Cells of the immune system bind immunoglobulins and immune complexes (IC) via receptors which recognize the Fc portion of immunoglobulins (Ig). Interaction of IC with Fc receptors (FcR) on macrophages and polymorphonuclear leukocytes induces cidal mechanisms and the release of mediators of inflammation. The function of FcR on subpopulations of B and T lymphocytes is unknown but reports or Fc receptors specific for each Ig isotype, the inducibility of isotype specific FcR by Ig and the description of soluble Ig binding factors suggest a role for FcR in the regulation of humoral immune responses. This proposal is directed towards an understanding of the structure-function relationship of membrane bound and soluble FcR. The FcR for IgG2b and IgG1 (FcRGamma2b/Gamma1) has been purified by affinity chromatography with a monoclonal anti-FcR antibody, 2.4G2. Similar methodology will be used to purify sufficient quantities of FcRGamma2b/Gamma1) to obtain a partial amino acid sequence. This amino acid sequence will be used to confirm the identity of putative FcRGamma2b/Gamma1) cDNA clones presently being isolated and characterized in the laboratories of Drs. Unkeless and Ravetch. Primary sequence data will be used to synthesize selected FcR peptides. Antibodies against specific peptides will enable us to orient FcR domains and probe receptor function. Recently, we have identified soluble factors which express FcR Gamma2b/Gamma1 antigenic determinants in cell free supernatants of activated murine spleen cells, FcR-positive macrophage-like (J774) and T cell (S49.1) lines. Affinity chromatography will be used to isolate these factorS. The antibodies and cDNA probes will be used to determine the structural and genetic relationship of membrane bound and soluble FcR. Purified FcR will be studied for its effects on in vitro immune responses. If membrane bound or soluble FcR prove to be important in the isotype specific regulation of antibody production we will, in the latter stages of this project, attempt to isolate FcR specific for other Ig isotopes. Approaches similar to that taken for the FcRGamma2b/Gamma2 will be used to purify FcR and clone the genes encoding these receptors. The importance of FcR in immune complex mediated disease states and the regulation of normal and pathologic antibody production is unclear. Antibodies and cDNA probes for FcR will provide tools for their detection and for the determination of their physiologic role.
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