The long-term objective of this research project is to elucidate the genetic and biochemical mechanisms responsible for variability in the structure and expression of murine Ia antigens. This variability is of major importance in determining immune response potential, due to its effects on T-cell activation. The planned experiments are designed to probe the extent and origin of variability in Ia antigen structure and the mechanisms by which it affects immune responsiveness. Specifically, polymorphic regions of Ia proteins that participate in T-cell activation will be identified by a combination of approaches including DNA cloning, gene transfection, site-specific mutagenesis, and T-cell proliferation assays. A variety of phenomena contribute to the variability in expression of the E Alpha and E Beta Ia chains, such as the lack of synthesis of EBeta chains in f and q haplotype mice, the low levels of EAlpha expression in strain A.TFR5, and the preferential association of certain allelic combinations of EAlpha and EBeta chains. The molecular mechanisms that are responsible for these differences will be examined by analysis of the specific genes and mRNAs for EAlpha and EBeta. Finally, the functional significance of Ia antigen variability in an outbred population will be studied. The extent and basis of polymorphism in Ia antigen structure and expression will be characterized in homozygous mouse stocks derived from a local population of wild mice, using serological, protein chemical, and molecular approaches. In parallel, these mice will be tested for their ability to respond to a series of antigens for which the genetics of responsiveness had been well-defined in inbred strains. The Ia analogues in man, controlled by the D region of the HLA complex, have been implicated in genetically-determined predisposition to a variety of diseases. The information gained from the proposed research should provide insights into genetic and evolutionary processes contributing to variation in immune responsivenss in man.
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