Tolerance in polyclonal and oligoclonal immune systems

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DESCRIPTION (provided by applicant): Autoreactive B cells are typically eliminated by mechanisms of tolerance before exiting the bone marrow or upon arrival in peripheral lymphoid organs. Despite this, autoantibody-secreting B cells are known to exist in healthy individuals and are not only the primary effectors of many autoimmune diseases, but they are also linked to lymphoproliferative disorders. The long-term goal of this application is to 1) define the parameters that determine which of the several available mechanisms of B cell tolerance is used to censor autoreactive B cells; 2) how these mechanisms may fail and allow autoreactive B cells to migrate to the periphery; and 3) how, once in the periphery, autoreactive B cells become activated to secrete autoantibodies. In mouse models of B cell tolerance, autoreactive B cells have been shown to evade mechanisms of central tolerance by co-expressing a non-autoreactive immunoglobulin specificity. Rare dual immunoglobulin-expressing human B cells are also found in healthy and diseased individuals, although it is not clear whether these cells are effectors of pathologic conditions. This proposal addresses the role of dual immunoglobulin expressing B cells as possible mediators of autoimmunity. Receptor editing is a major mechanism of B cell tolerance that operates within newly generated autoreactive B cells by secondary immunoglobulin gene rearrangements that most frequently eliminate autoreactivity. Interestingly, recent evidence has suggested that receptor editing may also generate dual immunoglobulin expressing B cells. The studies outlined in this proposal will define the potential of receptor editing to generate dual immunoglobulin-expressing autoreactive B cells and the ability of these cells to produce autoantibodies. Specifically, the Aims described in this proposal will determine whether: 1) the prevalence of dual immunoglobulin-expressing B cells depends on autoantigen avidity; 2) dual immunoglobulin-expressing autoreactive B cells are generated through receptor editing in wild type animals; 3) antigen stimulation of dual immunoglobulin-expressing autoreactive B cells can drive autoantibody production. The influence of antigen avidity and autoreactive B cell clonal frequency on the extent of receptor editing and on the development of dual antibody-expressing autoreactive B cells will be analyzed by using bone marrow chimeras of anti-MHC I immunoglobulin knock-in cells in various congenic wild type mouse strains. Receptor editing will be inhibited in vivo to determine whether this tolerance mechanism underlies the presence of dual antibody-expressing B cells. The capacity of dual-immunoglobulin expressing B cells to mount an immune response will be defined in vitro and in adoptive cell transfer in vivo systems.