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.
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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)
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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
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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)
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