title: Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients.
abstract: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pala
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.forename: Jean-Nicolas
authors.initials: JN
authors.lastname: Schickel
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
authors.forename: Salome
authors.initials: S
authors.lastname: Glauzy
authors.forename: Neil
authors.initials: N
authors.lastname: Romberg
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D017637:Clonal Deletion; D002999:Clone Cells / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D007108:Immune Tolerance; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000276:immunology / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein