Background: Occupational lung exposure to crystalline silica is confidently linked to systemic autoimmune diseases, including rheumatoid arthritis (RA). However, the absence of an animal model has significantly impeded mechanistic studies.

Objective: The goal was to develop a model of silica-induced silicosis and silica-exacerbated generalized autoimmunity and arthritis, using the autoimmune-prone BXD2/TyJ strain.

Methods: BXD2/TyJ mice were exposed to 5 mg silica or PBS by transoral instillation and examined 6- or 20-weeks later. Bronchoalveolar lavage fluid (BALF) and serum were collected for autoantibodies. Lung and ankles were harvested for histology. Spleen and lymph node weights were obtained.

Results: Silica-exposed mice exhibited significant silicosis at 20 weeks with marked alveolitis and peribronchial/vascular inflammatory infiltrates along with greater lymph node weights and BALF cell counts compared to corresponding controls. Anti-extractable nuclear antigens (ENA5) and anti-cyclic citrullinated proteins (CCP3) in BALF were significantly higher at 6 weeks versus controls and were further increased at 20 weeks. Serum anti-ENA5 was significantly higher in silica-exposed mice versus controls at both time points, but anti-CCP3 was significantly elevated only at 20 weeks. Spleen weights were also significantly higher in silica-exposed mice at only 20 weeks. Importantly, ankle synovitis and bone erosion scores were significantly higher in silica-exposed animals versus controls at 20 weeks.

Conclusion: We have developed a new model of silica-exacerbated autoimmunity and arthritis that can be used to study mechanisms underpinning the association of pulmonary silicosis with RA.