Mature B lymphocytes that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive or die by apoptosis (Fig. 1). Signals from helper T cells may be absent if these T cells are deleted or anergic (in the case of protein antigens) or if the self antigens are nonprotein antigens. Because self antigens do not elicit innate immune responses, B cells will also not be activated via complement receptors or pattern recognition receptors. Thus, as in T cells, antigen recognition without additional stimuli results in tolerance.
Several mechanisms of peripheral tolerance in B cells have been described.
• Anergy. Some self-reactive B cells that are repeatedly stimulated by self antigens become unresponsive to further activation. Anergic B cells require higher-than-normal levels of the growth factor BAFF (B cell–activating factor, also called BLys [B-lymphocyte stimulator]) for survival, and they cannot compete with normal naive B cells for BAFF. As a result, the B cells that have encountered self antigens have a shortened life span and are eliminated more rapidly than cells that have not recognized self antigens.
• Deletion. B cells that bind with high avidity to self antigens in the periphery may also undergo apoptotic death by the mitochondrial pathway. Deletion of B cells specific for protein anti gens may occur outside the bone marrow at the transitional B-cell stages found in the spleen and the blood. Transitional B cells are cells that are in the process of maturing in the periphery into follicular B cells. A substantial fraction of transitional B cells may be autoreactive, and most of them are deleted and do not mature into follicular B cells. The mechanisms of deletion at the transitional B-cell stage are not well defined.
• Signaling by inhibitory receptors. B cells that recognize self antigens may be prevented from responding by the engagement of various inhibitory receptors. The function of these inhibitory receptors is to set a threshold for B-cell activation, which allows responses to foreign antigens because these typically elicit strong signals from the combination of BCR, coreceptors, innate immune receptors, and helper T cells (for protein antigens), but does not allow responses to self antigens, which trigger weaker signals because they engage only the BCR. This mechanism of peripheral tolerance was revealed by studies showing that mice with defects in the inhibitory receptors FcγRIIB and CD22 develop autoimmunity. FcγRIIB mediates the process of antibody feedback, which limits B-cell responses. Variants of FcγRIIB are associated with susceptibility to the autoimmune disease systemic lupus erythematosus (SLE). CD22, also known as Siglec-2, binds to sialic acid that decorates sugar side chains of proteins on the B-cell surface and dampens BCR signaling. Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic tail of CD22 are phosphorylated by LYN, and this inhibitory receptor then recruits SHP-1, thus attenuating BCR signaling. Mice with knockout of LYN and SHP-1 also develop autoimmunity. How exactly CD22 contributes to B-cell tolerance is not fully understood.
• Regulation of B cells by Tregs. Tregs suppress B-cell responses, mainly by inhibiting the activation of helper T cells. A specialized subset of Tregs, called T follicular regulatory (Tfr) cells, enter lymphoid follicles and contribute to the attenuation of T-cell help to germinal center B cells during antibody responses. Defects in regulatory T cells have also been shown to result in increased numbers of Tfh cells being generated outside the follicle at the boundary between the B-cell zone and the T-cell zone. Thus, both Tregs outside the follicle and Tfr cells in the germinal center limit Tfh cell numbers and activity and thus inhibit the activation of B cells in germinal centers. the somatic hypermutation that occurs in germinal center B cells has the potential of generating B cells with receptors for self antigens, and these B cells have to be controlled or eliminated. Predictably, deficiency of Tregs is associated with autoantibody production.
Fig1. Peripheral tolerance in B cells. B cells that encounter self antigens in peripheral tissues become anergic or die by apoptosis. In some situations, recognition of self antigens may trigger inhibitory receptors that prevent B-cell activation.
