During the past decade my laboratory has initiated the characterization of a series of islet antigens (in particular antigens shared with neuronal cells such as carboxypeptidase H, gangliosides (A2B5, 3G5 and Gm2-1), HISL-19, PM-1, NGF receptor) utilizing monoclonal antibody techniques, glycolipid biochemistry, and screening of expression libraries with patients autoantibodies. At the same time we have explored the hypothesis that type I diabetes is a predictable disorder and that the pattern of autoantibodies produced, and in particular levels of specific autoantibodies would aid in predicting who is at risk for type I diabetes, and most importantly how rapidly an islet cell antibody positive individual will progress to type I diabetes. This has led to a dual parameter model for the prediction of type I diabetes where levels of insulin autoantibodies correlate with rate of progression to diabetes and first phase insulin secretion (IVGTT) correlates with the extent of beta cell destruction. Recently we have discovered an unusual form of ICA (expressed by 1/4 of ICA positive relatives) which we have termed """"""""restricted"""""""", and which appears to represent a """"""""Stiff-Man Syndrome"""""""" like autoantibody response to glutamic acid decarboxylase (GAD). Our preliminary results indicate that high levels of such ICA antibodies rather than accelerating progression to diabetes, inversely correlate with progression to diabetes and are associated with the """"""""protective"""""""" HLA allele DQB1*0602 usually found on DR2 haplotypes. At the time of the current competitive renewal we believe that sufficient biochemical and natural history data has been developed to allow over the next decade accurate definition of the heterogeneity of islet cell autoantibodies and with quantitative assays to improve the prediction of type I diabetes. In addition the development of quantitative assays should allow the development and testing of the hypothesis that protection may be associated with selected autoantibodies and increase our knowledge of islet physiology and biochemistry and the relation between anti-islet autoimmunity and the nervous system. In particular we propose to 1) Define further the relationship between anti-GAD autoantibodies and restricted ICA, lack of progression to diabetes and DQB1*0602. 2) Produce the Gm2-l ganglioside and isolate GT3 and define the relationship of these gangliosides to non-restricted ICA and utilize them for development of quantitative autoantibody assays. 3) Finish the sequencing of the PM-1 molecule and with PM-1, carboxypeptidase H and synaptophysin analyze the relationship of autoantibodies to these peptides and restricted ICA and disease progression.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Immunological Sciences Study Section (IMS)
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Joslin Diabetes Center
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