The proposed epidemiologic research is based on our prior 19-year achievements in the development of unique populations, both locally and globally, and a stored blood sample library. These resources will be used to search for environmental triggers that initiate beta cell destruction or precipitate clinical insulin dependent diabetes (IDDM) and identify factors that will differentiate those individuals who progress from autoimmune beta cell disease to total destruction for the insulin producing islet cells, from those who have an indolent autoimmune course without the development of diabetes or slow progression to insulin requirement. The hypothesis to be tested are: 1) IDDM is triggered by acute or chronic precipitating agents associated with evidence of an infection and immune reactions with characteristics typical of those which are superantigen mediated; 2) there is a variable rate of progression of the autoimmune process as identified by the presence of circulating islet cell antibodies. Independent determinants characterize rapid progressors or latent autoimmune diabetes in adults and non-progressors.
Specific aims based on these hypothesis are: A) to evaluate the potential contribution of superantigens as triggering events in a large consecutive series of childhood onset IDDM cases representative of the local population; B) to compare islet cell GAD and ICA512 antibodies in relatives who have slow and rapid or no progression of IDDM after the initial detection of autoimmunity; C) to evaluate HLA haplotypes and T-cell responses and T-cell responses to beta cell antigens and superantigens in these groups. Data derived from this research will give clues as to the pathogenesis of IDDM, the time course and characteristics of the prodrome and risk factors for progression to clinical disease. These will assist in the design of intervention strategies and populations to be tested in future studies. This research will also form the basis of other potential substudies of genetic heterogeneity, autoimmune abnormalities and decreased insulin secretion as surrogate markers of beta cell damage.
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