Autoreactive B and T cell response leading to arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of the population. Although both T and B cell‐mediated autoimmune components have been implicated, the mechanism leading to the initiation of disease is not known. K/BxN mice spontaneously develop a joint inflammatory response that mimics many of the features of human RA. Importantly, in this murine model, disease induction is synchronous and predictable, allowing for the study of the factors that contribute to disease initiation and pathogenesis. In K/BxN mice, arthritis is induced by autoantibodies against the glycolytic enzyme glucose‐6‐phosphate‐isomerase (GPI). How autoreactive B and T cells escape tolerance induction to this ubiquitously expressed self‐Ag and initiate a joint‐specific autoimmune response remains unclear. Previously, our laboratory generated low affinity anti‐GPI Ig tg mice to investigate how GPI‐reactive B cells are normally tolerized by the immune system. Surprisingly, although anti‐GPI B cells show evidence of autoantigen encounter beginning in the BM, they are not tolerant to GPI. The anti‐GPI B cells remain functionally competent and can be induced to secrete autoantibodies in response to cognate T cell help both in vitro and in vivo. This suggests that they have the potential to trigger the arthritogenic autoimmune response.