Although numerous environmental exposures have been suggested as triggers for sub-clinical autoimmunity, only a few have been confidently linked to autoimmune diseases such as lupus and rheumatoid arthritis. For disease-associated exposures, the lung is a common site where persistent exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating chronic inflammation. This leads to a complex interplay of immunological processes, including post-translational modification of self-antigens, and the formation of tertiary lymphoid structures that provide a milieu for the accumulation of autoreactive B and T cells necessary for the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish sub-clinical autoimmunity from clinical autoimmune disease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.