Autoreactive B cells are key contributors to autoimmune diseases. Despite a stringent central tolerance checkpoint, some B cells expressing autoreactive antibodies leave the bone marrow and enter the circulation. These B cells, moreover, break central tolerance in higher numbers in autoimmune individuals, and have been described to participate in disease flares in lupus patients. Despite the importance of newly generated autoreactive B cells in autoimmunity, how and why autoreactive B cell precursors undergo or escape central tolerance remains poorly understood. The current model of central tolerance takes into account only the strength of antigen-induced BCR signaling where increasing binding to antigen increases BCR signaling and the level of tolerance (a so called ?negative? model). This model, however, does not take into account the contribution of tonic BCR signaling, a ligand-independent signaling event that promotes differentiation of immature B cells and survival of mature B cells. In fact, removal of tonic BCR signals in nonautoreactive immature B cells causes a phenotype similar to that of autoreactive cells undergoing tolerance, including the induction of receptor editing. This and other findings do not fit well the ?negative? model of B cell tolerance. Our goal is to re-evaluate the model of central B cell tolerance to develop one that more accurately reflects all experimental observations. Specifically, we propose to test two alternative models of central tolerance (?yin- yang? and ?positive?) where tonic BCR signaling in combination or not with antigen-induced BCR signaling regulates receptor editing and cell differentiation in developing autoreactive B cells. Experiments will also test how the duration and amount of BCR stimulation, and the ensuing Ag-induced BCR internalization contribute to central B cell tolerance. The proposed studies are significant because they will lead to a better understanding of the fundamental processes regulating the development of autoreactive B cells and autoantibodies that contribute to autoimmune disorders, and why the B cell repertoire of some individuals is more autoreactive than others.
The proposed research aims at testing alternative models that account for how B cells that make autoantibodies are purged during their genesis. It is relevant to public health because these studies may improve the mechanistic understanding of why the B cell repertoire of some individuals is more self-reactive than others?a finding that might lead to novel methods for determining a predisposition toward B cell- mediated autoimmunity.