The ups and downs of negative (and positive) selection of B cells
Jean-Claude Weill, Claude-Agnès Reynaud
Jean-Claude Weill, Claude-Agnès Reynaud
Published September 14, 2015
Citation Information: J Clin Invest. 2015;125(10):3748-3750. https://doi.org/10.1172/JCI84009.
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Commentary

The ups and downs of negative (and positive) selection of B cells

Abstract

Central and peripheral tolerance checkpoints are in place to remove autoreactive B cell populations and prevent the development of autoimmunity. In this issue of the JCI, Pala and colleagues reveal that individuals with the X-linked immunodeficiency Wiskott-Aldrich syndrome (WAS) have opposite alterations at central and peripheral B cell checkpoints: a more stringent selection for central tolerance, resulting in reduced numbers of autoreactive cells at the emergent immature B cell stage, and a relaxed selection for peripheral tolerance, resulting in an increased frequency of autoreactive cells in the mature naive B cell compartment. Moreover, reinstatement of the WAS gene in these patients restored both B cell tolerance checkpoints. These results suggest that, in a normal situation, mature naive B cells undergo a positive selection step driven by self-antigens, kept in control by Tregs.

Authors

Jean-Claude Weill, Claude-Agnès Reynaud

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Figure 1

GT corrects abnormal B cell tolerance checkpoints in patients with WAS.

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GT corrects abnormal B cell tolerance checkpoints in patients with WAS. ...
Autoreactivity, as measured through the Hep-2 cell binding assay, is controlled at two steps: in the BM at the transition from pre-B to immature B cell stage (central tolerance) and at the periphery (evaluated in blood) at the transitional/immature to mature B cell stage (peripheral tolerance). In healthy donors (HDs), 70% of pre-B cells are autoreactive, with the central tolerance checkpoint reducing the proportion of autoreactive immature B cells to 40%. Following transition to the periphery, peripheral tolerance checkpoints result in autoreactivity in only 20% of the mature B cell population (5). B cells in WAS patients have an unusual profile with enhanced negative selection at the central tolerance checkpoint and relaxed negative (i.e., increased positive selection) at the peripheral checkpoint. Both anomalies are corrected after GT to restore a functional WAS gene.