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This dissertation, The Role of B Cell Activating Factor in B Cell Development and Autoimmunity by Min, Zhang, 張敏, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled The Role of B Cell-Activating Factor in B Cell Development and Autoimmunity submitted by Zhang Min for the degree of Doctor of Philosophy at the University of Hong Kong in October 2006 B cell activating factor (BAFF), a member of the TNF family cytokines, has been demonstrated to enhance B cell activation and survival both in vitro and in vivo. Although dysregulated BAFF production is associated with a variety of autoimmune diseases, its function in early B cell development and autoimmunity progression remains largely unclear. To study whether BAFF is expressed in the bone marrow, we detected abundant expression of BAFF transcripts and its sister gene, APRIL, in mouse bone marrow non-lymphoid cells. The expression of BAFF receptors was found in developing B cells at various differentiation stages. Both recombinant BAFF and APRIL can significantly promote the survival of precursor B cells whereas only BAFF can - - suppress apoptosis of immature B cells in short-term cultures in vitro. These findings suggest that BAFF and APRIL, in addition to their well established role in regulating peripheral B cell growth, can modulate the survival of developing B cells in the bone marrow. To study the expression and function of BAFF in the development of autoimmune arthritis, a mouse model of collagen II (CII)-induced arthritis (CIA) for human rheumatoid arthritis was established. Elevated levels of BAFF expression were found in the peripheral blood as well as joint tissue of the CIA mice. Splenic dendritic cells from the CIA mice at the early CIA stage showed markedly increased BAFF expression, but as the disease progressed to later stages, the abundant BAFF were produced by macrophages. In cultures, recombinant BAFF suppressed apoptosis of splenic B cells from arthritic mice and enhanced the survival of plasma cells. Moreover, dendritic cell (DC)-induced B cell proliferation was specifically blocked by the soluble decoy receptor BCMA-Fc. These findings suggest that overproduction of BAFF by DCs and macrophages may play a crucial role in the pathogenesis of autoimmune arthritis. To further investigate the in vivo function of BAFF in the development of autoantibody-producing plasma cells and the progression of arthritis, recombinant BAFF was intravenously administered into CIA mice. Severe increases in disease symptoms as evaluated by clinical arthritis scores were observed in BAFF-treated CIA mice, which were accompanied by markedly increased serum levels of anti-CII antibodies. Flow cytometric analysis showed an expansion of the peripheral B compartment in BAFF-treated CIA mice, in which splenic B cells exhibited a significantly higher proliferative response to LPS and anti-IgM stimulation as well as - - a lower apoptotic incidence compared to that of the control CIA mice. Immunohistochemical studies revealed a greater accumulation of CD138+ cells with typical plasma cell morphology in the inflamed joints of the BAFF-treated CIA mice. Moreover, ELISPOT assays detected significantly increased numbers of long-lived anti-CII antibody-producing plasma cells in the joint tissue. Importantly, histopathological studies of the joints showed more pronounced damage in the BAFF-treated CIA mice. These results suggest that BAFF plays a crucial role in the generation of anti-CII antibody-producing plasma cells in CIA mice. In summary, our findings have established a pre

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