Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes - Isotype restriction and polyclonality

OBJECTIVE - To determine the isotypes and clonality of antibodies to GAD (GADA) and 1A-2 (1A-2A) in patients with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS - We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and 1A-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed prospectively RESULTS- GADA or 1A-2A were detected in 37 (71%) type 1 diabetic patients compared with only 10 (5%) type 2 diabetic patients (P < 0.0001). Both GAD and 1A-2 antibodies, regardless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and 1A-2A were less prevalent than IgG 1 (P < 0.017 for either antibody), There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. CONCLUSIONS - These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.