This project is focused on the delineation of physiologically important functions of NF-kappaB and IkappaB proteins. The research is based on the discovery and analysis of specific immunologic defects in mice rendered deficient in various NF-kappaB and IkappaB proteins. The ultimate goal is to identify critical targets of these factors in specific immune responses. Previously we have generated mice deficient in the p52 subunit of NF-kappaB as well as mice deficient in Bcl-3, a member of the IkappaB family. We discovered that p52 deficient animals are impaired in antibody responses to T-dependent antigens due to microarchitectural defects in secondary lymphoid organs. p52 knockout mice lack B cell follicles and follicular dendritic cell (FDC) networks. Bcl-3 deficient animals have similar but less pronounced defects. Together with prior work that suggested a functional and physical interaction of p52 and Bcl-3, the data imply that Bcl-3 promotes an activity of p52 that is critical for formation of FDC networks and follicles. FDCs themselves appear to be intrinsically defective, a conclusion based in part on the failure of adoptively transferred wild-type bone marrow to correct the defect in p52 knockout mice. However, some defects of the marignal zone are corrected, suggesting that more than one cell type is impaired due to the lack of p52. We have also generated mice deficient in both p50 and p52 to uncover redundantly encoded functions of these highly homologous proteins. We made the significant discovery that these mice (but not single gene knockouts) are blocked in the development of both mature osteoclasts and mature B cells, thus adding differentiation of hematopoietic cells to the growing list of biologic activities of NF- kappaB factors. We further determined that the defects appear to be intrinsic to progenitor osteoclasts and to immature B cells. The research has implications for loss of bone associated with autoimmune diseases and for mechanisms of B cell tolerance. - Knockout mice; antibody responses; hematopoietic differentiation; follicular dendritic cells; splenic marginal zone; p52/NF-kappaB
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