One key element conferring specificity to the cellular immune response is the repertoire of T-cell receptor (TcR) molecules that an individual is able to generate. This is true both in response to a foreign antigen, and in the autoimmune destruction of the insulin secreting beta cells in insulin-dependent diabetes (IDDM). We propose to investigate the nature of this variation at the level of TcR expression in the families of IDDM patients. Studies in murine systems have shown that T-cells bearing the products of particular TcR V genes are eliminated during thymic development in mice of particular MHC haplotypes. The possibility that HLA haplotypes play a role in IDDM susceptibility or resistance by modulating peripherals T-cell TcR repertoire will be investigated by measuring peripheral lymphocyte TcR V gene usage in IDDM multiplex families. We will compare TcR V gene usage in affected individuals to their normal siblings who share one but not both parental HLA haplotypes. Particular emphasis will be placed on comparisons in which the shared haplotype is DR4-positive and the non-shared haplotype is DR2 or DR3-positive, which contribute to IDDM resistance or susceptibility, respectively, but by unknown mechanisms.
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