Mechanisms of Environment-Induced Autoimmunity

Abstract

Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic 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 persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote 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 preclinical autoimmunity from clinical autoimmunedisease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.

Keywords: adaptive; animal model; autoimmunity; environment; inflammation; innate; xenobiotic.

Figure 1.

Steps in the development of xenobiotic-induced autoimmunity and autoimmune disease. Information in the figure summarizes the major points discussed in the text as they relate to the seven hypothesized steps leading to autoimmunity or autoimmune disease following xenobiotic exposure. The lungs serve as a common site of xenobiotic exposure. Chronic exposure results in an inflammatory response beginning with cellular and tissue damage, DAMP activation of PRR including TLRs and expression of inflammatory cytokines. Phagocytosis of DAMPS, including particulate xenobiotics, leads to lysosomal damage, inflammasome activation and processing of pro-IL-1β, further enhancing inflammation. Coincident with the inflammatory response are stress response related events, including NETosis and release of PAD enzymes, that leads to post-translational modification of self-proteins, particularly citrullination, and production of neoantigens. The ensuing chronic inflammatory response results in development of TLS comprised of accumulations of B cells within surrounding CD4⁺ T cells, FDCs and plasma cells. Processing and presentation of self and modified-self proteins, particularly in the context of MHC restriction, leads to autoantibodies. Under appropriate gene-environment interactions these autoantibodies can have diagnostic specificity such as the ACPA response in RA. The culmination of these steps is the development of disease pathology in distant tissues such as the joint in RA, the kidney in SLE and sclerodactyly, a skin manifestation of SSc.

Figure 2.

B cell aggregates in the lung and lymph node of silica exposed mice. Representative images of lung sections from Diversity Outbred (DO) mice 12 weeks following one 50 μl transoral instillation of (A) PBS or (B) 5 mg of crystalline silica (Min-U-Sil 5). IHC staining indicates B220+ B cells (black arrow in B) surrounding blood vessel in silica, but not vehicle, exposed mice. Tracheobronchial lymph node of silica exposed DO mouse imaged using (C) bright-field and (D) polarized microscopy shows areas of cell death and/or granulomas (black arrows in C) containing silica (white arrows in D) surrounded by B cells. B220+ cells are stained with DAB (brown) and hematoxylin (purple) was used as the counterstain.