title: Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans.
abstract: Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Marita
authors.initials: M
authors.lastname: Bosticardo
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pala
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Catucci
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, 06150 CT, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: Department of Pediatrics, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
authors.forename: Gertjan J
authors.initials: GJ
authors.lastname: Driessen
authors.affiliation: Department of Immunology, The Children's Memorial Health Institute, 04 730 Warsaw, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Pac
authors.affiliation: Department of Immunology, The Children's Memorial Health Institute, 04 730 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Scaramuzza
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; Department of Public Health and Cell Biology, Tor Vergata University, 00173 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy.
authors.forename: Aisha V
authors.initials: AV
authors.lastname: Sauer
authors.affiliation: Novartis Institute for Research in Biomedicine, 4002 Basel, Switzerland.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, 06150 CT, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; IRGB CNR, Milan Unit, 20090 Milan, Italy. Electronic address: villa.anna@hsr.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
mesh_terms: D015551:Autoimmunity; D053264:B-Cell Activating Factor / Q000097:blood / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology*; D015870:Gene Expression; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency* / Q000235:genetics / Q000276:immunology
chemical_list: D053264:B-Cell Activating Factor; D054377:Chemokine CXCL12; D007143:Immunoglobulin Heavy Chains; D017464:Receptors, Complement 3d; C505719:TNFSF13B protein, human; D051316:Wiskott-Aldrich Syndrome Protein
keywords: Autoimmunity; B lymphocyte; B-cell activating factor (BAFF); Immunoglobulin repertoire; Primary immunodeficiency; Wiskott–Aldrich Syndrome