Modulation of B-cell tolerance by coreceptor molecules

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Induction of autoimmunity by infection and inflammation has been suggested in connection with a number of diseases and has been supported by demonstrations of cross-reactivity of certain self- and microbial antigens. It is noteworthy that B-lymphocytes are critical antigen presenting cells in the development of diabetes, arthritis and lupus in model systems. In this application, we seek to establish complement C3d generation as a predisposing factor for B cell-dependent autoimmune disease. Notably, C3d is deposited in the kidney and excreted in the urine during the advanced symptoms of renal disease. In this application, we will test the hypothesis that C3d is not only correlative, but can be causative of arthritis or a lupus-like disease when bound to the inducing self-antigen. This hypothesis will be examined in the type II collagen (CII)- and the glucose-6-phosphate isomerase (GPI)-induced models of arthritis by coupling C3d to CII or GPI and determining the potential of these C3d-bound self-antigens to induce disease. A similar approach will be used to form immunoconjugates of the Sm ribonucleoprotein and C3d to create a model of systemic lupus erythematosus (SLE). C3d-bound antigens promote B cell activation by binding the B cell receptor and CD21, which signals via CD19. CD19 has also been implicated as a target for negative regulation by Fc-gammaRIIB when co-engaged by immune complexes. To understand how CD21 binding may lead to a breach in B cell tolerance, experiments are proposed to address the role of CD21 in central tolerance of newly formed B cells. Moreover, we will investigate the issue of signal integration by the co-receptors as applied to the physiologic context of immune complexes and C3d-bound antigen co-engaging CD19/CD21/CD32 and the BCR. Completion of this R21 will lay the foundation for future studies defining the molecular basis of C3d/CD21 adjuvant potential in autoimmune disease, with the prospect of designing reagents to block CD21 function in some contexts to ameliorate disease.