Once a rearranged light chain has paired with a μ chain, IgM can be expressed on the cell surface (as a surface IgM, or sIgM) and the pre-B cell becomes an immature B cell. At this stage, the antigen receptor is first tested for reactivity to self antigens, or autoreactivity. The elimination or inactivation of autoreactive B cells ensures that the B-cell population as a whole will be tolerant of self antigens. The tolerance produced at this stage of B-cell development is known as central tolerance because it arises in a central lymphoid organ, the bone marrow. However, B cells leaving the bone marrow are not fully mature and require additional maturation steps that take place in peripheral lymphoid organs (see Section 8-8). As we shall see later in the chapter and in Chapter 15, self-reactive B cells that escape central tolerance may still be removed from
Fig. 8.9 Binding to self molecules in the bone marrow can lead to the death or inactivation of immature B cells.
First panels: immature B cells that do not encounter antigen mature normally; they migrate from the bone marrow to the peripheral lymphoid tissues, where they may become mature recirculating B cells bearing both IgM and IgD on their surface. Second panels: when developing B cells express receptors that recognize multivalent ligands, for example, ubiquitous cell-surface self molecules such as those of the MHC, these receptors are deleted from the repertoire. The B cells either undergo receptor editing (see Fig. 8.10), thereby eliminating the self-reactive receptor, or the cells themselves undergo programmed cell death (apoptosis), resulting in clonal deletion. Third panels: immature B cells that bind soluble self antigens able to cross-link the B-cell receptor are rendered unresponsive to the antigen (anergic) and bear little surface IgM. They migrate to the periphery, where they express IgD but remain anergic; if in competition with other B cells in the periphery, anergic B cells fail to receive survival signals and die. Fourth panels: immature B cells whose antigen is inaccessible to them, or which bind monovalent or soluble self antigens with low affinity, do not receive any signal and mature normally. Such cells are potentially self-reactive, however, and are said to be clonally ignorant because their ligand is present but is unable to activate them.
the repertoire after they have left the bone marrow, a process that takes place during the final peripheral stages of B-cell maturation, and is referred to as peripheral tolerance, described in Section 8-7.
sIgM associates with Igα and Igβ to form a functional B-cell receptor complex, and the fate of an immature B cell in the bone marrow depends on signals delivered from this receptor complex when it interacts with ligands in the environment. Igα signaling is particularly important in dictating the emigration of B cells from the bone marrow and/or their survival in the periphery: mice that express Igα with a truncated cytoplasmic domain that cannot signal show a fourfold reduction in the number of immature B cells in the marrow, and a hundredfold reduction in the number of peripheral B cells. The release of immature B cells from the bone marrow into the circulation is also dependent on their expression of S1PR1, a G-protein-coupled receptor that binds to the lipid ligand S1P and promotes cell migration towards the high concentrations of S1P that exist in the blood (see Section 8-27).
Immature B cells that have no strong reactivity to self antigens continue to mature (Fig. 8.9, first panel). They leave the marrow via sinusoids that enter the central sinus, enter the circulation, and are carried by the venous blood supply to the spleen. If, however, the newly expressed receptor encounters a strongly cross-linking antigen in the bone marrow—that is, if the B cell is strongly self-reactive—development is arrested at this stage.