The Wiskott-Aldrich syndrome (WAS) is a severe immune deficiency, caused by mutations of WASP, that belongs to a family of proteins that control de novo actin nucleation. It is unclear whether defects in humoral immunity observed in patients with WAS and in WASP-/- mice reflect a B-cell intrinsic role of WASP for B cell differentiation, and function, and whether N-WASP may play a compensatory role in these processes. We will test the hypothesis that lack of expression of WASP and/or N-WASP affects B lymphocyte maturation, homing and function in a cell-intrinsic fashion. To this purpose, we will study in vivo competition models between WASP+ and WASP- cells in humans and mice. We will also develop conditional knock-out models in which expression of WASP and/or N-WASP is ablated in B lymphocytes. Specifically, we will: 1) analyze the role of WASP in B cell development and maturation, through the analysis of in vivo competition models both in mice and in humans. The proportion of memory and naive B cells will be analyzed among WASP+ and WASP- cells in carriers of XLT. We will also analyze the role of WASP in germinal center reaction and somatic hypermutation following immunization in WASP+/- mice and in WASP+/- mice in which expression of N-WASP is deleted in B cells. 2) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell maturation, homing and function in vivo. To this purpose, we will develop a conditional model of WASP deficiency in B cells. We will test the peripheral distribution and homing of B cells, and response to immunization in mice with B-cell specific lack of WASP and/or N-WASP. We will analyze susceptibility of mice with B-cell-specific deficiency of WASP to invasive S. pneumoniae infection, and explore possible defects in the number of IgM memory B cells in patients with WASP gene mutations. 3) test the hypothesis that the B-cell specific lack of WASP and/or N-WASP affects B cell function in vitro. To this purpose, chemotaxis, activation and class-switch recombination will be studied in vitro in B cells from mice with B-cell specific lack of WASP and/or N-WASP. We anticipate that the results of .this project will allow a better understanding of the biology of WAS, and will be important for development of novel forms of treatment of WAS, including gene therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Baptista, Marisa A P; Keszei, Marton; Oliveira, Mariana et al. (2016) Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells. Nat Commun 7:12175
Volpi, Stefano; Santori, Elettra; Abernethy, Katrina et al. (2016) N-WASP is required for B-cell-mediated autoimmunity in Wiskott-Aldrich syndrome. Blood 127:216-20
Shouval, Dror S; Biswas, Amlan; Kang, Yu Hui et al. (2016) Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency. Gastroenterology 151:1100-1104
Lexmond, Willem S; Goettel, Jeremy A; Lyons, Jonathan J et al. (2016) FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy. J Clin Invest 126:4030-4044
Moran, Christopher J; Klein, Christoph; Muise, Aleixo M et al. (2015) Very early-onset inflammatory bowel disease: gaining insight through focused discovery. Inflamm Bowel Dis 21:1166-75
Crestani, Elena; Volpi, Stefano; Candotti, Fabio et al. (2015) Broad spectrum of autoantibodies in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia. J Allergy Clin Immunol 136:1401-4.e1-3
Grozovsky, Renata; Begonja, Antonija Jurak; Liu, Kaifeng et al. (2015) The Ashwell-Morell receptor regulates hepatic thrombopoietin production via JAK2-STAT3 signaling. Nat Med 21:47-54
Goettel, Jeremy A; Biswas, Subhabrata; Lexmond, Willem S et al. (2015) Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. Blood 125:3886-95
Begonja, Antonija Jurak; Pluthero, Fred G; Suphamungmee, Worawit et al. (2015) FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. Blood 126:80-8
Kolhatkar, Nikita S; Brahmandam, Archana; Thouvenel, Christopher D et al. (2015) Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome. J Exp Med 212:1663-77

Showing the most recent 10 out of 106 publications