What is the source of self-reactive B cells in the periphery? We have demonstrated that inflammation influences early B cell development by inducing early emigration into the blood and peripheral lymphoid tissues. This mobilization is mediated by IL-1 and TNFalpha and is correlated with increases in the frequency of auto-reactive peripheral B cells. Some evidence suggests that auto-antibody responses, even those characterized by lg class-switched (CSR) and hypermutated (SHM) antibody may bypass the germinal center (GC) reaction. In humans and mice, AID expression is generally believed to be restricted to B cells within GC where lg somatic hypermutation (SHM) and class-switch recombination (CSR) are most active. In birds, rabbits, and sheep AID expression in fetal tissues diversifies the primary antibody repertoire by gene conversion and/or SHM in the absence of activation by exogenous antigens. Recently, we and others demonstrated that immature and transitional B cells in mice constitutively express AID. AID levels are low in these developmental^ immature cells, but sufficient to drive CSR and SHM. We have now demonstrated similar levels of AID expression in human immature and transitional B cells, and most remarkably, in human fetal liver (FL). Indeed, the quantity of AID message (normalized to Igbeta) in FL is comparable to that of human tonsil, a tissue highly enriched for GC B cells. We shall investigate developmentally regulated AID expression in human pro-, pre-, and immature/transitional B cells to determine the consequences of early AID expression, and especially its role in the generation of auto-reactive, peripheral B lymphocytes. These experiments in normal subjects will be extended to patients with autoimmune disease and may reveal another pathway leading to mutated, self-reactive B cells that mature outside the normal boundaries of central tolerance.
We shall study the effects of inflammation on B-cell development and the acquisition self-reactivity. Our studies will be important in understanding pathogenesis of systemic auto-immune diseases, especially SLE, myasthenia gravis, and Goodpasture's syndrome.
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