Progression to type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65)

To investigate whether type 1 diabetes in man is associated with a preferen tial Th1/Th2 response, and whether antoantibodies to one of the main autoan tigens would reflect such a response, we characterized the immunoglobulin i sotype profile to the 65-kDa isoform of glutamic acid decarboxylase (GAD65) in siblings to IDDM patients. Samples obtained from affected subjects befo re and at clinical onset of IDDM, from unaffected individuals at high risk and at low risk and from healthy controls were studied. The immunoglobulin isotype profile in the siblings at low risk reflected a more immature, i.e. , IgM and Th2 like, i.e., IgE response compared to the progressors and sibl ings at high risk, with significantly higher median levels of IgM and IgE. The rank order of anti-GAD65 immunoglobulin isotypes was similar in the sib lings before and at clinical onset of IDDM, IgG1 > IgG4 > IgM > IgE > IgA > IgG3 > IgG2, but markedly different in the individuals at low risk, IgG1 > IgM > IgE > IgG4 > IgG3 > IgA > IgG2. Based on these observations, we sugg est that progression to clinical onset of IDDM is associated with a maturat ion and a decrease in the Th2 immune response against GAD65; findings which could have implications for future intervention and prediction strategies. (C) 1999 Academic Press.