Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by a chronic erosive inflammation in joints leading to the destruction of cartilage and bone. The mechanisms behind RA are still unclear but early therapy with disease-modifying drugs such as antibodies against tumor necrosis factor-α or methotrexate reduce disease manifestations, and treatment with anti-CD20 antibodies depleting B cells gives promising results [1]. The autoimmune targets in RA are not known but autoantibodies against various joint-related epitopes are detected in sera. Antibodies against epitopes modified by citrullination show the highest specificity for RA and can be detected very early in the disease course [2-4]. Antibodies against type II collagen (CII) occur in a subset of RA, and CII-specific B and T-cells have been identified in rheumatoid synovium and synovial fluid [5-10].Immunization of mice with CII leads to the development of arthritis, the collagen-induced arthritis (CIA) model for RA. CII-specific activation of both T and B cells is critical for the development of arthritis, and the transfer of both rodent [11] and human [12] serum with CII-specific antibodies induces arthritis in mice. Monoclonal CII-specific autoantibodies bind cartilage in vivo and induce arthritis [13]; the injection of large amounts of several of such mAbs in cocktails induces severe arthritis [14,15]. Collagen-antibody-induced arthritis (CAIA) is an inflammation that is dependent on Fc receptor and complement, involving the infiltration of both neutrophils and macrophages [15-18].The antibody response to CII is predominantly directed towards the conformational triple-helical structures. Immunization with CII α-chains (denatured CII) induces only a weak antibody response and is not arthritogenic [19]. Therefore identification of the relevant B cell epitopes required the construction of recombinant triple-helical proteins and synthetic triple-helical peptides [10,20]. The major epitopes were identi