Superantigens for the receptors of B lymphocytes that have properties akin to known superantigens for T-cells have only recently been identified. The current program is designed to investigate the immune modulatory properties of a bacterial membrane protein, that the investigator discovered has the structural and functional properties of a B-cell superantigen. The investigator s lab has have demonstrated that Staphylococcal protein A (SpA) has sites that enable variable region-mediated binding by more than 10% of human B-cells, and most (and perhaps all) functional germline gene segments for the VH clan III can encode for Fab-mediated binding of SpA. Recent observations also provide experimental evidence that in vivo exposure to SpA can result in positive selection of the 'primary' B-cell repertoire. To extend these investigations of this model B-cell superantigen, The application proposes to: i) evaluate the structural basis of SpA binding and identify potential contact sites at the molecular level following in vitro expression of immunoglobulins encoded by human and murine VH genes in bacterial and mammalian cells; ii) use murine immunization models to investigate the in vivo capacity for SpA to selectively influence VH-based clonal expansion, deletion and/or anergy within the peripheral B-cell compartment; iii) to investigate the distribution, phenotype and V gene expression of B-cell precursors in the central compartment of SpA-immunized mice to look for evidence of superantigen-induced positive and negative clonal selection; and iv) to evaluate whether this model superantigen is capable of VH-mediated interactions with the m/surrogate light chain membrane complexes of transformed preB-cell lines that express defined VH regions. A long-term goal of these studies is to evaluate the feasibility of using B-cell superantigens in clinically relevant therapies that include the down regulation of disease-associated autoimmune B-cell clones and the augmentation of protective immune responses against infectious pathogens.
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