Central B-cell tolerance mediated by Aicda and Myd88 (P4404)

Abstract

Abstract Elimination of autoreactive B cells and establishment of self-tolerance is crucial for the prevention of autoimmunity, nonetheless, the mechanism(s) of B-cell tolerance are not fully understood. Recently, we and others have reported that activation-induced cytidine deaminase (AID) and myeloid differentiation primary response gene 88 (MyD88) play unexpected roles in establishing central B-cell tolerance in mice and humans. AID expression in bone marrow immature B cells is synergistically elevated by anti-IgM F(ab’)2 and oligo CpG DNA co-stimulation; reaches to near germinal center levels in 24 hours, but the synergistic effect was not observed by anti-IgM and lipopolysaccharide co-stimulation. These results imply that co-ordination between BCR- and intracellular Toll-like receptors/MyD88 signals regulate AID expression in immature B cells. This synergy was not seen in mature follicular B cells. To explore molecular pathway(s) downstream of AID in B-cell tolerance, we analyzed B-cell development in uracil-DNA glycosylase (UNG)-deficient mice. Unlike AID- or MyD88-deficient background, UNG-deficiency did not impair central B-cell tolerance; because UNG-deficiency severely impairs class-switch recombination (CSR) but not somatic hypermutation, our results imply CSR, e.g., “locus suicide recombination”, may not play a major role in central B-cell tolerance.