A mutation in the ZAP-70 gene causes autoimmune arthritis in mice. ZAP-70 is a key signaling molecule in T cells. A spontaneous point mutation in the SH2 domain of the ZAP-70 gene leads to chronic autoimmune arthritis in mice, resembling human rheumatoid arthritis (RA). The mutation alters T-cell signaling through the T-cell antigen receptor, changing the threshold for thymic selection. This results in the positive selection of T cells that would otherwise be negatively selected, leading to the production of arthritogenic T cells. This altered T-cell selection may contribute to the development of RA in some patients. The SKG strain of mice, which spontaneously develops chronic arthritis, was derived from a closed breeding colony of BALB/c mice. Joint swelling and hyperemia became evident in SKG mice at about 2 months of age, progressing to larger joints by 8–12 months. Histological analysis of the swollen joints showed severe synovitis with infiltration of various immune cells, villus proliferation, and pannus formation. Immunohistochemical staining revealed that CD4+ T cells predominantly infiltrated the subsynovial tissue. Extra-articular manifestations included interstitial pneumonitis in most mice older than 6 months. The study suggests that altered T-cell selection due to a ZAP-70 mutation may play a role in the development of autoimmune diseases like RA.A mutation in the ZAP-70 gene causes autoimmune arthritis in mice. ZAP-70 is a key signaling molecule in T cells. A spontaneous point mutation in the SH2 domain of the ZAP-70 gene leads to chronic autoimmune arthritis in mice, resembling human rheumatoid arthritis (RA). The mutation alters T-cell signaling through the T-cell antigen receptor, changing the threshold for thymic selection. This results in the positive selection of T cells that would otherwise be negatively selected, leading to the production of arthritogenic T cells. This altered T-cell selection may contribute to the development of RA in some patients. The SKG strain of mice, which spontaneously develops chronic arthritis, was derived from a closed breeding colony of BALB/c mice. Joint swelling and hyperemia became evident in SKG mice at about 2 months of age, progressing to larger joints by 8–12 months. Histological analysis of the swollen joints showed severe synovitis with infiltration of various immune cells, villus proliferation, and pannus formation. Immunohistochemical staining revealed that CD4+ T cells predominantly infiltrated the subsynovial tissue. Extra-articular manifestations included interstitial pneumonitis in most mice older than 6 months. The study suggests that altered T-cell selection due to a ZAP-70 mutation may play a role in the development of autoimmune diseases like RA.