Human Fc receptors (FcgR) consist of three families with extensive diversity of structure and function. Recent advances bring into focus four observations pertinent to SLE: 1) FcgRIIa is a crucial receptor mediating phagocytic function; 2) FcgRIIa is unique among FcgR in that it is targeted for oxidant and protease-induced amplification of effector function as well as avidity modulation, independent of receptor number; 3) the H131 allele of FcgRIIa is the only human FcgR which recognizes IgG2 efficiently; 4) the distribution of FcgRIIa alleles is skewed in SLE patients compared to normals, with a highly significant decrease in FcgRIIa-H131 in lupus nephritis. In SLE, FcgR-specific immune complex removal by the mononuclear phagocytes system is impaired. This defect is related to renal disease, emphasizing the possible role of FcgR dysfunction in immune complex deposition and the pathogenesis of SLE. Despite the decrease in FcgR function in vivo , there is a paradoxical increase in FcgR binding in vitro. Preliminary data indicate that FcgRIIa is a compelling candidate for the FcgR dysfunction in SLE. Monocytes in SLE patients have increased FcgRIIa-mediated binding, but markedly decreased FcgRIIa phagocytosis, indicating dissociation of receptor-effector coupling. Disease-induced dysfunction superimposed upon inherited polymorphisms of FcgRIIa with decreased functional capacity may provide the milieu for the development of immune complex deposition and nephritis. Recent evidence for a role of IgG2 autoantibodies in nephritis underscores the importance of FcgRIIa in disease phenotype. Based on these observations, the investigators hypothesize that 1) abnormal FcgRIIa function provides a basis for disease-related defects in SLE, and 2) that alleles of FcgRIIa which affect ligand binding are important heritable disease susceptibility factors. Therefore, the specific aims of this application: 1. to define the mechanism of activation of FcgRIIa; 2. to define the basis for the defect in phagocytosis by FcgRIIa in SLE; 3. to define the role of FcgRIIa alleles as risk factors for lupus nephritis: (a) to establish genetic linkage of lupus and nephritis to FcgRIIa and (b) to define the relative importance of FcgRIIa alleles among different ethnic groups; and 4. to define subclasses of IgG deposited within glomeruli in lupus nephritis and their relationships to FcgRIIa alleles, autoantibodies, and induction of glomerular injury.
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