Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.
Insulin immunization in animal models induces T-helper (Th) 2-like antibody subclass responses to insulin and other beta-cell antigens. The aim of this study was to determine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subclass antibodies to insulin (IAs), GAD, and IA-2 were measured before and after treatment with insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcutaneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (CsA) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell antibody-positive relatives receiving either intravenous and subcutaneous insulin prophylaxis or no treatment. At the onset of diabetes, the major subclass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a lesser extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs were initially of the IgG1 subclass. IgG4-IAs appeared later, but at 12 months, they were at higher levels than IgG1-IAs in 11 patients. Responses were higher in children compared with adults and were higher in subjects with IAAs (P < 0.001). Insulin prophylaxis in relatives showed a similar profile, with a decline in levels of IgG1-IAs after cessation of daily subcutaneous insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IAs persistently rebounded after completion of CsA therapy. Despite the presence of IgG4-IAs in most insulin-treated patients and relatives, a shift to IgG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiation of insulin therapy. While our findings need to be correlated with T-cell cytokine responses, we suggest that the strong IgG4-IA response in insulin-treated patients is consistent with an enhancement of Th2 immunity, but there is no evidence of subsequent spreading of potentially Th2-associated IgG4 responses to other autoantigens.
Füchtenbusch
M
M
Diabetes Research Institute and Third Medical Department, Schwabing City Hospital, Munich, Germany.
Kredel
K
K
Bonifacio
E
E
Schnell
O
O
Ziegler
A G
AG
D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000032:analysis; D000917:Antibody Formation; D001323:Autoantibodies / Q000032:analysis; D001324:Autoantigens / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000032:analysis*; D007328:Insulin / Q000276:immunology* / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D000906:Antibodies; D001323:Autoantibodies; D001324:Autoantigens; D007004:Hypoglycemic Agents; D007074:Immunoglobulin G; D007328:Insulin; D016572:Cyclosporine; D005968:Glutamate Decarboxylase