Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients

Francesca Pala, Henner Morbach, Maria Carmina Castiello, Jean Nicolas Schickel, Samantha Scaramuzza, Nicolas Chamberlain, Barbara Cassani, Salome Glauzy, Neil Romberg, Fabio Candotti, Alessandro Aiuti, Marita Bosticardo, Anna Villa, Eric Meffre

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3941-3951
Number of pages11
JournalJournal of Clinical Investigation
Issue number10
Publication statusPublished - Oct 1 2015

ASJC Scopus subject areas

  • Medicine(all)


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