Regulation of the B-Cell Development and Differentiation

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EXCEED THE SPACE PROVIDED. The diversity and specificity of an immune response is embodied by the antigen-binding receptors on both B and T lymphocytes. The balance between proliferative expansion and programmed elimination of activated or autoreactive cells is also tightly regulated by these antigen receptors. Therefore, understanding the mechanisms of regulation of B-cell development and differentiation by B cell antigen receptors (BCR) is crucial for understanding normal B-cell development and for determining the molecular and cellular basis of immunodeficiency and autoimmune disorders. Immunoglobulin D (IgD) and IgM are the two major antigen receptor isotypes expressed on the vast majority of peripheral B cells in humans and mice. While much evidence indicates that IgM is important in driving B-cell development, the contribution of IgD remains unclear, as are the roles of IgM and IgD in regulating humoral immune responses. Recently, we demonstrated that IgM and IgD have distinct roles in the homeostasis of the B-cell compartment and in thymus-dependent humoral immune responses. These novel findings support a model in which signaling events through 5 or _ heavy chain differentially regulate B cell development and differentiation. This project will address several critical questions about the biological consequences and significances of the distinct signals through IgD or IgM in B-cell development and humoral immune responses using both IgM- and IgD-deficient mouse models. Specifically, we will test the hypothesis that IgM mediates a negative regulatory role while IgD acts as positive regulator in B cell activation and differentiation in the periphery. The proposed studies will illuminate distinct functional features of IgM and IgD both as antigen receptors and as secreted immunoglobulins and will enrich our understanding of how the B cell antigen receptors regulate B cell maturation and immune i responses. PERFORMANCE SITE ========================================Section End===========================================