Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance

A substantial fraction of mature naïve B cells recognize endogenous antigens, and this autoreactivity must be controlled to prevent autoantibody secretion. Selective downregulation of the IgM BCR on autoreactive B cells has long been appreciated, and recent findings illustrate how this might impose tolerance. The BCR isotype maintained on autoreactive B cells, IgD, is less sensitive to endogenous antigens than IgM. This reduced sensitivity may be conferred by structural properties of IgD and/or differential association with activating and inhibitory co-receptors. Once activated, autoreactive B cells are normally excluded from rapid plasma cell responses, but they can enter the germinal center and lose their autoreactivity through a mutation-selection process termed clonal redemption.