IntroductionMouse 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.MethodsTo 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.ResultsAfter 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.ConclusionsOverall, 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.

We have discovered a novel mouse strain that spontaneously develops arthritis, and we are currently assessing its viability as a new model of immune‐mediated arthritis. The purpose of this project was to characterize the immune response in this new strain. Cells of the spleen, lymph nodes, and joints were isolated from AR and non‐AR littermates and analyzed for immune cell proliferation and activation using flow cytometry. Serum was also collected and assayed for immunoglobulin levels and pro‐inflammatory cytokines. AR mice had significantly more immune cells in their joints. The vast majority were neutrophils, although T cells and B cells were also present. Surprisingly, AR mice tended to have lower numbers of total cells isolated from their spleen and lymph nodes, possibly indicating that the immune cells were largely localizing to the joints, the major site of inflammation. The CD4+and CD8+ T cells that were in these organs did show elevated signs of activation in the AR mice (i.e. increased CD25 and CD69 and decreased CD45RB). Mean serum levels of total Ig and IgG1 but not IgG2b were elevated in AR mice. Finally, interleukin‐6 was elevated in all the AR mice in the early stages of disease and tumor necrosis factor‐alpha was elevated in half of the AR mice. Overall, our data indicate that there is more robust inflammatory response occurring in the AR mice.