The Role of BAFF/APRIL-binding Receptor BCMA in Systemic Autoimmunity
Jiang, Chao, Department of Microbiology, University of Virginia
Erickson, Loren, Department of Microbiology, University of Virginia
Tung, Kenneth, Department of Pathology, University of Virginia
Systemic lupus erythematosus (SLE) and its preclinical lupus-prone mouse models are autoimmune disorders involving the production of pathogenic autoantibodies. Genetic predisposition to SLE results in B cell hyperactivity, survival of self-reactive B cells, and differentiation of B cells to autoantibody-secreting plasma cells (PCs). These corrupt B cell responses are due, in part, to excess levels of the cytokine B cell activation factor (BAFF) from the TNF family that normally regulates B cell homeostasis and self-tolerance. As an example, BAFF signaling through its receptor BCMA (B cell maturation antigen) is critical for the long-term survival of PC in the bone marrow (BM) under normal physiological conditions. In this dissertation, the role of BCMA in mediating survival of autoantibody-producing PC was examined by analyzing the development of autoimmunity in two different lupus-prone mouse models deficient in BCMA. We demonstrate that BCMA deficiency combined with either lpr mutation or the murine lupus susceptibility locus Nba2 causes a dramatic lymphoproliferative disorder, accompanied by increased BAFF production, accelerated autoantibody production, and early lethality. CD4 + T cells were necessary for the development of autoantibody-secreting PC, but not obligatory for the lymphoproliferation state, which predominantly comprised of increased numbers of B cells and PCs. This study reveals BCMA as a critical negative regulator for maintaining homeostasis and self-tolerance of B cells and PC in systemic autoimmunity.
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PHD (Doctor of Philosophy)
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