CRI (CD35) As a Cellular Receptor for CIq

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DESCRIPTION (provided by applicant): Clq and MBL participate in tissue remodeling by tagging apoptotic and necrotic tissue, respectively. Clq deficiency is associated with a 93% chance of developing a lupus-like syndrome characterized by an early onset of severe rash and nephritis with high morbidity and mortality. This striking association indicates an important role for Clq in the prevention of autoimmunity, which must depend upon interactions with Clq receptors, since the phenotypes of C4 and C2 deficiencies are much less severe. Our laboratories have demonstrated that Clq and MBL bind specifically to complement receptor 1 (CD35) on hematopoietic cells. Two hypotheses are proposed to link Clq deficiency and autoimmunity. First, Clq-dependent ligation of CD35 on B cells may evoke a negative signal that inhibits B cell proliferation. Second, Clq-dependent opsonization of apoptotic material and clearance by a CD35+ phagocyte prevents autoantigens from becoming immunogenic. The three aims of this proposal are: (1) To determine more precisely the binding site on CD35 for Clq and the binding site on Clq for CD35. (2) To define the functional consequences of Clq ligation of CD35 on leukocytes including the relevant signaling pathway utilized by CD35 on B cells and phagocytic cells. (3) To evaluate the ability of Clq-opsonized apoptotic material to be ingested via a CD35-mediated pathway and how cell surface calreticulin modulates this process. Although genetically determined Clq deficiency is a rare condition, it emphasizes the importance of Clq and its receptors. These studies of Clq receptor biology will provide insights into the pathogenesis of more common autoimmune diseases.