Cellular Mechanisms of Asbestos-Induced Autoimmunity

Jean Cooper Pfau

This proposal explores the cellular mechanisms whereby inhalation exposures such as asbestos can drive autoimmune responses. It is novel and compelling in that it provides a thorough analysis of two processes that must occur together in order to explain the mechanisms of autoimmunity following asbestos exposure: antigen exposure and immune activating antigen presentation. 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. Because asbestos can cause apoptosis and apoptosis can increase exposure of autoantigens, we will test the hypothesis that autoantigens exposed on the surface of cells by asbestos in vitro can predict the autoantibody specificities following that exposure in vivo. In addition, because simple exposure is inadequate to drive and immune response, we hypothesize that B1a B cells help overcome tolerance to these self antigens and can be shown to play a role in asbestos-associated autoimmunity. Although implicated in autoimmune responses, the specific roles of apoptosis and of B1a B cells in environmental autoimmunity have not been rigorously tested. The impact of this study is profound in its potential to elucidate the mechanisms of xenobiotic-induced autoimmunity and guide new approaches to prevention or management of the ensuing disease process. The proposed project provides a strong foundation for development toward an R01 grant application by providing critical data about how particular environmental exposures drive the specificity of the autoantibody profile and overcomes normal tolerance to those targeted antigens.