Crystalline silica exposure of genetically diverse mice exacerbates subclinical autoimmunity into systemic autoimmune disease phenotypes including inflammatory arthritis in female mice.

Inhalation of respirable crystalline silica (c-silica), an occupational hazard, has been associated with the development of systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, it is unclear if c-silica-mediated autoimmune disease requires pre-existing subclinical autoimmunity or to what extent the severity of existing subclinical autoimmunity influences the spectrum and severity of c-silica-induced autoimmune phenotypes. Sixty-one naïve Collaborative Cross (CC) strains, a multiparental panel of recombinant inbred (RI) mouse strains derived from eight founder strains, were assessed for the presence of subclinical autoimmunity via autoantibodies and inflammatory markers. These studies revealed a broad spectrum of subclinical autoimmune responses in naïve CC RI strains. Six strains, chosen to represent the range of subclinical autoimmunity, were exposed to c-silica or saline and studied for development of lung inflammation, autoantibodies, inflammatory markers, and the presence of connective tissue disease. Silica exposure resulted in the development of strain-selective systemic autoimmune disease phenotypes of varying severity. Specifically, c-silica exposure triggered inflammatory arthritis in female CC039 mice and lupus nephritis in CC061 mice. Other strains demonstrated lupus-like disease features without clear tissue involvement. The presence of subclinical autoimmunity dramatically influences the severity and specific disease phenotype of c-silica-induced systemic autoimmunity. These observations identify CC RI mice as a valuable resource to study the influence that subtle genetic differences and pre-existing subclinical autoimmune phenotypes have on the development and severity of autoimmune diseases linked to occupational and environmental exposures.