This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Inhaled silicates such as silica and asbestos can lead to complex pathologies, including pulmonary fibrosis, pleural abnormalities, cancer and systemic autoimmune diseases (SAID). One of the major gaps of knowledge regarding environmental autoimmunity is how specific autoantibody profiles are induced by particular exposures, and whether that defines the clinical disease outcome of the autoimmune response. This proposal addresses critical questions about the cellular mechanisms leading to immunopathology following inhaled silicate exposures. Amphibole asbestos exposure is associated with pulmonary fibrosis and self-reported SAID in Libby MT. Also, C57Bl/6 mice respond to asbestos with interstitial lung fibrosis, as well as production of antinuclear antibodies (ANA) and immune complex glomerulonephritis, closely resembling SAID. This novel mouse model can therefore be used to elucidate the mechanism whereby asbestos leads to the production of pathogenic autoantibodies, and to determine whether various types of inhaled silicates lead to unique autoantibody profiles. Environmental exposures have been hypothesized to expose autoantigens to the immune system via modified protein exposure, particularly during apoptosis. However, exposure of autoantigens is not sufficient to drive an autoimmune response without a second mechanism to overcome peripheral tolerance. Inhaled silicates contact several cell types that could be activated to drive antigen presentation, including macrophages and B1a B cells. Our central hypothesis is that asbestos drives exposure of a set of autoantigens that will be reflected in the autoantibody specificities produced in asbestos-exposed mice, and that B1a B cells play a role in overcoming tolerance to these antigens.
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