The repertoire of mature B cells is positively selected from the pool of immature B cells. As we shall see later, positive selection is well defined in T lymphocytes and is responsible for matching the TCRs on newly generated CD8+ and CD4+ T cells with their ability to recognize self MHC class I and MHC class II molecules, respectively. There is no comparable restriction for B cell antigen recognition. Nevertheless, positive selection appears to be a general phenomenon primarily geared to identification of lymphocytes that have completed their antigen receptor gene rearrangement program successfully. It is believed that only B cells that express functional membrane Ig molecules receive constitutive BCR-derived survival signals, also known as "tonic" BCR signals. Tonic BCR signals mediate the shutoff of Rag gene expression in immature B cells and activate cell survival pathways in all B cells. Self antigens may influence the strength of the BCR signal and thereby the subsequent choice of peripheral B cell lineage during B cell maturation.
Immature B cells that recognize self antigens with high avidity may be induced to change their specificities by a process called receptor editing. In this process, antigen recognition leads to reactivation of Rag genes, additional light chain V-J recombination events, and production of a new Ig light chain, allowing the cell to express a different B cell receptor that is not self-reactive. Receptor editing generally is targeted at self-reactive k light chain genes. VJk exons encoding the variable domains of autoreactive light chains are deleted and replaced by new VJk exons or by newly rearranged X light chain genes. The new VJk exon may be generated by the rearrangement of a Vk gene upstream of the original Vk gene that produced an autoreactive light chain to a Jk segment downstream of the originally rearranged Jk segment.
If receptor editing fails, the immature B cells that express high-affinity receptors for self antigens and encounter these antigens in the bone marrow or the spleen may die by apoptosis. This process is also called negative selection. The antigens mediating negative selection—usually abundant or polyvalent (e.g., membrane-bound) self antigens—deliver strong signals to IgM-expressing immature B lymphocytes that happen to express receptors specific for these self antigens. Both receptor editing and deletion are responsible for maintaining B cell tolerance to self antigens that are present in the bone marrow (see Chapter 14).
Once the transition is made to the IgD+IgM+ mature B cell stage, antigen recognition leads to proliferation and differentiation, not to receptor editing or apoptosis. As a result, mature B cells that recognize antigens with high affinity in peripheral lymphoid tissues are activated, and this process leads to humoral immune responses. Follicular B cells make most of the helper T cell-dependent antibody responses to protein antigens (see Chapter 11).
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