Cells in the immune system bind IgG via Fcgamma receptors (FcgammaR). These receptors have a central role in signalling phagocytes to secrete activated oxygen intermediates, hydrolytic enzymes, and to phagocytose immune complexes. FcgammaRs on B cells are thought to downregulate the immune response, and NK cells are triggered to release cytokines and to carry out ADCC. A close study of the biochemistry of these receptors is warranted because of the central role they play in immune defense and in the pathology of autoimmune diseases. The rapid progress in the cloning and analysis of the heterogeneity of the FcgammaR gene family now offers the opportunity to explore the function and structure on the protein level. This proposal has four aims. 1) We will analyze the structure of the recombinant truncated FcgammaR ()gammaR) we have expressed in CHO cells by crosslinking the gammaR with heterobifunctional reagents and by X-ray crystallography. Interaction of dansylated gammaR with ligand will be examined by fluorescence polarization spectroscopy. 2) We will examine various aspects of signal transduction mediated by chimeric receptors consisting of human serum albumin (HSA) linked to the transmembrane and cytoplasmic domains of mouse FcgammaRIIbeta2. 3) We will characterize a novel member of the FcgammaRII family that is expressed on macrophages and that is distinct from FcgammaRIIalpha and FcgammaRIIbeta. The new FcgammaR protein will be characterized and a cDNA encoding the receptor isolated. 4) We will study the effects of naturally occurring anti-FcgammaR Ig, which we have recently characterized in sera of autoimmune mice, on B cell and macrophage function. We will, in particular, examine the significance of the anti-FcgammaR Ig as a causative agent for stimulation of macrophages in scleroderma.
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