IA-2 Autoantibodies Restricted to the IgG4 Subclass are Associated with Protection from Type 1 Diabetes

Abstract

The tyrosine phosphatase-like protein IA-2 is a major target antigen for autoantibodies in the preclinical period of type 1 diabetes. In this study, we examined whether immunoglobulin isotypes and IgG subclass specific autoantibodies directed at IA-2 discriminate between children at risk of type 1 diabetes who progressed to diabetes vs. those who remained diabetes-free. IgG1-4, IgA and the IgE-specific IA-2 antibody (IA-2A) were measured by radioligand assays in 50 patients with type 1 diabetes and 41 ICA-positive siblings of patients with type 1 diabetes who were followed for diabetes development. Of 41 siblings, 32 were positive for IA-2A; of these, 59 % had IA-2 IgG1, 59 % IgG4, 16 % IgG3, 9 % IgG2, 16 % IgA and 13 % IgE antibodies. IA-2 IgG1 was the dominant isotype in prediabetic children (n = 14, 86 % positive) and patients with type 1 diabetes (98 % positive) whereas only 7 of 18 (39 %) non-progressors had antibodies of this isotype. In subjects that remained diabetes-free, a significantly higher frequency of IA-2 IgG4 in the absence of IgG1 was observed (50 %) compared to progressors (7 %) and patients with type 1 diabetes (0 %). Life-table analysis revealed that IA-2A restricted to IgG4 correlated with protection from type 1 diabetes (p < 0.003). In contrast, IA-2 IgG2, IgG3, IgE and IgA did not differ significantly between study groups. Our findings suggest that the measurement of IA-2 IgG1 and IgG4 subclass antibodies can serve as surrogate marker to discriminate between antibody positive subjects at high or low risk for rapid development of diabetes.

IA-2 - Autoantibodies - Isotype - Prediction - Type 1 Diabetes

References

• 1 Schranz D B, Lernmark A. Immunology in diabetes: an update.  Diabetes Metab Rev. 1998;  14 3-29
• 2 Christie M R, Roll U, Payton M A, Hatfield E C, Ziegler A G. Validity of screening for individuals at risk for type I diabetes by combined analysis of antibodies to recombinant proteins.  Diabetes Care. 1997;  20 965-970
• 3 Pastore M R, Bazzigaluppi E, Bonfanti R et al. Two-step islet autoantibody screening for risk assessment of type 1 diabetes in relatives.  Diabetes Care. 1998;  21 1445-1450
• 4 Dittler J, Seidel D, Schenker M, Ziegler A G. GADIA2-combi determination as first-line screening for improved prediction of type 1 diabetes in relatives.  Diabetes. 1998;  47 592-597
• 5 Kulmala P, Savola K, Petersen J S et al. Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study.  J Clin Invest. 1998;  101 327-336
• 6 Seissler J, Morgenthaler N G, Achenbach P et al. Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM.  Diabetologia. 1996;  39 1351-1356
• 7 Christie M R, Genovese S, Cassidy D et al. Antibodies to islet 37k antigen, but not to glutamate decarboxylase, discriminate rapid progression to IDDM in endocrine autoimmunity.  Diabetes. 1994;  43 1254-1259
• 8 Bingley P J, Christie M R, Bonifacio E et al. Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives.  Diabetes. 1994;  43 1304-1310
• 9 Bonifacio E, Genovese S, Braghi S et al. Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity.  Diabetologia. 1995;  38 816-822
• 10 Verge C F, Gianani R, Kawasaki E. et al . Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies.  Diabetes. 1996;  45 926-933
• 11 Nicholson L B, Kuchroo V K. Manipulation of the Th1/Th2 balance in autoimmune disease.  Curr Opin Immunol. 1996;  8 837-842
• 12 Mosmann T R, Coffman R L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.  Annu Rev Immunol. 1989;  7 145-173
• 13 Romagnani S. Human TH1 and TH2 subsets: regulation of differentiation and role in protection and immunopathology.  Int Arch Allergy Immunol. 1992;  98 279-285
• 14 Coffman R L, Mosmann T R. Isotype regulation by helper T cells and lymphokines.  Monogr Allergy. 1988;  24 96-103
• 15 Shparago N, Zelazowski P, Jin L et al. IL-10 selectively regulates murine Ig isotype switching.  Int Immunol. 1996;  8 781-790
• 16 Stavnezer J. Molecular processes that regulate class switching.  Curr Top Microbiol Immunol. 2000;  245 127-168
• 17 Snapper C M, Marcu K B, Zelazowski P. The immunoglobulin class switch: beyond ”accessibility“.  Immunity. 1997;  6 217-223
• 18 Schloot N C, Willemen S, Duinkerken G, de Vries R R, Roep B O. Cloned T cells from a recent onset IDDM patient reactive with insulin B-chain.  J Autoimmun. 1998;  11 169-175
• 19 Kallan A A, Duinkerken G, de Jong R et al. Th1-like cytokine production profile and individual specific alterations in TCRBV-gene usage of T cells from newly diagnosed type 1 diabetes patients after stimulation with beta-cell antigens.  J Autoimmun. 1997;  10 589-598
• 20 Kallmann B A, Lampeter E F, Hanifi M P, Hawa M, Leslie R G, Kolb H. Cytokine secretion patterns in twins discordant for Type I diabetes.  Diabetologia. 1999;  42 1080-1085
• 21 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
• 22 King C L, Nutman T B. IgE and IgG subclass regulation by IL-4 and IFN-gamma in human helminth infections. Assessment by B cell precursor frequencies.  J Immunol. 1993;  151 458-465
• 23 Lundgren M, Persson U, Larsson P. et al . Interleukin 4 induces synthesis of IgE and IgG4 in human B cells.  Eur J Immunol. 1989;  19 1311-1315
• 24 Yazdanbakhsh M, Paxton W A, Brandenburg A et al. Differential antibody isotype reactivity to specific antigens in human lymphatic filariasis: gp15/400 preferentially induces immunoglobulin E (IgE), IgG4, and IgG2.  Infect Immun. 1995;  63 3772-3779
• 25 Singh V K, Mehrotra S, Agarwal S S. The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy.  Immunol Res. 1999;  20 147-161
• 26 Lampeter E F, Klinghammer A, Scherbaum W A. et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes.  Diabetes. 1998;  47 980-984
• 27 Seissler J, de Sonnaville J J, Morgenthaler N G et al. Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease.  Diabetologia. 1998;  41 891-897
• 28 Verge C F, Stenger D, Bonifacio E et al. Combined use of autoantibodies (IA-2) autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies in type 1 diabetes: Combinatorial Islet Autoantibody Workshop.  Diabetes. 1998;  47 1857-1866
• 29 Scherbaum W A, Mirakian R, Pujol-Borrell R, Dean B M, Bottazzo G F. Immunochemistry in the study and diagnosis of organ-specific autoimmune disease. In: Polak JM, Van Noorden S editors. Immunohistochemistry. Modern Methods and Applications. England; Wright Bistrol 1986: 456-476
• 30 Guo J, Rapoport B, McLachlan S M. Thyroid peroxidase autoantibodies of IgE class in thyroid autoimmunity.  Clin Immunol Immunopathol. 1997;  82 157-162
• 31 Esnault V L, Jayne D R, Weetman A P, Lockwood C M. IgG subclass distribution and relative functional affinity of anti-myeloperoxidase antibodies in systemic vasculitis at presentation and during follow-up.  Immunology. 1991;  74 714-718
• 32 Dozio N, Belloni C, Girardi A M et al. Heterogeneous IgG subclass distribution of islet cell antibodies.  J Autoimmun. 1994;  7 45-53
• 33 Couper J J, Harrison L C, Aldis J J, 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
• 34 Petersen J S, Kulmala P, Clausen J T, Knip M, Dyrberg T. 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. 1999;  90 276-281
• 35 Hawa M I, Fava D, Medici F, Deng Y J, Notkins A L, de Mattia , Leslie R DG. Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.  Diabetes Care. 2000;  23 228-233
• 36 Bonifacio E, Scirpoli M, Kredel K, Füchtenbusch M, Ziegler A G. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation.  J Immunol. 1999;  163 525-532
• 37 Riley W J, Maclaren N K, Krischer J et al. A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes.  N Engl J Med. 1990;  323 1167-1172
• 38 Jelinek D F. Regulation of B lymphocyte differentiation.  Ann Allergy Asthma Immunol. 2000;  84 375-386