Figure 1.

Intrinsic molecular requirements for human B cell development as revealed by IEIs. B cell development occurs in the BM and involves the sequential progression of HSCs into CLP, which then gives rise to progenitor B cells committed to a B cell fate. B cell development requires assembly and expression of a functional BCR. The initial stages of Ig gene rearrangement occur at the early and late pro-B cell stages. Pro-B cells that successfully express cytoplasmic Igµ chains develop into pre-BI cells that express a preBCR; rearrangement of Ig L chain genes occurs in pre-BII cells, which then express a functional sIgM molecule. Pre-B cells develop into immature B cells which then give rise to transitional B cells which egress from the BM and enter the peripheral circulation. Genetic variants causing severe disruption to B cell development are shown in red, and those having a milder effect on B cell development are shown in blue. Some of these latter variants also result in an accumulation of transitional B cells (shown in purple). Data for the impact of Pax5 deficiency on B cell development are inferred from studies of a mouse model expressing the human mutations.