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The contribution of anergy to silencing of autoreactive B cells in physiologic settings is unknown. By comparing anergic and nonanergic immunoglobulin-transgenic mouse strains, we defined a set of surface markers that were used for presumptive identification of an anergic B cell cohort within a normal repertoire. Like anergic transgenic B cells, these physiologic anergic cells exhibited high basal intracellular free calcium and did not mobilize calcium, initiate tyrosine phosphorylation, proliferate, upregulate activation markers, or mount an immune response upon antigen-receptor stimulation. Autoreactive B cells were overrepresented in this cohort. On the basis of the frequency and lifespan of these cells, it appears that as many as 50% of newly produced B cells are destined to become anergic. In conclusion, our findings indicate that anergy is probably the primary mechanism by which autoreactive B cells are silenced. Thus maintenance of the unresponsiveness of anergic cells is critical for prevention of autoimmunity.

Available evidence indicates that B cell tolerance is attained by receptor editing, anergy, or clonal deletion. Here, we describe a p-azophenylarsonate (Ars)-specific immunoglobulin transgenic mouse in which B cells become anergic as a consequence of cross-reaction with autoantigen in the bone marrow. Developing bone marrow B cells show no evidence of receptor editing but transiently upregulate activation markers and appear to undergo accelerated development. Mature B cells are present in normal numbers but are refractory to BCR-mediated induction of calcium mobilization, tyrosine phosphorylation, and antibody responses. Activation marker expression and acquisition of the anergic phenotype is prevented in bone marrow cultures by monovalent hapten. In this model, it appears that induction of anergy in B cells can be prevented by monovalent hapten competing with autoantigen for the binding site.