Mouse C4b-binding Protein in Adaptive Immunity

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DESCRIPTION (provided by applicant): The objective of this research proposal is to evaluate the mouse complement C4b binding protein (C4BP) "knock-out" mouse as an in vivo model to delineate the overall contribution of human C4BP in adaptive immunity. The aims of this proposal are driven the the central hypothesis that C4BP on binding CD40 expressed on B cells mediates many important biological responses important in immune regulation, including immunoglobulin class switching in response to T-dependent antigens, and proliferation and rescue of germinal center B cells. Our recent generation of a C4BP "knock-out" mouse provides a unique opportunity to evaluate the physiological impact of C4BP as a significant contributor to adaptive immunity. The results from this proposal will significantly advance the understanding of how the innate and adaptive immune systems interact in providing a robust immune response. Moreover, these studies will also provide basic information that will facilitate a better understanding of B-cell maturation and immunoglobulin production, and thereby provide significant insights into the pathogenesis of autoimmune diseases such as systemic lupus erythematosus as well as IgE associated allergic diseases, including atopic asthma. To accomplish the overall objective of the proposal, three aims are proposed. Aim one will evaluate the binding interactions between mouse C4BP and CD40 expressed on mouse B cells. Aim two will examine lymphocyte development in C4BP-deficient (-/-) mice compared to wild-type mice. Aim three will determine the antibody response to T-dependent and T-independent antigens in C4BP-deficient (-/-) mice compared to wild-type mice, as well as to examine germinal center formation in C4BP-deficient (-/-) mice compare to wild- type mice.