EXCEED THE SPACE PROVIDED. The long-term goal of this investigation is to increase our understanding of the acute phase proteins, C- reactive protein (CRP) and the related protein, serum amyloid P component (SAP) with respect to their functional importance in inflammatory states, especially in the autoimmune diseases. Our earlier work and the work of others established that a major activity of CRP and SAP is to bind to nuclear antigens. Our recent work supported by this grant has shown that the major receptor for CRP on myeloid cells is FcyRII and that CRP also binds to FcyRI. The study will characterize the interaction of CRP and SAP with Fc receptors (FcyR) on myeloid cells and examine the functional consequences of these interactions on inflammatory models.
The first aim i s to examine the interaction of SAP with FcyR. SAP binding to human FcyR will be analyzed using peripheral blood leukocytes and COS cells transfected with human FcyR. Knockout mice deficient in FcyR will be used to examine binding and/or phagocytosis through each of the three forms of FcyR in the mouse.
The second aim i s to use site-directed mutagenesis to define binding sites on CRP for FcyRI and FcyRIIa. These studies will be based on preliminary data regarding the binding site on CRP for FcyRI, and on crystallographic data now available for CRP, IgG and FcyRII. The development of mutants that bind to individual receptors will allow analysis of responses induced by interactions of CRP with individual FcyR on leukocytes.
The third aim i s to determine whether CRP and/or SAP regulate inflammatory responses to immune complexes (1C) through interactions with FcyR. We hypothesize that CRP and/or SAP bind(s) to nuclear antigens released from apoptotic or necrotic cells and to 1C containing these autoantigens. It is further hypothesized that this interaction leads to the activation of complement and binding of these complexes to FcyR. IC-mediated peritonitis and cutaneous anaphylaxis will be used as models to study the effect of CRP and/or SAP on the acute inflammatory response to 1C. It is anticipated that these studies will provide important information regarding the effect of the acute phase proteins, CRP and SAP, on the inflammatory and autoimmune diseases and could potentially lead to new therapeutic approaches to these diseases. PERFORMANCE SITE ========================================Section End===========================================
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