Autoimmunity results when the toleragenic mechanisms that restrict the responses of self-reactive T and B cells fail. In addition to tissue damage caused by self-reactive T cells, autoantibody production by self-reactive B cells is directly pathogenic in several systemic and 'organ-specific' autoimmune diseases, such as systemic lupus erythematosus, idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and myasthenia gravis. Moreover, autoantibodies are also frequently observed in type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, and the presence of self-antibodies against specific self-antigens can often be used as diagnostic/prognostic marker in several of these diseases. The regulatory mechanisms that normally prevent autoantibody formation are complex, and remain poorly understood. However, recent work has indicated that dominant tolerance mediated by a specialized lineage of CD4+FoxP3+ regulatory T cells (Treg) is essential for normal immune homeostasis and for preventing severe systemic autoimmunity. Importantly, Treg have been implicated in preventing autoantibody production by self-reactive B cells. The goal of the proposed experiments is to define the functional mechanisms by which Treg limit autoantibody production. We hypothesize that Treg block autoantibody production not only by restricting the responses of self-reactive CD4+ helper T cells, but also by direct inhibitory interactions with self-reactive B cells within B cell follicles and germinal centers. As autoantibody production often precedes the onset of clinical autoimmunity, delineating the mechanisms by which Treg function to maintain B cell tolerance in vivo is key to understanding the etiology and progression of these diseases. In addition, discerning how Treg function within GC is directly relevant to understanding how tolerance is maintained in the neonatal period, a time in which individuals mount robust B cell responses following initial exposure to a wide variety of pathogens, environmental antigens and deliberate immunizations. ? ? ? ?
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