An innate path to human B cell tolerance

Abstract

Self-reactive B cells are eliminated during development by antibody-affinity selection and receptor-editing mechanisms. Work by Isnardi et al. (2008) in this issue of Immunity suggests that removal of autoreactivity from the immature B cell pool also requires innate immunity pathways.

Figure 1. Alterations in Both Central and Peripheral B Cell Tolerance Checkpoints in Humans with Deficiencies in Innate Immunity

Healthy controls generate highly autoreactive repertoires in the early immature stage. A central-tolerance checkpoint removes a large proportion of autoreactive B cells in the bone marrow, primarily through receptor editing. Immature B cells exit from the bone marrow as new emigrant B cells, normally with a low degree (7%) of autoreactivity. A second tolerance checkpoint occurs during B cell maturation, although its molecular mechanism is largely unknown and might depend on BAFF or T cell help. Work by Isnardi et al. (2008) now shows that deficiencies in IRAK-4 and MyD88 in humans result in alterations of the central- and peripheral-tolerance checkpoints and a defect in B cell receptor editing. In contrast, UNC93B mutations in humans change the peripheral-tolerance checkpoint, but not the central-tolerance checkpoint.