Silicosis and Silica-Induced Autoimmunity in the Diversity Outbred Mouse.
Epidemiological studies have confidently linked occupational crystalline silica exposure to autoimmunity, but pathogenic mechanisms and role of genetic predisposition remain poorly defined. Although studies of single inbred strains have yielded insights, understanding the relationships between lung pathology, silica-induced autoimmunity, and genetic predisposition will require examination of a broad spectrum of responses and susceptibilities. We defined the characteristics of silicosis and autoimmunity and their relationships using the genetically heterogeneous diversity outbred (DO) mouse population and determined the suitability of this model for investigating silica-induced autoimmunity. Clinically relevant lung and autoimmune phenotypes were assessed 12 weeks after a transoral dose of 0, 5, or 10 mg crystalline silica in large cohorts of DO mice. Data were further analyzed for correlations, hierarchical clustering, and sex effects. DO mice exhibited a wide range of responses to silica, including mild to severe silicosis and importantly silica-induced systemic autoimmunity. Strikingly, about half of PBS controls were anti-nuclear antibodies (ANA) positive, however, few had disease-associated specificities, whereas most ANAs in silica-exposed mice showed anti-ENA5 reactivity. Correlation and hierarchical clustering showed close association of silicosis, lung biomarkers, and anti-ENA5, while other autoimmune characteristics, such as ANA and glomerulonephritis, clustered separately. Silica-exposed males had more lung inflammation, bronchoalveolar lavage fluid cells, IL-6, and autoantibodies. DO mice are susceptible to both silicosis and silica-induced autoimmunity and show substantial individual variations reflecting their genetic diverseness and the importance of predisposition particularly for autoimmunity. This model provides a new tool for deciphering the relationship between silica exposure, genes, and disease.
['Mayeux|Jessica M|JM|', 'Escalante|Gabriela M|GM|', 'Christy|Joseph M|JM|', 'Pawar|Rahul D|RD|', 'Kono|Dwight H|DH|', 'Pollard|Kenneth M|KM|']
D000818:Animals D000974:Antibodies, Antinuclear D015551:Autoimmunity D001992:Bronchoalveolar Lavage Fluid D000076724:Collaborative Cross Mice D004195:Disease Models, Animal D005260:Female D005921:Glomerulonephritis D006801:Humans D007668:Kidney D008168:Lung D008297:Male D051379:Mice D012737:Sex Factors D012822:Silicon Dioxide D012829:Silicosis
silicosis autoimmunity diversity outbred silica lung inflammation autoantibody environmental autoimmunity