Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients.
Détails
Télécharger: BIB_B13635B49D35.P001.pdf (3353.20 [Ko])
Etat: Public
Version: Author's accepted manuscript
Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_B13635B49D35
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients.
Périodique
Journal of Clinical Investigation
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
125
Numéro
10
Pages
3941-3951
Langue
anglais
Résumé
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients.
Pubmed
Open Access
Oui
Création de la notice
24/09/2015 14:46
Dernière modification de la notice
20/08/2019 16:20