The SKG strain, which spontaneously develops chronic arthritis, is derived from our closed breeding colony of BALB/c mice. It shows the following clinical and immunopathological features . Clinically, hyperemia becomes macroscopically evident around 2 months of age, initially at a few interpharangeal joints of the fore paws, then progressing in a symmetrical fashion to swelling of other finger joints of the fore and hind paws, and larger joints (wrists and ankles). Although swelling of small joints sometimes shows remission, swelling of large joints does not, eventually resulting in ankylosis of wrists and ankles by 8-12 months of age due to destruction and fusion of the subchondral bones, joint dislocation, and osteoporosis. Irrespective of suffering from such severe chronic arthritis, the majority of SKG mice survive well to 1 year of age generally with more severe arthritides in females.
Histologically, SKG arthritis shows severe synovitis with massive subsynovial infiltration of neutrophils, lymphocytes, macrophages and plasma cells, villus proliferation of synoviocytes accompanying pannus formation and neovascularization, and neutrophil-rich exudates in the joint cavity. With progression of synoviocyte proliferation, pannus erodes adjacent cartilage and subchondral bone. CD4+ T-cells predominantly infiltrate the subsynovial tissue.
Serologically, SKG mice develop high titers of rheumatoid factor (RF), autoanti-bodies specific for type II collagen, antibodies reactive with heat shock protein (HSP)-70 of Mycobacterium tuberculosis presumably due to cross-reaction with a conserved epitope of HSP, severe hypergammaglobulinemia, and high concentration of circulating immune complexes, but no significant titer of anti-DNA antibodies or organ-specific autoantibodies such as anti-thyroglobulin autoantibody. Some SKG mice develop anti-cyclic citrullinated peptide (CCP) antibody (M. Hashimoto et al., unpublished data) .
As extra-articular manifestations of the disease, the majority (>90%) of mice older than 6 months of age develop interstitial pneumonitis with various degrees of perivascular and peribronchiolar cellular infiltration; more than 90% show infiltration of inflammatory cells in the skin. Some (10-20%) mice had subcutaneous necrobiotic nodules, not unlike rheumatoid nodules in RA, and vasculitides. SKG mice do not develop lymphoadenopathy or lupus-like diseases (such as immune-complex glomerulonephritis).
Proinflammatory cytokines such as TNF-a, IL-1, IL-6 are abundantly produced in the affected joints . Furthermore, the incidence and severity of SKG arthritis is significantly reduced when the mice are rendered TNF-a, IL-1 or IL-6-deficient, similar to the effects of anti-cytokine therapy in human RA [2, 15]. Notably, cytokine-deficient SKG mice free of arthritis still develop RF and anti-CCP antibody, indicating that these autoantibodies are not the consequence of joint inflammation (, M. Hashimoto, unpublished data) (see below).
Thus, spontaneous autoimmune disease in SKG mice resembles RA in clinical, histological, and serological characteristics of arthritis, the presence of extra-articular lesions, and the roles of proinflammatory cytokines in arthritis.
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