Central B-Cell Tolerance:Where Selection Begins

The development of an adaptive immune system based on the random generation of antigen receptors requires a stringent selection process that sifts through receptor specificities to remove those reacting with self-antigens. In the B-cell lineage, this selection process is first applied to IgMþ immature B cells. By using increasingly sophisticated mouse models, investigators have identified the central tolerance mechanisms that negatively select auto-reactive immature B cells and prevent inclusion of their antigen receptors into the peripheral B-cell pool. Additional studies have uncovered mechanisms that promote the differentiation of nonautoreactive immature B cells and their positive selection into the peripheral B-cell population. These mechanisms of central selection are fundamental to the generation of a naı̈ve B-cell repertoire that is largely devoid of self-reactivity while capable of reacting with any foreign insult. B-cell generation in the bonemarrow of adultmammals occurs through a tightly con-trolled developmental process (Fig. 1). Produc-tive rearrangement of immunoglobulin heavy (IgH) and light (IgL) chain gene segments in