There has been a marked increase in our knowledge of human FcgR which we now understand as three families of related molecules. The various FcgR forms have different functional capacities based on different functional domains and/or sequence motifs. Furthermore, allelic variants also have distinct functional capacities. The importance of these advances are highlighted by several critical observations for autoimmune immune complex disease: 1. FcgR participate critically in murine models of immune complex (IC)-mediated inflammation demonstrated by blocking receptor engagement with soluble FcgR and in a knock-out mice lacking phagocytic FcgR; 2. The g-chain associated FcgR, FcgRIa and FcgRIIIa, participate importantly in the handling of model IC in humans and primates and both have novel point polymorphisms which may affect function (Preliminary Data); and 3. Preliminary analysis in two independent genetic linkage studies suggests linkage of the SLE phenotype with chromosome 1q20-22, the region containing the FcgR and the associated g-chain. The applicants hypothesize 1) that abnormal FcgR function (both genetically determined and disease-acquired) is a contributory factor in disease pathogenesis; 2) that different FcgR structural forms are under differential control (at the level of both expression and function); and 3) that the different capacities of the FcgR forms preferentially associated with SLE patients contribute to the abnormal FcgR function and to disease predisposition. The applicant's Preliminary Data indicate a central role for FcgRIa and FcgRIIIa, - which associate with the signal transducing, accessory g-chain, - and indicate a novel role in function for the cytoplasmic domain of the ligand-binding a-chain which lacks signaling motifs. They therefore propose: 1. to define the functions and mechanisms of function of the g-chain associated FcgRIa and FcgRIIIa and the contributions of the unique a-chain cytoplasmic domains of each; 2. to define the different structural isoforms of the FcgRI family, their relative expression and relationship to one another, and their functional capacities; and 3. to define the allelic forms of the g-chain associated FcgR, their functional characteristics and their association with autoimmune immune complex diseases such as SLE. Identification of genetic risk factors for SLE and appropriate regulation of FcgR will allow novel therapy for SLE.
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