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The Role of BAFF/APRIL-Binding Receptor BCMA in Systemic Autoimmunity

Jiang, Chao
Format
Thesis/Dissertation; Online
Author
Jiang, Chao
Advisor
Tung, Kenneth
Erickson, Loren
Abstract
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. Note: Abstract extracted from PDF text
Language
English
Published
University of Virginia, Department of Microbiology, PHD, 2010
Published Date
2010-12-01
Degree
PHD
Rights
All rights reserved (no additional license for public reuse)
Collection
Libra ETD Repository

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