Autoimmune diseases result from perturbations of the afferent and efferent immune responses, culminating in the inapproppiate activation of inflammation. FcgammaRs are central regulators of both afferent and efferent immune responses, regulating thresholds for B cell antigen receptor stimulation and effector cell responses. Disruption of the inhibitory FcgammaRIIB pathway enhances autoimmune disease resulting in spontaneous autoimmune disease and enhanced disease in induced models. Conversely, disruption of the activation FcgammaR pathway protects animals from autoimmune disease in models of both spontaneous and induced disease. The mechanisms by which FcRs contribute to both afferent and efferent autoimmune responses will be investigated by: Dissecting the spontaneous autoimmunity which arises in FcRIIB deficient animals by: 1) Characterizing B cell, T cell and dendritic cell development and function in the autoimmune RIIB-/- /B6 as compared to non autoimmune RIIB-/-/BALB; 2) Constructing bone marrow chimeras of RIIB-/- and wild-type B6 mice to assess the contribution of B cells, T cells and APCs to development of autoimmunity; 3) Generating conditional knockouts and 4) transgenic strains of RIIB mutants in B cells to dissect the roles of the pro-apoptotic and inhibitory activities of RIIB in the afferent autoimmune response and 5) Identify the role of genetic modifiers in RIIB-/- induced autoimmunity by crossing to known modifier strains and defining the contributions of the B6 and BALB backgrounds. FcgammaR function in the efferent response will be addressed by: 1) Defining the effector cells and FcRs involved in inflammation in spontaneous and induced models of autoimmune disease by constructing RIII conditional knockouts and transgenics; 2) Developing receptor specific mAbs to block activation and inhibitory FcRs as potential treatments for autoimmune disease development and progression and 3) Manipulating RIIB expression and function as an approach to modulating autoimmunity and autoimmune disease. These studies will dissect the novel, FcR-dependent pathways involved in autoimmunity and exploit these observations for the development of innovative therapies.