The genetic ablation of cyclooxygenase 2 prevents the development of autoimmune arthritis

Objective. To determine the effects of cyclooxygenase 1 (COX-1) and COX-2 g ene deletion on collagen-induced arthritis (CIA), Methods. Mice that were susceptible to CIA but lacked either the COX-1 or t he COX-2 gene were immunized,vith type II collagen (CII), and the incidence and severity of arthritis were compared,vith findings in wild-type animals , by clinical and histologic examination. The immune response was assessed by measuring total CII IgG, IgG1, and IgG2 antibody production in sera from immunized mice. The passive transfer of arthritis, accomplished using anti -Cn monoclonal antibodies, was tested in wild-type and COX-deficient (-/-) mice. Splenocytes cultured from CII-immunized wild-type and COX-/- mice wer e challenged with bovine alpha1(II), and cytokine production was assessed. Results. COX-2 gene deletion reduced the incidence and severity of CIA comp ared with findings in wild-type and COX-1-/- mice. Histologic examination o f joints after the onset of clinical arthritis revealed cartilage erosions, proliferation of the synovial lining, and inflammatory cell infiltration i n wild-type and COX-1-/- mice, but not in COX-2-/- mice. COX-2-/- mice exhi bited reduced anti-CII IgG antibody levels, indicating a decreased immune r esponse, However, cytokine production by spleen cells from immunized mice i ndicated no cytokine deficiencies in COX-2-/- mice compared with wild-type or COX-1-/-mice. More important, arthritis could not be passively transferr ed to naive COX-2-/- mice, indicating a requirement for COX-2 in the pathog enesis of arthritis, independent of the immune response. Conclusion. COX-2-/- mice exhibit at least 2 defects resulting in down-modu lation of the development of CLA: a reduced immune response to CII demonstr ated by a markedly reduced antibody titer, and an "inflammatory" defect ref lected by the inability to passively transfer arthritis to COX-2-/- mice.