title: N-WASP is required for B-cell-mediated autoimmunity in Wiskott-Aldrich syndrome.
abstract: Mutations of the Wiskott-Aldrich syndrome gene (WAS) are responsible for Wiskott-Aldrich syndrome (WAS), a disease characterized by thrombocytopenia, eczema, immunodeficiency, and autoimmunity. Mice with conditional deficiency of Was in B lymphocytes (B/WcKO) have revealed a critical role for WAS protein (WASP) expression in B lymphocytes in the maintenance of immune homeostasis. Neural WASP (N-WASP) is a broadly expressed homolog of WASP, and regulates B-cell signaling by modulating B-cell receptor (BCR) clustering and internalization. We have generated a double conditional mouse lacking both WASP and N-WASP selectively in B lymphocytes (B/DcKO). Compared with B/WcKO mice, B/DcKO mice showed defective B-lymphocyte proliferation and impaired antibody responses to T-cell-dependent antigens, associated with decreased autoantibody production and lack of autoimmune kidney disease. These results demonstrate that N-WASP expression in B lymphocytes is required for the development of autoimmunity of WAS and may represent a novel therapeutic target in WAS.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA; Division of Immunology and Allergy, University Hospital of Lausanne, Laboratory Center of Epalinges, Lausanne, Switzerland; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa and Unità Operativa Pediatria 2, Istituto Giannina Gaslini, Genoa, Italy;
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0002-7129-868X
authors.initials: S
authors.lastname: Volpi
authors.affiliation: Division of Immunology and Allergy, University Hospital of Lausanne, Laboratory Center of Epalinges, Lausanne, Switzerland;
authors.forename: Elettra
authors.initials: E
authors.lastname: Santori
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Katrina
authors.initials: K
authors.lastname: Abernethy
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Carin I M
authors.identifier: http://orcid.org/0000-0002-8610-6302
authors.initials: CI
authors.lastname: Dahlberg
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Mike
authors.initials: M
authors.lastname: Recher
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Kelly
authors.initials: K
authors.lastname: Capuder
authors.affiliation: Transplantation Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Douglas
authors.initials: D
authors.lastname: Ryan
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Divij
authors.initials: D
authors.lastname: Mathew
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Diseases, Massachusetts General Hospital, Boston, MA; Gastroenterology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Westerberg
authors.affiliation: Centre for Immunodeficiency, Section of Molecular and Cellular Immunology, Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, United Kingdom; and.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Division of Immunology and Allergy, University Hospital of Lausanne, Laboratory Center of Epalinges, Lausanne, Switzerland;
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Boston, MA.
authors.forename: Luigi D
authors.identifier: http://orcid.org/0000-0002-8335-0262
authors.initials: LD
authors.lastname: Notarangelo
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000502:physiology*
chemical_list: D011947:Receptors, Antigen, B-Cell; C495772:Wasl protein, mouse; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal