TY - JOUR
T1 - Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans
AU - Castiello, Maria Carmina
AU - Bosticardo, Marita
AU - Pala, Francesca
AU - Catucci, Marco
AU - Chamberlain, Nicolas
AU - Van Zelm, Menno C.
AU - Driessen, Gertjan J.
AU - Pac, Malgorzata
AU - Bernatowska, Ewa
AU - Scaramuzza, Samantha
AU - Aiuti, Alessandro
AU - Sauer, Aisha V.
AU - Traggiai, Elisabetta
AU - Meffre, Eric
AU - Villa, Anna
AU - Van der Burg, Mirjam
PY - 2014
Y1 - 2014
N2 - 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 invivo 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.
AB - 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 invivo 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.
KW - Autoimmunity
KW - B lymphocyte
KW - B-cell activating factor (BAFF)
KW - Immunoglobulin repertoire
KW - Primary immunodeficiency
KW - Wiskott-aldrich syndrome
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U2 - 10.1016/j.jaut.2013.10.006
DO - 10.1016/j.jaut.2013.10.006
M3 - Article
C2 - 24369837
AN - SCOPUS:84898802787
VL - 50
SP - 42
EP - 50
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
SN - 0896-8411
ER -