CR1 (CD35) AS A CELLULAR RECEPTOR FOR CIQ

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DESCRIPTION: (Adapted from Investigator's abstract) Complement is required for the normal clearance of immune complexes, for initiation of the humoral response to physiological doses of antigen, for antibody affinity maturation and isotype switching and for development of a memory T cell response. All of these vital elements of the immunologic response are mediated by cellular receptors for complement fragments. While the receptors for C3b, iC3b, C3d,g, C4b, C5a and C3a are well-known, the receptor for Clq has been elusive. The importance of Clq is exemplified by the severe autoimmune diseases caused by Clq deficiency, including glomerulonephritis and vasculitis. In preliminary studies, our laboratories have demonstrated that complement receptor type 1 (CR1, CD35), the C3b/C4b receptor, also functions as a Clq receptor. Thus the immune adherence receptor, CD35, is able to bind immune complexes that have fixed any of the opsonizing complement fragments. In this application, it is proposed to identify the binding site on CD35 for Clq; and conversely, the site on Clq for binding CD35. Because CD35 is structurally homologous to Clr and Cls, the other components of C1, serum and membrane proteins structurally homologous to CD35 will be assessed as potential Clq receptors. Similarly, proteins structurally and functionally related to Clq, such as mannose binding protein and surfactant protein A, will be assessed as ligands for CD35. Finally, the biological role of CD35 as a Clq receptor will be investigated. The role of CD35 in the cellular response known to be triggered by Clq, such as enhanced phagocytosis by monocytes and neutrophils; and enhanced Ig production by B cells will be determined. Using Clq as a ligand signaling by CD35 will be investigated in phagocytes and B cells. A role of CD35 associated proteins will be examined. Specifically, the possible participation of previously described molecules involved in Clq binding and Clq mediated responses will be determined by collaborative studies. When completed, proposed research will clarify the role of Clq in the handling of immune complexes, and address the mechanisms underlying the interaction of C1q with CD35 on leukocytes.