ORGAN-SPECIFIC DISEASE PROVOKED BY SYSTEMIC AUTOIMMUNITY

Rheumatoid arthritis (RA) is a chronic joint disease characterized by leukocyte invasion and synoviocyte activation followed by cartilage an d bone destruction. Its etiology and pathogenesis are poorly understoo d. We describe a spontaneous mouse model of this syndrome, generated f ortuitously by crossing a T cell receptor (TCR) transgenic line with t he NOD strain. All offspring develop a joint disease highly reminiscen t of RA in man. The trigger for the murine disorder is chance recognit ion of a NOD-derived major histocompatibility complex (MHC) class II m olecule by the transgenic TCR; progression to arthritis involves CD4T, B, and probably myeloid cells. Thus, a joint-specific disease need not arise from response to a joint-specific antigen but can be precipi tated by a breakdown in general mechanisms of self-tolerance resulting in systemic self-reactivity. We suggest that human RA develops by an analogous mechanism.