One of the fundamental questions that remains unanswered in the study of autoimmunity is how autoantibody producing cells arise. We propose that autoantibodies can result from the activation of self- reactive B cells that evade the mechanisms of central tolerance by co-expressing two different antigen receptors, one receptor specific for foreign antigen and one receptor specific for self antigen. Hence, activation of these dual receptor expressing cells by foreign antigen can lead to the production of autoantibodies. Although dual antibody expressing B cells have been observed in wild type mice and humans, their reactivity toward autoantigens is unknown. We hypothesize that dual receptor B cells are generated from self-reactive cells that have escaped tolerance by co-expressing both an autoreactive and non-autoreactive antigen receptor. To test our hypotheses, we wish to develop the following aims: 1) Characterize dual antigen receptor B cells in a wild type mouse model, 2) Determine if dual antigen receptor B cells in wild type mice carry an autoreactive receptor, 3) Determine if dual antigen receptor B cells are the source of self-reactive antibodies in an autoimmune disease model.
