A novel model of severe inflammatory arthritis induced by pulmonary silica exposure - Occupational silica exposure is linked with systemic autoimmune diseases including rheumatoid arthritis (RA) systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and anti-neutrophil cytoplasmic antibody (ANCA)-related vasculitis. The health burden is significant because systemic autoimmune diseases have been reported in 6% of those employed in mining occupations, and 21% of those with severe forms of silicosis. Although several novel animal models of systemic autoimmunity induced by exposure to crystalline silica (cSi) exist, there is no experimental model in which cSi exposure results in inflammatory arthritis. This is a significant barrier to our understanding of how occupational/environment exposures contribute to the development of arthritis. The “mucosal origins hypothesis” argues that arthritis pathogenesis originates at mucosal sites and then transitions to articular joints. Crucial to this is a pre-clinical phase of autoantibody production and chronic systemic inflammation influenced by genetic susceptibility to systemic autoimmunity. Using BXD2 recombinant inbred mice, which develop generalized systemic autoimmunity and erosive arthritis, we found that transoral instillation of cSi led to an exaggerated serum anti-ENA5 autoantibody response followed by pronounced synovial inflammation, cartilage damage, bone erosion, and pannus formation of ankle joints. The anti-ENA5 response is strongly associated with cSi induced systemic autoimmunity, suggesting that its induction contributes to the aggressive nature of the inflammatory arthritis in the context of an appropriate genetic susceptibility. To study the feasibility of the BXD2 as a model of cSi induced arthritis we propose two aims to define the relationship between pulmonary exposure, systemic autoimmunity, and inflammatory arthritis. Aim 1 will address the hypothesis that severe inflammatory arthritis in cSi exposed BXD2 mice depends on a cSi driven autoantibody response that requires the autoimmune prone genetic susceptibility of the BXD2 to mature into a chronic inflammatory response leading to severe inflammatory arthritis. The proposed studies will determine if genetic predisposition is essential to development of cSi induced inflammatory arthritis. They will also examine the relationship between cSi exposure, pulmonary inflammation, systemic autoimmunity, and inflammatory arthritis to identify how immunological events occurring at a mucosal site relate to development of joint arthritis. In Aim 2 we will test the hypothesis that cSi particles find their way to joint spaces, resulting in localized inflammatory events which are then aggravated by an already existing cSi induced chronic autoantibody response leading to severe inflammatory arthritis. We will test this by asking if cSi particles can be found in ankle and knee joints, and if intra-articular injection of cSi is sufficient for arthritis or if passive transfer of IgG from anti-ENA5 positive cSi exposed BXD2 mice is necessary to enhance arthritis severity. Successful completion of these studies will result in a novel experimental model of cSi induced inflammatory arthritis, and provide a better understanding of how adverse immunological events at mucosal surfaces can impact pathology in distant tissues.
