Fig. 10.

The model of classical versus alternate B-cell development. The classical B-cell developmental pathway is favored in the bone marrow where high levels of STAT5 signaling inhibit Igk recombination at the pro-B cell stage. At the large pre-B cell stage, a productive heavy-chain pairs with SLC and pre-BCR signaling at this stage leads to proliferative expansion and positive selection. Autoreactive heavy-chains pair poorly with SLC, and will not experience positive selection in this manner. Following Igk recombination (blue) at the small pre-B cell stage, self-reactive B cells can undergo receptor editing to further select against self-reactive BCRs. The alternate B-cell developmental pathway is favored in fetal liver where low levels of STAT5 signaling in pro-B cells promotes Igk recombination at the same stage as Igh recombination (blue). This enables the generation of B cells expressing a mature BCR instead of a pre-BCR. Here, self-reactive B cells are initially positively selected by self-antigens. Although these B cells can potentially undergo receptor editing to modify their BCRs, the initial positive selection of autoreactive B cells skews the B-1a BCR repertoire toward autoreactivity