The smaller form of the biosynthesizing enzyme for the inhibitory neurotransmitter GABA, glutamic acid decarboxylase (GAD65), is expressed at comparable levels in GABA-ergic neurons in the central nervous system and in pancreatic (3-cells. This protein is a major autoantigen in two human diseases that affect its sites of expression, insulin dependent diabetes mellitus (IDDM), which results from an autoimmune destruction of the (3-cell, and stiff-man syndrome (SMS), a rare neurological disorder caused by a dysfunction of GABA-ergic neurons. Although there is a high coincidence of IDDM in SMS patients, very few IDDM patients develop SMS. The major hypothesis to be tested are i) that SMS is caused by autoantibodies to a distinct epitope in GAD65 ii) that IDDM is caused by GAD65 specific cytotoxic T-cells which destroy the (3-cell, and iii) that B-cells play a role as antigen presenting cells in IDDM. The overall objective of the work proposed here is to understand the molecular mechanisms of autoimmunity to GAD65 and its role in each disease. The first and second aims propose to characterize the human B-cell and T-cell epitopes in GAD65 and their correlation with each disease and with HLA-susceptibility and protective haplotypes in humans. The larger form of the enzyme, GAD67, which is highly homologous to GAD65 and yet does not play a role as an autoantigen in either disease, provides an important reference molecule for those studies.
The third aim i s to study mechanisms of autoimmunity and tolerance to GAD65 in animal models. If autoimmunity to GAD65 is causative for either disease, the results will be important for development of antigen specific methods of immuno prevention. If autoimmunity to GAD65 is not pathogenic but rather a marker of disease development, the results are important for diagnosis and prediction in each disease and for mechanisms of tolerance and autoimmunity to peripheral antigens.
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