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Horm Metab Res 2002; 34(10): 596-600
DOI: 10.1055/s-2002-35422
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

IgG1 Subclass Dominates Autoimmune Response to Tyrosine Phosphatase-Like Molecule IA-2 in Chinese Type 1 Diabetes Patients

W.  Y.  Ng1 , K.  F.  Lui1 , J.  S.  Cheah1 , A.  C.  Thai1
  • 1Department of Medicine, National University of Singapore, Republic of Singapore
Further Information

Publication History

Received: 13 February 2002

Accepted after revision: 24 July 2002

Publication Date:
19 November 2002 (online)

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Abstract

Background and Aims: Islet autoantibodies are known markers for type 1 diabetes with an immune-mediated basis; their isotype or subclass profiles may also provide clues to changes in immune response during disease or after intervention. For ICAs and GADab, the IgG1 subclass consistently dominates in recent-onset disease. The aims of our study were to determine the isotype patterns for IA-2ab in Asian Chinese patients with autoimmune diabetes. Materials and Methods: From an initial screening of over 400 diabetes patients, 40 subjects (mean age 22.2 ± 15.8 years) with IA-2ab were enrolled for this study. IA-2ab was detected by radioimmunoassay of [35S]-labelled recombinant human IA-2ic(605 - 979). Of them, 31 (median age 15 years, range 2 - 57 years; 16 children) had clinical type 1 diabetes (that is, they required insulin at onset or within 1 year) with the majority having been recently diagnosed (< 1 year). The other 9 patients had clinical type 2 diabetes phenotype. Results: IA-2ab IgG subclasses determined with monospecific secondary antibodies showed that both type 1 diabetic adults and children had similarly non-restricted isotype patterns with a strong presence of IgG1-IA-2ab. The rank order was IgG1 > 3 > 2 > 4; 15 subjects had detectable IgG4-IA-2ab. Clonality of immune response determined with kappa/lambda chain-specific antibodies also showed a non-restricted pattern. Patients aged 38.2 ± 15.2 years with type 2 diabetes had broad patterns of isotypes - IgG1/3 was detected more frequently (n = 8) than IgG2/4 (n = 5). Of three patients on insulin treatment, one was also positive for GADab. The remaining 6 patients were on oral hypoglycaemic treatment. IA-2ab in type 2 diabetes showed a low titre compared to type 1 diabetes. Conclusions: Isotype responses to IA-2 had a strong IgG1 presence, similar to ICAs and GADab. With IgG3 subclass representation, a predominant Th1 milieu in the systemic environment is likely. There is no suggestion of differences in immune response to IA-2 between adults and children with type 1 diabetes.

Key words

IA-2 Antibodies - Isotypes - Immune-Mediated Diabetes

References

  • 1 Liblau R S, Singer S M, McDevitt H O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.  Immunol Today. 1995;  16 34-38
    CrossrefPubMedGoogle Scholar
  • 2 Rabinovitch A. Immunoregulatory and cytokine imbalance in the pathogeneisis of IDDM. Therapeutic intervention by immunostimulation?.  Diabetes. 1994;  43 613-621
    PubMedGoogle Scholar
  • 3 De Carli M, D’Elios M M, Zancuoghi G, Romagnani S, Del Prete G. Human Th1 and Th2 cells: functional properties, regulation of development and role in autoimmunity.  Autoimmunity. 1994;  18 301-308
    PubMedGoogle Scholar
  • 4 Widhe M, Ekerfelt C, Forsberg P, Bergstrom S, Ernerudh J. IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease.  Scand J Immunol. 1998;  47 575-581
    PubMedGoogle Scholar
  • 5 Sousa A O, Henry S, Maroja F M, Lee F K, Brum L, Singh M, Lagrange P H, Aucouturier P. IgG subclass distribution of antibody response to protein and polysaccharide mycobacterial antigens in leprosy and tuberculosis patients.  Clin Exp Immunol. 1998;  111 48-55
    CrossrefPubMedGoogle Scholar
  • 6 Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler A-G. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation.  J Immunol. 1999;  163 525-532
    PubMedGoogle Scholar
  • 7 Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult).  Diabetes Care. 2001;  24 1460-1467
    CrossrefPubMedGoogle Scholar
  • 8 Tuomi T, Carlsson A, Li H, Isomaa A, Miettinen A, Nissen M, Ehrnstrom B-J, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen M-R, Groop L C. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.  Diabetes. 1999;  48 150-157
    CrossrefPubMedGoogle Scholar
  • 9 Ng W Y, Thai A C, Lui K F, Yeo P PB, Cheah J S. Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients.  Diabetes Res Clin Pract. 1999;  43 127-135
    CrossrefPubMedGoogle Scholar
  • 10 Ng W Y, Thai A C, Lui K F, Yeo P PB, Cheah J S. Non-restricted immunoglobulin-G subclass islet cell antibodies in Chinese.  Autoimmunity. 1993;  15 305-309
    PubMedGoogle Scholar
  • 11 Lan M S, Lu J, Goto Y, Notkins A L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2 from human insulinoma.  DNA Cell Biol. 1994;  13 505-514
    PubMedGoogle Scholar
  • 12 Lan M S, Wasserfall N K, Maclaren N H, Notkins A L. IA-2, a transmembranous protein of the protein tyrosine phosphatases family, is a major autoantigen in insulin-dependent diabetes mellitus.  Proc Natl Acad Sci USA. 1996;  93 63-67
    PubMedGoogle Scholar
  • 13 Zhang B, Lan M, Notkins A. Autoantibodies to IA-2 in IDDM: location of major antigenic determinants.  Diabetes. 1997;  46 40-43
    PubMedGoogle Scholar
  • 14 Dozio N, Belloni C, Girardi A M, Genovese S, Sodoyez J C, Bottazzo G F, Pozza G, Bosi E. Heterogenous IgG subclass distribution of islet cell antibodies.  J Autoimmun. 1994;  7 45-53
    CrossrefPubMedGoogle Scholar
  • 15 Millward A, Hussain M J, Peakman M, Pyke D A, Leslie R D, Vergani D. Characterization of islet cell antibody in insulin dependent diabetes: evidence for IgG1 subclass restriction and polyclonality.  Clin Exp Immunol. 1988;  71 353-356
    PubMedGoogle Scholar
  • 16 Schatz D A, Barrett D J, Maclaren N K, Riley W J. Polyclonal nature of islet cell antibodies in insulin-dependent diabetes.  Autoimmunity. 1988;  1 45-50
    PubMedGoogle Scholar
  • 17 Omar M A, Srikanta S, Eisenbarth G S. Human islet cell antibodies: immunoglobulin class and subclass distribution defined by monoclonal antibodies.  Diabetes Res. 1987;  4 155-157
    PubMedGoogle Scholar
  • 18 Kasuga A, Shimada A, Ozawa Y, Maruyama T, Oya K, Saruta T. IgG1 is the dominant subclass of antibody against glutamic acid decarboxylase among type 1 diabetes in Japanese.  Endocr J. 2000;  47 57-62
    PubMedGoogle Scholar
  • 19 Petersen J S, Kulmala P, Clausen J T, Knip M, Dyrberg T, and the Childhood Diabetes in Finland Study Group. Progression to type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65).  Clin Immunol Immunopathol. 1999;  90 276-281
    PubMedGoogle Scholar
  • 20 Couper J J, Harrison L C, Aldis J JE, Colman P G, Honeyman M C, Ferrante A. IgG subclass antibodies to glutamic acid decarboxylase and risk for progression to clinical insulin-dependent diabetes.  Hum Immunol. 1998;  59 493-499
    CrossrefPubMedGoogle Scholar
  • 21 Hawa M, Fava D, Medici F, Deng Y-J, Notkins A L, De Mattia G, Leslie R DG. Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes.  Diabetes Care. 2000;  23 228-233
    PubMedGoogle Scholar
  • 22 Seissler J, Elkamp K, Schott M, Scherbaum W A, DENIS Study Group. IA-2 autoantibodies restricted to the IgG4 subclass are associated with protection from type 1 diabetes.  Horm Metab Res. 2002;  34 186-191
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Lohmann T, Kellner K, Verlohren H-J, Krug J, Steindorf J, Scherbaum W A, Seissler J. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA).  Diabetologia. 2001;  44 1005-1010
    CrossrefPubMedGoogle Scholar

A. C. Thai

Dept of Medicine, National University Hospital

5 Lower Kent Ridge Road · Singapore 119074 · Republic of Singapore ·

Phone: + 65-67724352

Fax: + 65-67794112

Email: mdctac@nus.edu.sg

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