Self-tolerance is achieved by receptor editing, a process that revises genes that code for autoreactive receptors by secondary V gene rearrangement. We think that once editing creates a receptor that does not bind a self-antigen, rearrangement stops. However, autoreactive lymphocytes from autoimmune mice show evidence for more rearrangement than normal B cells. Thus, it appears that autoimmunity is not because of failure to edit but instead because of excess or overzealous editing. We plan to test this idea by analyzing rearrangement of transgenic-autoimmune mice. Re-editing would require on going expression of RAG and we will measure to expression of RAG before and during the onset of autoimmunity. The model also predicts that the repertoire of B cells should be altered as a result of re-editing, in particular, to favor lambda-associated antibodies and free L chains. We will develop L-chain deficient autoimmune mice to test these predictions. If extended expression of RAG is a mechanism by which autoantibodies are generated, then by manipulating RAG expression or inhibiting RAG action might prevent autoantibody production and activity. The L-chain deficient autoimmune mice are likely to provide a model for studying the etiology of free L chains and for studying the role that free L chains play in autoimmunity and other L chain associated diseases. ? ?
