Susceptibility to systemic autoimmunity rather than the presence of the HLA-DR4 peptide binding domain alone leads to severe inflammatory arthritis following inhalation of crystalline silica

Abstract Background The mucosal origins hypothesis of rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses in the lungs that contribute to joint disease onset. However, the relationship between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood. Results This study compared the development of inflammatory arthritis in two genetically susceptible mouse strains, the BXD2/TyJ (BXD2) and chimeric HLA-DR4-IE transgenic (DR4-Tg), following delivery of c-silica to the lungs via oropharyngeal aspiration. In BXD2 mice, c-silica exposure was associated with rapid arthritis development, marked by synovial cell hyperplasia, pannus formation, and severe erosion of cartilage and bone. These features were preceded by pulmonary inflammation characterized by lymphoid-like cell clusters lining vessels and bronchi which cell-specific immunofluorescent microscopy identified as organized lymphoid structures consistent with inducible bronchus-associated lymphoid tissue (iBALT). Inflammatory arthritis was also preceded by autoantibodies associated with RA and other systemic autoimmune diseases including anti-citrullinated protein autoantibodies (ACPA) and rheumatoid factor (RF) in bronchoalveolar lavage fluid (BALF). However, the most predominant autoantibodies in BALF were against extractable nuclear antigens (ENA). Anti-ENA were also prominent in serum and microarray autoantigen analysis confirmed the response as targeting components of Sm and RNP small nuclear ribonucleoproteins (snRNPs). In contrast, DR4-Tg mice had no signs of arthritis, milder lung inflammation lacking iBALT, and negligible autoantibody responses. Conclusion Genetic predisposition beyond HLA-DR4 alone is required for the immunological manifestations that lead to c-silica mediated inflammatory arthritis. These findings provide novel insights into the relationship between mucosal exposure and RA pathogenesis.