B-cells develop in a series of programmed developmental stages. These in-built mechanisms are subject to selective forces through the B-cell receptor (BCR) from both self and extrinsic antigens. It is proposed that interactions through the BCR influence the fate of individual cells with respect to their phenotype and function. Conventional and germfree mice will be compared with respect to the diversity of B-cells that populate the different areas of the spleen and other sites including the peritoneal cavity and gut-associated tissues. The localization of follicular (FO) marginal zone (MZ) in the spleen and B-1 cells in the peritoneal cavity reflects the different functions of each with respect to the types of antigens recognized by each subset and their roles as antibody producers and antigen presenters. MZ B-cells are strategically located in the spleen where they are able to interact with blood born antigens. The hypothesis will be tested that this B-cell subset expresses BCR's that bind common bacterial antigens and can mount a rapid, protective T-cell- independent antibody response to blood borne organisms. In addition they propose that MZ B-cells play an important role in the presentation of antigens in T-dependent response involving T-follicular B-cell interactions. The MZ is a late developing site with the important consequence, that in man and mouse, neonates are particularly susceptible to bacterial infections including Gram positive organisms. A variety of transgenic and gene targeted mice will be used to determine the developmental origins of this area of the spleen. Monoclonal antibodies (MAbs) specific for MZ B-cells will be used to identify (i) these and related B-cells in other tissues, and (ii) to define molecules expressed by these cells that are involved in localizing them to this area of the spleen and endow them with unique functions. MZ B and B-1 cells, different from FO B-cells, appear to be chronically activated by self-antigen and have special survival mechanisms that permit them to remain as useful members of the B-cell repertoire despite their self-reactivity. Genes will be sought that are uniquely expressed in these subsets that keep them in this activated state, and are responsible for their survival. A consequence of their activated state is a predisposition to give rise to lymphomas with characteristic phenotypes. The various MAbs and genetic probes developed to characterize normal B-cells will be used to trace the development of B-cell neoplasia in mouse models. By this approach a role will be determined for chronic antigenic stimulation in the development of B-cell tumors. The overall goals of this application are to determine the role that these B-cell subsets play in the development of the normal immune system. As a result, new information will be forthcoming with respect to the immune response to bacterial infections, immunodeficiencies, autoimmune disease and B-cell neoplasia.
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