In insulin-dependent diabetes mellitus (IDDM) in humans and BB rats, islet cell autoimmunities associated with autoantibodies to a β-cell protein of 64,000 Mr (64K) have been described. We report that sera from newly diagnosed nonobese diabetic (NOD) mice similarly contain an autoantibody that immunoprecipitates 64K autoantigen from detergent lysates of [35S]methionine-labeled murine islet cells. The autoantibody was detectable by weaning; it disappeared within weeks after diabetes onset and was absent in older nondiabetic NOD mice as well as all of three non-diabetes-prone control strains tested. The 64K β-cell autoantigen may be a critical target in the immunopathogenesis of IDDM.

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