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: Maria Carmina Castiello, Marita Bosticardo, Francesca Pala, Marco Catucci, Nicolas Chamberlain, Menno C van Zelm, Gertjan J Driessen, Malgorzata Pac, Ewa Bernatowska, Samantha Scaramuzza, Alessandro Aiuti, Aisha V Sauer, Elisabetta Traggiai, Eric Meffre, Anna Villa, Mirjam van der Burg
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 50 Pg. 42-50 (May 2014) ISSN: 1095-9157 [Electronic] England
• PMID: 24369837 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• B-Cell Activating Factor
• Chemokine CXCL12
• Immunoglobulin Heavy Chains
• Receptors, Complement 3d
• TNFSF13B protein, human
• Wiskott-Aldrich Syndrome Protein

Topics

• Autoimmunity
• B-Cell Activating Factor (blood, genetics, immunology)
• B-Lymphocytes (immunology, pathology)
• Bone Marrow (immunology, pathology)
• Cell Differentiation
• Cell Movement
• Chemokine CXCL12 (genetics, immunology)
• Disease Susceptibility (immunology)
• Gene Expression
• Homeostasis (immunology)
• Humans
• Immunoglobulin Heavy Chains (genetics, immunology)
• Immunologic Memory
• Receptors, Complement 3d (genetics, immunology)
• Wiskott-Aldrich Syndrome (genetics, immunology, pathology)
• Wiskott-Aldrich Syndrome Protein (deficiency, genetics, immunology)