Silica has been convincingly linked to multiple autoimmune diseases associated with major morbidity and mortality due to kidney, lung, joint, and other organ damage. However, at present essentially nothing is known about the mechanism of autoimmune induction or the role of genetic susceptibility, and an established animal model does not exist. The studies proposed here are intended to fill this critical void. Each of the silica-associated autoimmune disorders is associated with respiratory exposure and has a prominent humoral autoimmune component, implicating silica-exposed lung in loss of B cell tolerance, the fundamental immune abnormality in these diseases. It is thus notable that silica has been demonstrated to induce tertiary lymphoid structures in affected lungs. Ectopic lymphoid tissue in other organs develops prominent B cell follicles that support antigen-specific immune responses and favor survival and activation of autoreactive lymphocytes. In the proposed studies the investigators will explore the hypothesis that respiratory silica leads to a breach in B cell tolerance in genetically susceptible individuals through the intermediary of pulmonary tertiary lymphoid structures. First, the investigators will use a novel autoantibody transgenic mouse model system to determine whether inhaled silica induces loss of B cell tolerance and autoantibody production in each of four distinct disease-relevant genetic backgrounds, and identify the tolerance mechanism breached and the autospecificities induced. Second, the investigators will use the model system to define the role of environmental co-exposure to Toll-like receptor ligands in silica-induced loss of tolerance. Third, the investigator will conduct parallel studies in a humanized model that enriches for tolerance-susceptible B cells to determine under what conditions silica induces human autoantibody production. Last, the investigators will use the models to determine whether lung lymphoid tissue is the site of loss of tolerance and autoantibody production. The information generated in these studies will substantially heighten understanding of the requirements for and mechanisms by which inhaled silica induces autoimmunity.
Autoimmunity afflicts an estimated 7% of the U.S. population, causing injury to joints, kidneys, lungs, and other organs. It often strikes young adults, such tha extensive morbidity accrues over a lifetime, along with high associated health care costs. Considerable evidence implicates the interaction of genetic susceptibility and environmental factors, and silica inhalation in particular, in the development of autoimmune diseases. Yet the nature of this interaction and pathogenic mechanisms remain poorly understood and existing models are inadequate, seriously hampering efforts to prevent or treat these debilitating disorders. The model systems and experiments proposed here are designed to address these gaps and to provide new tools and insights that can be applied toward alleviating this growing disease burden.
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