Characterization of a novel and spontaneous mouse model of inflammatory arthritis.

Introduction: Mouse models of rheumatoid arthritis (RA) have proven critical for identifying genetic and cellular mechanisms of the disease. Upon discovering mice in our breeding colony that had spontaneously developed inflamed joints reminiscent of RA, we established the novel IIJ (inherited inflamed joints) strain. The purpose of this study was to characterize the histopathological, clinical, genetic and immunological properties of the disease.

Methods: To begin the IIJ strain, an arthritic male mouse was crossed with SJL/J females. Inheritance of the phenotype was then tracked by intercrossing, backcrossing and outcrossing to other inbred strains. The histopathology of the joints and extraarticular organ systems was examined. Serum cytokines and immunoglobulins (Igs) were measured by ELISA and cytometric bead array. Transfer experiments tested whether disease could be mediated by serum alone. Finally, the cellular joint infiltrate and the composition of secondary lymphoid organs were examined by immunohistochemistry and flow cytometry.

Results: After nine generations of intercrossing, the total incidence of arthritis was 33% (304 of 932 mice), with females being affected more than males (38% vs. 28%; P < 0.001). Swelling, most notably in the large distal joints, typically became evident at an early age (mean age of 52 days). In addition to the joint pathology, which included bone and cartilage erosion, synovial hyperproliferation and a robust cellular infiltration of mostly Gr-1(+) neutrophils, there was also evidence of systemic inflammation. IL-6 was elevated in the sera of recently arthritic mice, and extraarticular inflammation was observed histologically in multiple organs. Total serum Ig and IgG1 levels were significantly elevated in arthritic mice, and autoantibodies such as rheumatoid factor and Ig reactive to joint components (collagen type II and joint homogenate) were also detected. Nevertheless, serum failed to transfer disease. A high percentage of double-negative (CD4(-)CD8(-)) CD3(+) TCRα/β(+) T cells in the lymphoid organs of arthritic IIJ mice suggested significant disruption in the T-cell compartment.

Conclusions: Overall, these data identify the IIJ strain as a new murine model of inflammatory, possibly autoimmune, arthritis. The IIJ strain is similar, both histologically and serologically, to RA and other murine models of autoimmune arthritis. It may prove particularly useful for understanding the female bias in autoimmune diseases.