Boehm B. O. Immunoglobulin variable gene analysis of human autoantibodies reveals antigen-driven immune response to glutamate decarboxylase in type 1 diabetes mellitus. Eur J Immunol. 1995 Jun;25(6):1703–1712. doi: 10.1002/eji.1830250633. [DOI] [PubMed] [Google Scholar]
  38. 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. doi: 10.1073/pnas.90.7.2832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schmidli R. S., Colman P. G., Bonifacio E., Bottazzo G. F., Harrison L. C. High level of concordance between assays for glutamic acid decarboxylase antibodies. The First International Glutamic Acid Decarboxylase Antibody Workshop. Diabetes. 1994 Aug;43(8):1005–1009. doi: 10.2337/diab.43.8.1005. [DOI] [PubMed] [Google Scholar]
  40. Schütte J., Viallet J., Nau M., Segal S., Fedorko J., Minna J. jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell. 1989 Dec 22;59(6):987–997. doi: 10.1016/0092-8674(89)90755-1. [DOI] [PubMed] [Google Scholar]
  41. Srikanta S., Ganda O. P., Jackson R. A., Gleason R. E., Kaldany A., Garovoy M. R., Milford E. L., Carpenter C. B., Soeldner J. S., Eisenbarth G. S. Type I diabetes mellitus in monozygotic twins: chronic progressive beta cell dysfunction. Ann Intern Med. 1983 Sep;99(3):320–326. doi: 10.7326/0003-4819-99-3-320. [DOI] [PubMed] [Google Scholar]
  42. Svejgaard A., Ryder L. P. HLA and insulin-dependent diabetes: an overview. Genet Epidemiol. 1989;6(1):1–14. doi: 10.1002/gepi.1370060104. [DOI] [PubMed] [Google Scholar]

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