Negative Selection of B Cells

Immature B cells that encounter antigen with high affinity for the BCR may die in the bone marrow by apoptosis. This process appears to be very effective for B cells specific to abundant, multivalent self-antigens displayed on cell surfaces, as has been shown for an MHC class I epitope [78] or for epitopes on erythrocytes [79], presumably resulting in extensive BCR cross-linkage. A concern of studies directly demonstrating deletion of Ig transgenic B cells is that these cells may not respond in a normal way to receptor engagement. However, comparisons in normal mice of the production of immature B cells in the bone marrow with B-cell emigration to the spleen indicate that only 15-20% [80] or 10% [81] of newly arising B cells reach the periphery, suggesting that the vast majority of newly formed B cells die in the bone marrow [81]. It is possible that many of these cells do not survive because they fail to produce functional BCR signaling machinery. However, Wardemann et al. [82] demonstrated that while 76% of pre-B cells or early immature B cells from human bone marrow are potentially self-reactive, this number drops to 40% in immature bone marrow

Fig. 4.2 B-cell tolerance and autoreactivity. In the bone marrow (upper panel), random rearrangement of genetic elements encoding the BCR produces pre-B cells that either die through neglect because of failure to assemble a functioning signaling complex or are tested for reactivity to multivalent self-antigens in their environment. Reactive cells either die through negative selection or engage the DNA recombinase machinery to produce an alternate light chain. Cells that replace their light chains by receptor editing to produce a BCR with low avidity for self emigrate to the periphery. Many B cells escape this central tolerance machinery and enter the periphery with autoreactive potential. Under some conditions, immature auto-reactive B cells may become anergic by con tact with antigen. In the periphery, if a B cell encounters antigen with high affinity for its BCR as well as specific T-cell help, it may become activated, multiply into a B-cell clone, and secrete antibody. Some B cells can be activated by multivalent antigens in the absence of T-cell help (not shown). Somatic mutation of the BCR driven by T-cell help can enhance the affinity of the BCR to produce an overtly autoreactive B cell. Upre-gulation of Fas limits expansion of the B-cell clone by initiating cell death upon encountering Fas ligand on activated T cells or as a soluble agonist in its environment. Other peripheral tolerance mechanisms have also been observed, including receptor editing, failure to develop proper germinal centers, and cytokine-mediated suppression.

B cells and 20% in mature, peripheral B cells, suggesting that most of the discrepancy between B-cell production in the bone marrow and B-cell immigrants in the periphery is due to negative selection of autoreactive cells. Nevertheless, the importance of this process in maintaining self-tolerance is unclear because it has not yet been shown that failure of or deficiency in negative selection of B cells results in autoimmunity.

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