Effect of autoantibodies on lung fibroblast phenotype

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DESCRIPTION (provided by applicant): Asbestos exposure is associated with pulmonary fibrosis as well as autoimmune responses, including increased antinuclear antibodies. We have recently completed a pilot study of the asbestos-exposed population of Libby MT that suggests that these autoantibodies may be associated with disease progression. The specific aims of this proposal are based on the hypothesis that asbestos exposure leads to the altered expression and presentation by cells within the lung of unique antigens to the immune system, which then mounts an antibody response. These antibodies may then exacerbate chronic inflammatory conditions responsible for asbestos-related disease (ARD) by binding to fibroblasts and increasing their pro-fibrotic activities. The approach is to first demonstrate recognition of fibroblasts by autoantibodies generated in asbestos exposed subjects, then to determine whether asbestos exposure to fibroblasts leads to altered expression of target antigens, and finally to demonstrate that antibodies targeting the fibroblasts can affect pro-inflammatory activities. The long-term goal will be to understand the possible role of autoantibodies in the pathogenesis of lung disease in individuals exposed to a known environmental agent, asbestos. This understanding may be of relevance to other autoimmune diseases where no known inciting agent is known, and therefore these studies will have the potential to provide an approach to prevention and therapeutic modalities.