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 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.

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Keywords Autoimmunity, B lymphocyte, B-cell activating factor (BAFF), Immunoglobulin repertoire, Primary immunodeficiency, Wiskott-Aldrich Syndrome
Persistent URL dx.doi.org/10.1016/j.jaut.2013.10.006, hdl.handle.net/1765/61072
Journal Journal of Autoimmunity
Castiello, M.C, Bosticardo, M, Pala, G, Catucci, M, Chamberlain, N, van Zelm, M.C, … van der Burg, M. (2013). Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans. Journal of Autoimmunity. doi:10.1016/j.jaut.2013.10.006