Castiello, MC, Bosticardo, M, Pala, F, Catucci, M, Chamberlain, N, van Zelm, MC, Driessen, GJ, Pac, M, Bernatowska, E, Scaramuzza, S, Aiuti, A, Sauer, AV, Traggiai, E, Meffre, E, Villa, A and van der Burg, M (2013) Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans. Autoimmunity.

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-1alpha, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21low 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

Item Type:	Article
Additional Information:	pubid: 246 nvp_institute: NIBR contributor_address: San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, ItalyDepartment of Immunobiology, Yale University School of Medicine, New Haven, 06150 CT, USADepartment of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The NetherlandsDepartment of Pediatrics, Erasmus MC, 3015 CE Rotterdam, The NetherlandsDepartment of Immunology, The Children's Memorial Health Institute, 04 730 Warsaw, PolandDepartment of Immunology, The Children's Memorial Health Institute, 04 730 Warsaw, PolandSan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, ItalySan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; Department of Public Health and Cell Biology, Tor Vergata University, 00173 Rome, ItalySan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, ItalyNovartis Institute for Research in Biomedicine, 4002 Basel, SwitzerlandDepartment of Immunobiology, Yale University School of Medicine, New Haven, 06150 CT, USASan Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), 20132 Milan, Italy; IRGB CNR, Milan Unit, 20090 Milan, Italy. Electronic address: villa.anna@hsr.itDepartment of Immunology, Erasmus MC, University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22051