Author:

Abstract:

Exposure to crystalline silica (c-silica) remains a pivotal concern in several occupational settings, such as mining and construction work, as inhalation of c-silica dust is implicated in severe conditions such as silicosis, a debilitating lung disease, and systemic autoimmune diseases (SAD), such as rheumatoid arthritis (RA). Although the pathogenesis of silicosis has been extensively studied, the complex mechanisms that link c-silica exposure to the onset of SAD are still largely uncharted, despite the emerging epidemiological evidence for an association between occupational c-silica exposure and the development of several different SAD. Hypotheses for c-silica-mediated autoimmunity describe a disease progression that begins with activation of proinflammatory cytokine production, inflammation of the lung leading to activation of innate and adaptive immunity, breaking of tolerance, development of autoantibodies, and finally disease in target organs, such as the kidneys and joints. However, limited availability of suitable animal models hamper the ability to confirm the posed hypotheses, and to investigate the complex interplay between genetic background, subclinical autoimmunity, and mucosal inflammation in the initiation of systemic autoimmunity. Thus, this doctoral thesis focused on establishing and comparing novel mouse models of c-silica-induced autoimmunity, to study the requirements and mechanisms in c-silica-associated autoimmunity and systemic autoimmune diseases. Firstly, a systematic review of existing literature on mouse models of c-silica and/or asbestos-induced autoimmune features was undertaken, assessing the current state and the limitations of these models. This review of the literature highlighted the need for future research that considers genetic factors and the combination of exposures to fully understand the mechanisms behind silica-induced autoimmunity. Next, we explored lung inflammation, encompassing lung function, as well as local and systemic autoimmunity (ANA) in two mouse strains, the C57BL/6J and NOD/ShiLtJ, known for their significant variability in immune baseline states and (sub)-clinical autoimmune traits, following pulmonary exposure to c-silica dust and/or diesel exhaust particles (DEP). Our results elucidated that c-silica exposure initiated a pronounced inflammatory response in the lungs of both mouse lines. These strains demonstrated diverse outcomes regarding respiratory functionality and lung capacities, both spontaneously and after c-silica exposure. Furthermore, c-silica exposure was found to induce airway hyperreactivity in NOD/ShiLtJ mice. In terms of subclinical autoimmunity, increases in antinuclear antibody levels were observed in serum and bronchoalveolar lavage fluid following c-silica exposure. No synergistic or additive effects between c-silica and DEP were detected in inducing lung injury, inflammation, and ANA in either mouse line. Thirdly, we utilized a broad array of multi-parental RI mouse strains, known as the Collaborative Cross (CC), to investigate spontaneous and c-silica induced sub-clinical and disease autoimmune traits across strains derived from the same founders with a known genetic makeup. We determined that subclinical autoimmune traits were indicative of c-silica-induced autoimmunity and autoimmune diseases. Notably, one strain exhibited a higher incidence of glomerulonephritis, and another showed more pronounced inflammatory arthritis (predominantly synovitis) in c-silica-exposed animals. Finally, in the absence of a mouse model for c-silica-induced autoimmune arthritis, our goal was to develop a model of c-silica-induced arthritis, mirroring human RA. This model could help us investigate how environmental exposures, such as those to c-silica dust, contribute to the development of RA. We showed that pulmonary exposure to c-silica could accelerate autoimmunity and inflammatory arthritis in mice with a genetic susceptibility to the spontaneous development of RA. C-silica induced a wide range of different autoantibodies, many of which are associated with autoimmune diseases in humans. Further research is now needed to unravel the mechanisms in this model. In summary, this doctoral thesis marks a significant step forward in our comprehension of the link between environmental exposures, lung inflammation and autoimmune diseases. The development of advanced mouse models, as demonstrated by our research, provides critical insights into the early triggers and pathways of autoimmunity. Furthermore, the findings from this thesis highlight the importance of a comprehensive approach in tackling the complexities of autoimmune diseases, and the need for continued awareness about occupational crystalline silica exposure.