Silencing of autoreactive B cells by anergy: a fresh perspective

B-cell antigen receptor (BCR) signals are crucial for initiation of humoral immune responses and must be actively modulated and/or terminated in preparation for receipt of subsequent cues for progression. BCR signaling is also actively inhibited in autoreactive cells in which unresponsiveness is maintained by anergy. This serves to prevent cell activation and autoimmunity. Importantly, the feedback mechanisms that modulate and/or terminate signaling during normal antigen-induced B-cell activation appear to also be involved in maintaining B-cell anergy. In fact, it is suggested that anergy reflects nothing more than the normal inability of cells to respond to antigen following preceding stimulation of normal inhibitory feedback mechanisms. Thus, the time-honored two-signal hypothesis is almost certainly correct, with second signals being required to release the cell from inhibitory BCR-specific and trans-active feedback regulation.