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. The localization of follicular (FO), marginal zone (MZ) B cells 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 borne antigens. The hypothesis will be tested that this B cell subset expresses BCR's that bind common bacterial antigens and certain self or modified self-antigens and can mount a rapid, protective T cell-independent antibody response to blood borne organisms. 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 (i) identify these and related B cells in other tissues, and (ii) to define molecules expressed by these cells that are involved in localizing them in the MZ 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 that are responsible for their survival. A third major goal will be to study the role of MZ B cell interactions with dendritic cells in response to bacterial antigens. The overall goals of this proposal 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 diseases, and B cell neoplasia. ? ? ?
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