B cell–intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice

Abstract

Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS IntroductionWiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by mutations of the WAS gene that is widely expressed within hematopoietic cells. 1 The clinical phenotype of WAS is characterized by congenital thrombocytopenia, combined immunodeficiency, and eczema. 1 The WAS protein (WASp) includes several functional domains that couple signal transduction to reorganization of the actin cytoskeleton. As a result, WASp has significant influence on processes such as cell adhesion, migration, assembly/turnover of cell surface receptors, and immunologic synapse formation. 1,2 Several studies in patients with WAS and in Was knock-out (WKO) mice have shown that WASp plays a critical role in the function of T and natural killer lymphocytes and dendritic cells. 1,3 However, the importance of WASp in B-cell development and function is less clearly defined. In vitro studies have shown that WASp-deficient B cells display defective actin polymerization on activation, 4 and impaired migration in response to CXCL13 5 ; however, calcium mobilization and proliferation after B-cell receptor ligation were found to be normal or only slightly reduced. 3 Studies in heterozygous Was ϩ/Ϫ mice have found progressive in vivo selection for WASp-expressing cells in T, B, and natural killer lineages. 6 Within the B-cell lineage, such selective advantage was especially prominent in marginal zone (MZ) B cells. 2,6 However, the in vivo effect of selective deficiency of WASp expression within a single lineage has not been analyzed so far and is of critical importance to understand WAS pathophysiology. Recently, with the use of a chimeric BM transplantation reconstitution model, Becker-Herman et al have provided evidence that lack of WASp expression in B lymphocytes causes immune dysregulation and may lead to fatal autoimmunity. 7 However, mixed chimerism in non-B lineages, irradiation-induced load of The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 2819BLOOD, 22 MARCH 2012 ⅐ VOLUME 119, NUMBER 12For personal use only. on May 9, 2018. by guest www.bloodjournal.org From apoptotic bodies, and homeostatic B-cell proliferation may also have contributed to autoimmunity in that model.We describe here the generation of mice in which the Was locus has been floxed by homologous recombination. By crossing these mice to mb1-Cre knock-in mice, 8 which express the Cre recombinase under control of the CD79a promoter, the Was locus is selectively and efficiently deleted in B cells only, allowing analysis of the effect of B cell-restricted deficiency of WASp in vivo. Methods MiceAll mice were bred on a C57BL/6 background. WKO mice have been described. 3 Mb1-Cre mice 8 were a generous gift from Dr Michael Reth (Max Planck Institute of Immunobiology, ...

The sting of WASP deficiency: autoimmunity exposed

“…Solid tumors were observed at a similar rate to the general population. This incidence of MDS/AML is lower than has been reported by the MD Anderson group with FCR, 5,6 perhaps relating to the duration of follow-up. It has yet to be determined how these long-term toxicities compare with kinase inhibitors, but this will be an important question for the future.…”

Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor

“…(B) Quantification of CXCL12 mRNA in spleen cells (B) and in BM (C) in the steady-state (n=5). *P value < 0.05, **P value < 0.01, ***P value < 0.001. have only been recently fully appreciated 19 and include defective B-cell homing to the spleen 36 as we report here. Such defective B-cell homing may partly explain the marked B lymphopenia that is observed in the steadystate in adult WKO mice.…”

“…[15][16][17][18] WASp deficiency causes a marked defect in localization and trafficking of phagocytes and lymphocytes, including B cells, affecting their function. 18,19 The Wiskott-Aldrich syndrome protein is an essential cytoskeleton regulator found in cells of the hematopoietic lineage and controls the motility of leukocytes. The impact of WAS gene deficiency on the mobilization of hematopoietic progenitor/stem cells in circulation has remained unexplored but information would be pertinent in the context of autologous gene therapy of Wiskott-Aldrich syndrome.…”

Cytoskeletal control of B cell responses to antigens

“…B cells express both members of the family, the ubiquitous WASL and the hematopoietic WAS. Loss of WAS in mouse B cells leads to reduction of filamentous actin in resting B cells and impairs the development, adhesion and migration of B cells in the periphery (Table 1) 8,34 . In response to antigen, WASdeficient B cells have reduced BCR internalization and increased signalling and antibody production 7,35 , resembling the B cell phenotype in patients with WiskottAldrich syndrome.…”

“…For instance, the majority of patients with Wiskott-Aldrich syndrome suffer from antibody-mediated autoimmunity, which is largely caused by B cell hyperactivity [5][6][7][8] . These symptoms suggest that cytoskeleton dynamics are closely interwoven with both positive and negative regulation of B cell activation.…”