Peripheral B Cell Tolerance

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. 14-9). Signals from helper T cells may be absent if these T cells are deleted or anergic or if the self antigens are nonprotein antigens. Since self antigens do not elicit innate immune responses, B cells will also not encounter any of the cytokines or other signals that are induced during such responses. Thus, as in T cells, antigen recognition without additional stimuli results in tolerance. Peripheral tolerance mechanisms also eliminate autoreactive B cell clones that may be generated as an unintended consequence of somatic mutation in germinal centers.

• Anergy and deletion. Some self-reactive B cells that are repeatedly stimulated by self antigens become unresponsive to further activation. These cells require high levels of the growth factor BAFF/BLys for survival (see Chapter 11) and cannot compete efficiently with less BAFF-dependent normal naive B cells for survival in lymphoid follicles. As a result, these 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. B cells that bind with high avidity to self antigens in the periphery may also undergo apoptotic death by the mitochondrial pathway independent of growth factor dependence.

The high rate of somatic mutation of Ig genes that occurs in germinal centers has the risk of generating self-reactive B cells (see Chapter 11). These B cells may be actively eliminated by the interaction of FasL on helper T cells with Fas on the activated B cells. The same interaction was described before as a mechanism for the death of self-reactive T cells. Failure of this pathway of peripheral B cell tolerance may contribute to the autoimmunity that is caused by mutations in the Fas and FasL genes in mice, and in patients with the autoimmune lymphoproliferative syndrome, referred to earlier.

• Signaling by inhibitory receptors. B cells that recognize self antigens with low affinity 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 with T cell help or innate immunity but does not allow responses to self antigens. This mechanism of peripheral tolerance was revealed by studies showing that mice with defects in the SHP-1 tyrosine phosphatase or the CD22 inhibitory receptor develop autoimmunity. ITIM motifs in

High-avidity self antigen recognition

Self antigen

Self antigen

Self antigen recognition (low or high avidity)

Self antigen

FIGURE 14-9 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.

Inhibitory receptors (e.g.,

CD22)

Inhibitory receptors (e.g.,

CD22)

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