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However, it remains unclear if silica-mediated autoimmune disease requires preexisting subclinical autoimmunity, and to what extent the severity of the preexisting condition influences silica-induced disease. The aim of the current study was to examine whether silica-mediated autoimmune disease requires preexisting subclinical autoimmunity, using the Collaborative Cross (CC) mouse model system, recognized for its ability to mimic the genetic diversity observed in human populations. Sixty-one CC strains were assessed for the presence of subclinical autoimmunity via autoantibodies and inflammatory markers. Six CC strains, chosen to represent a range of subclinical autoimmunity, were exposed transorally to 5 mg silica or PBS and examined 12 weeks later for lung inflammation, autoantibody responses, total immunoglobulin levels, and the manifestation of glomerulonephritis and autoimmune arthritis. Results indicated a spectrum of spontaneous subclinical autoimmunity among naive CC strains, with silica exposure leading to significant pulmonary inflammation and systemic autoimmunity, including glomerulonephritis and synovitis. 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