Negative selection of autoreactive antibodies
Autoimmune disease is a major health problem in the US and diagnostic tests for early stage disease and curative therapies are lacking. Improving this situation will require detailed understanding of how lymphocyte tolerance is maintained in healthy people and how tolerance pathways are perturbed at the onset of the development of autoimmune disease. The use of mouse models has proven invaluable in elucidating mechanisms of tolerance as well as the many environmental influences and genetic susceptibility loci that promote the development of autoimmunity. However, most of these studies have focused on tolerance checkpoints that operate during the primary development of lymphocytes. The characteristics of the pathological autoantibodies that arise in systemic autoimmune diseases such as systemic lupus erythematosus (SLE) are analogous to those elicited in a T cell dependent B cell germinal center (GC)/memory response to a foreign antigen. These autoantibodies are class-switched, hypermutated and bear mutations indicative of strong antigenic selection. However, these antibodies have high avidity for a select group of usually intracellular autoantigens. This has prompted us, and others to hypothesize that a B cell peripheral tolerance checkpoint must be operative in the GC/memory pathway and that its disruption is one of the crucial first steps in development of systemic autoimmune diseases such as SLE. To test this hypothesis, in the previous funding period we developed and characterized targeted antibody VH transgenic mice that express B cell antigen receptors (BCRs) with affinity for both the hapten arsonate (Ars) and intracellular autoantigens. This system is unique in that it allows us to drive B cells expressing lupus like BCRs into an immune response to a foreign antigen. The use of this approach revealed that autoreactive B cells recruited into such a response are actively negatively regulated in the GC. Moreover, several genetic alterations known to predispose to autoimmunity were found to perturb the action of this checkpoint. In the next funding period we propose to expand our mechanistic studies of the GC B cell tolerance checkpoint. We will also extend these studies to the analysis additional stages of memory B cell development, maintenance and activation at which other peripheral checkpoints may be operative.