The goal of this project is to characterize the function of B lymphocyte Fc-gamma receptors. Previous findings indicate that the Fc-gamma receptors of B lymphocytes interact with: a) the lymphocyte cytoskeleton, b) Ia antigens, c) LyM antigens, d) surface IgM, and e) surface IgD. Each of these interactions is distinct, specific, and non-random. Studies utilizing antigen antibody complexes indicate that B lymphocyte Fc-gamma receptors cross-linked by their physiologic ligand down regulate B lymphocyte differentiation without affecting proliferation. Resting but not activated B lymphocytes are susceptible to this negative regulation. Occupancy of B lymphocyte surface IgM by a separate ligand is necessary for inhibition to occur, suggesting that the previously described interaction between these two membrane receptors may be involved in generating the negative signal. Studies using monoclonal anti-Fc-gammaR antibody (2.4G2) in a variety of forms including native, chemically cross-linked into homodimers or heterodimers with anti-delta or F(ab')2 anti-mu antibodies, and on a Sepharose matrix indicate that the monoclonal antibody only generates the negative regulatory signal if effective cross-linking of the receptor is obtained. Various B lymphocyte populations have been evaluated for susceptibility to Fc-gamma receptor mediated downregulation. LyB5 negative B cells are susceptible but antigen-primed B cells are not. B cells from autoimmune MRL/l mice are susceptible but not those from autoimmune NZB mice. Lack of responsiveness to Fc-gamma receptor downregulation may play a pathogenic role in NZB autoimmune mice. IL-4 specifically induces a marked (90%) loss of binding of complexes to B lymphocyte Fc-gammaR II. The IL-4 induced loss of binding of complexes was time and temperature dependent and was reversible. IFN-gamma could partially prevent this effect. The loss of binding of complexes did not appear to be due simply to a loss of expression of Fc-gammaR II because IL-4 induced only a moderate reduction in the binding of two Fc-gammaR II specific monoclonal antibodies.
