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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024322-09
Application #
2062543
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1986-03-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
9
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Xiong, Huabao; Li, Hongxing; Kong, Hee Jeong et al. (2005) Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. J Biol Chem 280:23531-9
Zhou, Hui; Xiong, Huabao; Li, Hongxing et al. (2004) Microtubule-associated serine/threonine kinase-205 kDa and Fc gamma receptor control IL-12 p40 synthesis and NF-kappa B activation. J Immunol 172:2559-68
Xiong, Huabao; Li, Hongxing; Chen, Yibang et al. (2004) Interaction of TRAF6 with MAST205 regulates NF-kappaB activation and MAST205 stability. J Biol Chem 279:43675-83
Chuang, F Y; Sassaroli, M; Unkeless, J C (2000) Convergence of Fc gamma receptor IIA and Fc gamma receptor IIIB signaling pathways in human neutrophils. J Immunol 164:350-60
Unkeless, J C; Jin, J (1997) Inhibitory receptors, ITIM sequences and phosphatases. Curr Opin Immunol 9:338-43
Edberg, J C; Lin, C T; Lau, D et al. (1995) The Ca2+ dependence of human Fc gamma receptor-initiated phagocytosis. J Biol Chem 270:22301-7
Unkeless, J C; Shen, Z; Lin, C W et al. (1995) Function of human Fc gamma RIIA and Fc gamma RIIIB. Semin Immunol 7:37-44
Zhang, F; Yang, B; Odin, J A et al. (1995) Lateral mobility of Fc gamma RIIa is reduced by protein kinase C activation. FEBS Lett 376:77-80
Ghirlando, R; Keown, M B; Mackay, G A et al. (1995) Stoichiometry and thermodynamics of the interaction between the Fc fragment of human IgG1 and its low-affinity receptor Fc gamma RIII. Biochemistry 34:13320-7
Boros, P; Odin, J A; Chen, J et al. (1994) Specificity and class distribution of Fc gamma R-specific autoantibodies in patients with autoimmune disease. J Immunol 152:302-6

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