During their maturation in the bone marrow, B lymphocytes first express IgM as their antigen receptor and are function ally immature at this stage. Many immature B lymphocytes that recognize self antigens in the bone mar row either change their specificity or are deleted (Fig. 1).
• Receptor editing. If immature B cells recognize self antigens that are present at a high concentration in the bone marrow, and especially if the antigen is displayed in multivalent form (e.g., on cell surfaces), several antigen receptors on each self reactive B cell are cross-linked, thus delivering strong signals to the cells. One consequence of such signaling is that the self-reactive immature B cells reactivate their RAG1 and RAG2 genes and initiate a new round of VJ recombination in the Ig κ light chain gene locus. A Vκ segment upstream of the already rearranged VκJκ unit is joined to a downstream Jκ. As a result, the previously rearranged VκJκ exon in the self-reactive B cell is removed, and a new Ig light chain is expressed, thus creating a B-cell receptor (BCR) with a new specificity. This process, called receptor editing, is an important mechanism for eliminating self-reactivity from the mature B-cell repertoire. If the edited light chain rearrangement is nonproductive or if the new receptor is self reactive, additional Vκ-to-Jκ rearrangements will be made in the same locus, and if these are nonproductive or produce self-reactive receptors, the process may proceed at the κ locus on the other chromosome; if that is also nonproductive or generates self-reactive receptors, rearrangements at the λ light chain loci may follow. A B cell expressing a λ light chain is usually a cell that has undergone receptor editing. It is estimated that among peripheral blood B cells in humans, as many as one-quarter to one-half of all the cells and the majority of λ-expressing cells have undergone receptor editing during their maturation.
• Deletion. Strong recognition of self antigens by immature B cells in the bone marrow may lead to apoptosis of these B cells. This is presumably similar to apoptosis in T cells, when high-affinity antigen recognition in the thymus triggers the mitochondrial pathway of apoptosis, but the mechanisms are not well defined. It is possible that self-reactive B cells first change their specificity and they are eliminated only if receptor editing fails. Some B cells that are specific for DNA receive simultaneous signals from the BCR and from TLR9 in endosomes that can lead to death of the B cells.
• Anergy. If developing B cells recognize self antigens weakly (e.g., if the antigen is soluble and does not cross-link many antigen receptors or if the BCRs recognize the antigen with low affinity), the cells become functionally unresponsive (anergic) and exit the bone marrow in this unresponsive state. Anergy is due to downregulation of antigen receptor expression and a block in antigen receptor signaling.
Fig1. Central tolerance in B cells. (A) Immature B cells that recognize self antigens in the bone marrow with high avidity (e.g., multivalent arrays of antigens on cells) die by apoptosis or change the specificity of their antigen receptors (receptor editing, which involves only light chains but is illustrated as a change in the antigen-binding region of the receptor). (B) Weak recognition of self antigens in the bone marrow may lead to anergy (functional inactivation) of the B cells. Ig, Immunoglobulin.
