During B cell development in the bone marrow (BM) random immunoglobulin (Ig) gene rearrangement? generates a highly diverse antibody repertoire, including B cells that express autoreactive antibodies.? Experiments with transgenic mice indicate that three mechanisms - receptor editing, deletion and anergy -? account for silencing of self-reactive B cells and ensure self-tolerance. We have recently shown that the? majority of antibodies expressed by developing B cells in the BM of healthy human donors recognize selfantigens,? but self-reactive antibodies are lost from the repertoire at two checkpoints: at the immature B cell? stage in the BM and in the periphery before maturation into naive immunocompetent B cells. Autoantibodies? can also be generated by random somatic hypermutation of Ig genes during active immune responses, but? the frequencies at which such autoantibodies are generated, how they are regulated and the role of B cell? tolerance checkpoints during antigen-mediated B cell differentiation into memory and plasma cells are not? known. The finding that large numbers of autoantibodies are produced under physiologic circumstances? suggests that even small changes in the efficiency of autoantibody regulation at any stage during B cell? development and differentiation would lead to increased susceptibility to autoimmunity. A hallmark of the? systemic autoimmune disease lupus erythematosus (SLE) is the production of autoantibodies making this? disease a useful model to study B cell tolerance checkpoints. Our preliminary data show that early? checkpoints in B cell tolerance are abnormal in SLE, and that B cells emerging from the bone marrow of? such patients are not adequately filtered to remove autoreactivity. The long-range goal of the proposed? research project is (I) to define B cell tolerance checkpoints in healthy humans, (II) to determine where B cell? tolerance is broken in SLE and (III) how B cell tolerance checkpoints are affected by therapy in patients with? SLE.
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