Activation of Anergic B Cells During Development of Autoimmunity

In healthy individuals, autoreactive B cells are normally silenced via central and peripheral tolerance mechanisms. In the periphery, when autoreactive B cells recognize self-antigen via their B cell receptor (BCR) (signal 1) but do not receive T cell help (signal 2), they undergo the tolerance mechanism called anergy. Human anergic B cells are termed B_ND (Naïve IgD+ B cells). Previous studies have shown that B_ND cells are decreased in the peripheral blood of individuals with autoimmunity, suggesting they may have become activated and contributed to the development of disease. In line with this, recently it has been found that a portion of the remaining anergic B cells present in the blood of autoimmune individuals exhibit an activated phenotype. In this review, we will summarize what is known and unknown about these cells, including their relation to other recognized autoreactive B cell subsets, how they become activated in the first place, and what their pathogenic functions are. Understanding how B_ND cells break tolerance and contribute to disease will advance the development of new therapeutic approaches and highlight novel cell populations amenable to depletion.