Although RA has been considered primarily a type IV autoimmune reaction for many years, the finding that autoantibodies against glucose-6-phosphate isomerase (GPI) can transfer RA-like joint disease to normal mice has rekindled interest in the possibility that antibody-mediated autoimmune mechanisms (type II or type II) could play a role in the pathogenesis of RA. K/BxN T-cell-receptor transgenic mice express a transgenic T-cell receptor specific for a peptide of the ubiquitously expressed self-protein GPI. Arthritis in this model is initiated by antibodies against GPI. The resulting synovitis is chronic, erosive and associated with pannus formation. Paradoxically, although the GPI antigen is ubiquitous, autoimmunity is focused on the joints. It appears that the GPI protein, not a cross-reactive synovial antigen, is the target of the pathogenic antibodies. Although the histological appearance of the affected joints is reminiscent of RA, there is no evidence that RA in humans can be caused by antibodies against GPI. The classic serological abnormalities, rheumathoid factor, and anti CCP antibodies are not seen, and anti TNF-α antibodies have little effect in this model.