We have established a mouse strain, designated SKG mice, which spontaneously develop chronic autoimmune arthritis. The arthritis resembles rheumatoid arthritis in the proliferative synovial inflammation accompanying infiltration of CD4+ T cells, formation of pannus eroding cartilage and bone, development of autoantibodies including rheumatoid factor, and various extra-articular manifestations. It can be adoptively transferred to histocompatible athymic mice by peripheral CD4+ T cells or thymocytes, or to histocompatible SCID mice by bone marrow cells. Thus, the abnormality in this model seems to be expressed in the bone marrow-derived cellular components, leading to thymic generation and activation of CD4+ T cells recognizing/attacking normal self-antigens in the joints. In genetic analysis, the offspring of crosses between SKG mice (which has a BALB/c genetic background) and normal BALB/c mice, whether the mother was SKG or BALB/c, developed no arthritis. In contrast, arthritis occurred in approximately 50% of the N2 generation obtained by crossing the nonarthritic F1 hybrids with SKG mice; the arthritides in the N2 generation showed a similar clinical course and severity as in SKG mice. Thus, the genetic abnormality is presumably of a single gene locus, designated as the skg gene, and inherited in an autosomal recessive fashion with nearly 100% penetrance of the trait in homozygotes raised in our conventional environment. Linkage analysis between the development of macroscopically evident arthritis and the homozygosity of chromosome-specific microsatellite markers by utilizing the N2 generation of back-crossing the F1 generation of SKG and Mus musculus castaneus to SKG mapped the skg locus to the centromeric portion of chromosome 1, with the lod score of the locus as infinite. Positional cloning of the skg gene revealed that the gene encodes a signal transduction molecule in T cells. Altered signal transduction from the T-cell antigen receptor through the mutated molecule changes the thresholds of T cells to thymic selection, leading to positive selection of otherwise negatively selected autoimmune T cells. This genetically determined 'selection shift' of the T-cell repertoire towards high self-reactivity and resulting thymic production of pathogenic autoimmune T cells may be a primary cause of and also a predisposing factor for RA in humans.