Role of collagen type II specific antibodies in arthritis
Sammanfattning: Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting in destruction of cartilage and bone. The role of the B cells in RA pathogenesis clearly involves autoantibodies. Collagen type II (CII)-specific antibodies have been identified in RA synovium and synovial fluid. The work in this thesis is focused on the role of CII specific antibodies in the initiation and pathogenesis of arthritis. Additionally, the importance of B cell tolerance in the development of autoimmune disease has been investigated. To study some of the pathogenic mechanisms involved in RA, we used the animal model collagen-induced arthritis (CIA), where the disease characteristics resembles RA in many ways. We investigated the epitope selection and V gene usage of CII specific monoclonal antibodies (mAbs) and demonstrated that the presence of a selective V gene repertoire could result in CII epitope binding capacity. Further, the antibody response and B cell epitope specificity was examined in chronic relapsing CIA models. We found that the B cell responses against CII in both mice and rats were directed against immunodominant epitopes that were conserved between the species, including humans. Here the development of chronic arthritis was related to an antibody response to defined epitopes on CII (C1, J1 and U1) and mAbs to these epitopes could induce relapses. A significant correlation between U1-specific antibodies and disease progression was found in CIA. We also detected U1-specific autoantibodies in RA, especially in association with early joint erosions. U1 specific antibodies bound cartilage in vivo and triggered the development of arthritis on its own. Therefore, antibodies directed to a specific epitope on CII could be related to arthritis progression and the epitope specificity of the mAb could determine its arthritogenicity. Finally, the importance of B cell tolerance in autoimmune arthritis development was investigated. By creating a gene replacement mouse with an inserted VDJ region coding for an anti-CII antibody, we could study some of the B cell tolerance mechanisms. Our findings suggested that B cells expressing autoantibodies directed against CII may escape negative selection events and could be present in the periphery with a maintained specificity. In conclusion, CII specific antibodies are essential for the induction and pathogenesis of arthritis.
KLICKA HÄR FÖR ATT SE AVHANDLINGEN I FULLTEXT. (PDF-format)