Mechanism of Silica-Induced Autoimmune Responses

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DESCRIPTION (provided by applicant): This proposed study uses in vivo and in vitro techniques to explore a murine model of environmentally induced autoimmunity, in which silica is thought to lead to apoptosis of alveolar macrophages in an inflammatory setting with loss of peripheral tolerance. Antigen presentation of the self antigens of apoptotic macrophages would lead to T helper cell activation and subsequent B cell production of autoantibodies. This study is important due to the lack of understanding of mechanisms of autoimmunity following environmental exposures, the severity and increasing incidence of environmentally induced autoimmune diseases, and the need for an animal model to study them. Three hypotheses will be tested with the specific aims. First, preliminary data shows that silica leads to silicosis and autoantibody development in Balb/c mice, so I hypothesize that this represents an autoimmune syndrome that can be at least partially characterized in terms of target antigens and isotypes. Other mouse models will be considered with the understanding that genetic susceptibility will undoubtedly play a role in the kinetics and characteristics of the response. Second, by blocking silica-induced increases in antigen presentation and by altering the cytokine profile during exposure, I will test the hypothesis that the response is antigen-driven through antigen presenting cells in a Th1 setting. Finally, the hypothesis suggests that silica-induced apoptosis of alveolar macrophages can provide the epitopes required for autoimmune responses. This will be tested using apoptotic cells as antigens in an antigen presentation assay to T cells from our silica-exposed mice. Whether the silica-induced autoantibodies are pathogenic will not be explored in this study, but since autoantibodies are correlated with, and often implicated in the process of autoimmune disease, this study and the development of the animal model will no doubt provide clues to subsequent pathology as well.