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Published in: Diabetologia 11/2004

01-11-2004 | Article

IgG4-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes

Authors: M. Hillman, C. Törn, H. Thorgeirsson, M. Landin-Olsson

Published in: Diabetologia | Issue 11/2004

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Abstract

Aims/hypothesis

Glutamic acid decarboxylase autoantibodies (GADA) are the most frequent beta-cell-specific autoantibodies in type 1 diabetes and in latent autoimmune diabetes in adults (LADA). The autoimmune attack on pancreatic islet cells is associated with a T helper 1 cell (Th1) response, mainly represented by IgG1-subclass in humans. It has been proposed that the presence of IgG4 may be associated with a Th2 response. The aim of our study was to compare the GADA IgG-subclass distribution between adult patients with type 1 diabetes and LADA.

Methods

Patients with type 1 diabetes (n=45) and patients with LADA (n=60) were included. Radioimmunoprecipitation assay with IgG-subclass specific Sepharose (IgG1, IgG2, IgG3 and IgG4) was used to precipitate the antibody/antigen-complex.

Results

We only detected IgG4-subclass of GADA in subjects with LADA (26.7%; p<0.001). IgG1 was the most common GADA-subclass in both groups, however IgG1 as the solely expressed subclass was more common among type 1 diabetic patients (77.8%; p<0.05). The rank order of the frequencies of IgG-subclasses in type 1 diabetes was IgG1>IgG3>IgG2>IgG4 and in LADA patients IgG1>IgG4>IgG2>IgG3.

Conclusions/interpretation

The difference in GADA IgG-subclasses could indicate a different immune response, possibly an altered balance between Th1 and Th2 cytokine profile in pancreatic islets. This difference could contribute to the slower rate of beta cell destruction in LADA patients, as reflected by a higher C-peptide level at clinical onset.
Literature
1.
go back to reference Törn C, Landin-Olsson M, Östman J et al. (2000) Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds. Diabetes Metab Res Rev 16:442–447CrossRefPubMed Törn C, Landin-Olsson M, Östman J et al. (2000) Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds. Diabetes Metab Res Rev 16:442–447CrossRefPubMed
2.
go back to reference Carlsson A, Sundkvist G, Groop L, Tuomi T (2000) Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J Clin Endocrinol Metab 85:76–80CrossRefPubMed Carlsson A, Sundkvist G, Groop L, Tuomi T (2000) Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J Clin Endocrinol Metab 85:76–80CrossRefPubMed
3.
go back to reference Törn C, Gupta M, Nikitina Zake L, Sanjeevi CB, Landin-Olsson M (2003) Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults. Hum Immunol 64:902–909CrossRefPubMed Törn C, Gupta M, Nikitina Zake L, Sanjeevi CB, Landin-Olsson M (2003) Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults. Hum Immunol 64:902–909CrossRefPubMed
4.
go back to reference Tuomi T, Carlsson A, Li H et al. (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150–157PubMed Tuomi T, Carlsson A, Li H et al. (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48:150–157PubMed
5.
go back to reference Hagopian WA, Sanjeevi CB, Kockum I et al. (1995) Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J Clin Invest 95:1505–1511PubMed Hagopian WA, Sanjeevi CB, Kockum I et al. (1995) Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J Clin Invest 95:1505–1511PubMed
6.
go back to reference Turner R, Stratton I, Horton V et al. (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350:1288–1293CrossRefPubMed Turner R, Stratton I, Horton V et al. (1997) UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350:1288–1293CrossRefPubMed
7.
go back to reference Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler AG (1999) Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J Immunol 163:525–532PubMed Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler AG (1999) Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J Immunol 163:525–532PubMed
8.
go back to reference Couper JJ, Harrison LC, Aldis JJ, Colman PG, Honeyman MC, Ferrante A (1998) IgG subclass antibodies to glutamic acid decarboxylase and risk for progression to clinical insulin-dependent diabetes. Hum Immunol 59:493–499CrossRefPubMed Couper JJ, Harrison LC, Aldis JJ, Colman PG, Honeyman MC, Ferrante A (1998) IgG subclass antibodies to glutamic acid decarboxylase and risk for progression to clinical insulin-dependent diabetes. Hum Immunol 59:493–499CrossRefPubMed
9.
go back to reference Schmid S, Molteni A, Fuchtenbusch M, Naserke HE, Ziegler AG, Bonifacio E (2002) Reduced IL-4 associated antibody responses to vaccine in early pre-diabetes. Diabetologia 45:677–685CrossRefPubMed Schmid S, Molteni A, Fuchtenbusch M, Naserke HE, Ziegler AG, Bonifacio E (2002) Reduced IL-4 associated antibody responses to vaccine in early pre-diabetes. Diabetologia 45:677–685CrossRefPubMed
10.
go back to reference Hawa MI, Fava D, Medici F et al. (2000) Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. Diabetes Care 23:228–233PubMed Hawa MI, Fava D, Medici F et al. (2000) Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality. Diabetes Care 23:228–233PubMed
11.
go back to reference Koczwara K, Schenker M, Schmid S, Kredel K, Ziegler AG, Bonifacio, E (2003) Characterization of antibody responses to endogenous and exogenous antigen in the nonobese diabetic mouse. Clin Immunol 106:155–162CrossRefPubMed Koczwara K, Schenker M, Schmid S, Kredel K, Ziegler AG, Bonifacio, E (2003) Characterization of antibody responses to endogenous and exogenous antigen in the nonobese diabetic mouse. Clin Immunol 106:155–162CrossRefPubMed
12.
go back to reference Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146CrossRefPubMed Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146CrossRefPubMed
13.
go back to reference Petersen JS, Kulmala P, Clausen JT, Knip M, Dyrberg T (1999) Progression to Type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65). Childhood Diabetes in Finland Study Group. Clin Immunol 90:276–281CrossRefPubMed Petersen JS, Kulmala P, Clausen JT, Knip M, Dyrberg T (1999) Progression to Type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65). Childhood Diabetes in Finland Study Group. Clin Immunol 90:276–281CrossRefPubMed
14.
15.
go back to reference Grubin CE, Daniels T, Toivola B et al. (1994) A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37:344–350CrossRefPubMed Grubin CE, Daniels T, Toivola B et al. (1994) A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37:344–350CrossRefPubMed
16.
go back to reference Verge CF, Stenger D, Bonifacio E et al. (1998) Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in Type 1 diabetes: Combinatorial Islet Autoantibody Workshop. Diabetes 47:1857–1866PubMed Verge CF, Stenger D, Bonifacio E et al. (1998) Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell antibodies) in Type 1 diabetes: Combinatorial Islet Autoantibody Workshop. Diabetes 47:1857–1866PubMed
17.
go back to reference Törn C, Landin-Olsson M, Scherstén B (2001) Predictability of C-peptide for autoimmune diabetes in young adult diabetic patients. Pract Diab Int 18:83–88CrossRef Törn C, Landin-Olsson M, Scherstén B (2001) Predictability of C-peptide for autoimmune diabetes in young adult diabetic patients. Pract Diab Int 18:83–88CrossRef
18.
go back to reference Seissler J, Eikamp K, Schott M, Scherbaum WA (2002) IA-2 autoantibodies restricted to the IgG4 subclass are associated with protection from Type 1 diabetes. Horm Metab Res 34:186–191CrossRefPubMed Seissler J, Eikamp K, Schott M, Scherbaum WA (2002) IA-2 autoantibodies restricted to the IgG4 subclass are associated with protection from Type 1 diabetes. Horm Metab Res 34:186–191CrossRefPubMed
19.
go back to reference Ng WY, Lui KF, Cheah JS, Thai AC (2002) IgG1 subclass dominates autoimmune response to tyrosine phosphatase-like molecule IA-2 in Chinese Type 1 diabetes patients. Horm Metab Res 34:596–600CrossRefPubMed Ng WY, Lui KF, Cheah JS, Thai AC (2002) IgG1 subclass dominates autoimmune response to tyrosine phosphatase-like molecule IA-2 in Chinese Type 1 diabetes patients. Horm Metab Res 34:596–600CrossRefPubMed
20.
go back to reference Kero J, Gissler M, Hemminki E, Isolauri E (2001) Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, Type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 108:781–783CrossRefPubMed Kero J, Gissler M, Hemminki E, Isolauri E (2001) Could TH1 and TH2 diseases coexist? Evaluation of asthma incidence in children with coeliac disease, Type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 108:781–783CrossRefPubMed
21.
go back to reference Ng WY, Thai AC, Lui KF, Yeo PP, Cheah JS (1999) Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients. Diabetes Res Clin Pract 43:127–135CrossRefPubMed Ng WY, Thai AC, Lui KF, Yeo PP, Cheah JS (1999) Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients. Diabetes Res Clin Pract 43:127–135CrossRefPubMed
22.
go back to reference Kasuga A, Shimada A, Ozawa Y, Maruyama T, Oya K, Saruta T (2000) IgG1 is the dominant subclass of antibody against glutamic acid decarboxylase among Type 1 diabetes in Japanese. Endocr J 47:57–62PubMed Kasuga A, Shimada A, Ozawa Y, Maruyama T, Oya K, Saruta T (2000) IgG1 is the dominant subclass of antibody against glutamic acid decarboxylase among Type 1 diabetes in Japanese. Endocr J 47:57–62PubMed
23.
go back to reference Rook G (2001) Th1- or Th2-cell commitment during infectious disease: an oversimplification? Trends Immunol 22:481–482CrossRefPubMed Rook G (2001) Th1- or Th2-cell commitment during infectious disease: an oversimplification? Trends Immunol 22:481–482CrossRefPubMed
24.
go back to reference Sheikh A, Smeeth L, Hubbard R (2003) There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: Lack of support for the hygiene hypothesis. J Allergy Clin Immunol 111:131–135CrossRefPubMed Sheikh A, Smeeth L, Hubbard R (2003) There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: Lack of support for the hygiene hypothesis. J Allergy Clin Immunol 111:131–135CrossRefPubMed
25.
go back to reference Feili-Hariri M, Falkner DH, Gambotto A et al. (2003) Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis. Hum Gene Ther 14:13–23CrossRefPubMed Feili-Hariri M, Falkner DH, Gambotto A et al. (2003) Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis. Hum Gene Ther 14:13–23CrossRefPubMed
26.
go back to reference Yang Z, Chen M, Wu R et al. (2002) Suppression of autoimmune diabetes by viral IL-10 gene transfer. J Immunol 168:6479–6485PubMed Yang Z, Chen M, Wu R et al. (2002) Suppression of autoimmune diabetes by viral IL-10 gene transfer. J Immunol 168:6479–6485PubMed
27.
go back to reference Cameron MJ, Arreaza GA, Zucker P et al. (1997) IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 159:4686–4692PubMed Cameron MJ, Arreaza GA, Zucker P et al. (1997) IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 159:4686–4692PubMed
28.
go back to reference Kukreja A, Maclaren NK (2000) Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes. Cell Mol Life Sci 57:534–541PubMed Kukreja A, Maclaren NK (2000) Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes. Cell Mol Life Sci 57:534–541PubMed
29.
go back to reference Petrovsky N, Silva D, Schatz D (2003) Vaccine therapies for the prevention of Type 1 diabetes mellitus. Paediatr Drugs 5:575–582PubMed Petrovsky N, Silva D, Schatz D (2003) Vaccine therapies for the prevention of Type 1 diabetes mellitus. Paediatr Drugs 5:575–582PubMed
Metadata
Title
IgG4-subclass of glutamic acid decarboxylase antibody is more frequent in latent autoimmune diabetes in adults than in type 1 diabetes
Authors
M. Hillman
C. Törn
H. Thorgeirsson
M. Landin-Olsson
Publication date
01-11-2004
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1558-5

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