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EnglishWiskott-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
Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients / F. Pala, H. Morbach, M. Castiello, J. Schickel, S. Scaramuzza, N. Chamberlain, B. Cassani, S. Glauzy, N. Romberg, F. Candotti, A. Aiuti, M. Bosticardo, A. Villa, E. Meffre. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 125:10(2015 Oct), pp. 3941-3951. [10.1172/JCI82249]
| Titolo: | Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients | |
| Autori: | ||
| Settore Scientifico Disciplinare: | Settore BIO/13 - Biologia Applicata Settore MED/04 - Patologia Generale | |
| Data di pubblicazione: | ott-2015 | |
| Rivista: | ||
| Tipologia: | Article (author) | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1172/JCI82249 | |
| Appare nelle tipologie: | 01 - Articolo su periodico |
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