The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Hans D. Ochs - One of the best experts on this subject based on the ideXlab platform.
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r loops cause genomic instability in t helper lymphocytes from patients with Wiskott Aldrich Syndrome
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: Koustav Sarkar, Loic Dupre, Hans D. Ochs, Seongsu Han, Kuokuang Wen, Michael M Seidman, Yatin M VyasAbstract:Background Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich Syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. Objective We sought to define how dysfunctional gene transcription is causally linked to the degree of T H cell deficiency and genomic instability in the XLT/WAS clinical spectrum. Methods In human T H 1- or T H 2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. Results WASp deficiency provokes increased R-loops and R-loop–mediated DSBs in T H 1 cells relative to T H 2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop–enriched regions of IFNG and TBX21 (T H 1 genes) in T H 1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (T H 2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores. Conclusion Transcriptional R-loop imbalance is a novel molecular defect causative in T H 1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically.
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clinical spectrum pathophysiology and treatment of the Wiskott Aldrich Syndrome
Current Opinion in Hematology, 2011Co-Authors: Michael H Albert, Luigi D. Notarangelo, Hans D. OchsAbstract:Purpose of review The Wiskott-Aldrich Syndrome (WAS), caused by mutations in the WAS gene, is a complex and diverse disorder with X-linked inheritance. This review focuses on recent developments in the understanding of its basic pathophysiology, diverse clinical phenotypes and optimal patient management including novel therapies. Recent findings The protein encoded by the WAS gene is a multifunctional signaling element expressed in immune and hematopoietic cells that plays a critical role in cytoskeletal reorganization, immune synapse formation and intracellular signaling. The type of specific mutation, its location within the gene and its effect on protein expression play a major role in determining an individual patient's clinical phenotype. Recent clinical observations and molecular studies have created a sophisticated picture of the disease spectrum. The improved outcome of stem cell transplantation from related and unrelated matched donors and promising early results from the first clinical gene therapy trial have added new therapeutic options for these patients. Summary Classic WAS, X-linked thrombocytopenia and X-linked neutropenia are caused by WAS gene mutations, each having a distinct pattern of clinical symptoms and disease severity. New developments in the understanding of these Syndromes and novel therapeutic options will have a major impact on the treatment of individuals with WAS mutations.
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mutations of the Wiskott Aldrich Syndrome protein affect protein expression and dictate the clinical phenotypes
Immunologic Research, 2009Co-Authors: Hans D. OchsAbstract:Mutations of the Wiskott–Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott–Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that are involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis. Mutations of WASP are located throughout the gene and either inhibit or disregulate normal WASP function. Analysis of a large patient population demonstrates a strong phenotype–genotype correlation. Classic WAS occurs when WASP is absent, XLT when mutated WASP is expressed and XLN when missense mutations occur in the Cdc42-binding site. However, because there are exceptions to this rule it is difficult to predict the long-term prognosis of a given affected boy solely based on the analysis of WASP expression.
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Mutations of the Wiskott–Aldrich Syndrome Protein affect protein expression and dictate the clinical phenotypes
Immunologic Research, 2008Co-Authors: Hans D. OchsAbstract:Mutations of the Wiskott–Aldrich Syndrome Protein (WASP) are responsible for classic Wiskott–Aldrich Syndrome (WAS), X-linked thrombocytopenia (XLT), and in rare instances congenital X-linked neutropenia (XLN). WASP is a regulator of actin polymerization in hematopoietic cells with well-defined functional domains that are involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis. Mutations of WASP are located throughout the gene and either inhibit or disregulate normal WASP function. Analysis of a large patient population demonstrates a strong phenotype–genotype correlation. Classic WAS occurs when WASP is absent, XLT when mutated WASP is expressed and XLN when missense mutations occur in the Cdc42-binding site. However, because there are exceptions to this rule it is difficult to predict the long-term prognosis of a given affected boy solely based on the analysis of WASP expression.
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Wiskott Aldrich Syndrome
Current Opinion in Hematology, 2008Co-Authors: Luigi D. Notarangelo, Carol H Miao, Hans D. OchsAbstract:Purpose of reviewWiskott-Aldrich Syndrome is caused by mutations of the Wiskott-Aldrich Syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review will focus on recent progress in understanding the molecular basis of Wiskott-Aldrich Syndrome and its ramificatio
Adrian J. Thrasher - One of the best experts on this subject based on the ideXlab platform.
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how i manage patients with Wiskott Aldrich Syndrome
British Journal of Haematology, 2019Co-Authors: Elizabeth Rivers, Adrian J. Thrasher, Austen Worth, Siobhan O BurnsAbstract:Wiskott Aldrich Syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.
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autonomous role of Wiskott Aldrich Syndrome platelet deficiency in inducing autoimmunity and inflammation
The Journal of Allergy and Clinical Immunology, 2018Co-Authors: Lucia Piceni Sereni, Adrian J. Thrasher, Maria Carmina Castiello, Francesco Marangoni, Achille Anselmo, Dario Di Silvestre, Sara Motta, Elena Draghici, Stefano Mantero, Silvia GilianiAbstract:Background Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. Objective To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich Syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS. Methods Phenotypic and functional characterization of megakaryocytes and platelets in mutant CoWas mice and patients with WAS with and without autoantibodies was performed. Platelet antigen expression was examined through a protein expression profile and cluster proteomic interaction network. Platelet immunogenicity was tested by using ELISAs and B-cell and platelet cocultures. Results CoWas mice showed increased megakaryocyte numbers and normal thrombopoiesis in vitro , but WASp-deficient platelets had short lifespan and high expression of activation markers. Proteomic analysis identified signatures compatible with defects in cytoskeletal reorganization and metabolism yet surprisingly increased antigen-processing capabilities. In addition, WASp-deficient platelets expressed high levels of surface and soluble CD40 ligand and were capable of inducing B-cell activation in vitro . WASp-deficient platelets were highly immunostimulatory in mice and triggered the generation of antibodies specific for WASp-deficient platelets, even in the context of a normal immune system. Patients with WAS also showed platelet hyperactivation and increased plasma soluble CD40 ligand levels correlating with the presence of autoantibodies. Conclusion Overall, these findings suggest that intrinsic defects in WASp-deficient platelets decrease their lifespan and dysregulate immune responses, corroborating the role of platelets as modulators of inflammation and immunity.
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Wiskott‐Aldrich Syndrome protein: Emerging mechanisms in immunity
European Journal of Immunology, 2017Co-Authors: Elizabeth Rivers, Adrian J. ThrasherAbstract:The Wiskott Aldrich Syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich Syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling. This article is protected by copyright. All rights reserved
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current and emerging treatment options for Wiskott Aldrich Syndrome
Expert Review of Clinical Immunology, 2015Co-Authors: Austen Worth, Adrian J. ThrasherAbstract:Wiskott-Aldrich Syndrome is a life-threatening primary immunodeficiency associated with a bleeding tendency, eczema and a high incidence of autoimmunity and malignancy. Stem cell transplantation offers the opportunity of cure for all these complications, and over the past 35 years there has been a remarkable improvement in survival following this treatment. Here, we review advances in management of clinical complications pre- and post-transplant, as well as discuss the morbidity Wiskott-Aldrich Syndrome patients experience following treatment. For patients with a poorly matched stem cell donor, recent gene therapy trials demonstrate encouraging results and the potential of low-toxicity therapy for all patients.
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the Wiskott Aldrich Syndrome the actin cytoskeleton and immune cell function
Disease Markers, 2010Co-Authors: Michael P Blundell, Austen Worth, Gerben Bouma, Adrian J. ThrasherAbstract:Wiskott-Aldrich Syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct Syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich Syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third Syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and a lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.
Scott B. Snapper - One of the best experts on this subject based on the ideXlab platform.
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neuronal Wiskott Aldrich Syndrome protein regulates tgf β1 mediated lung vascular permeability
The FASEB Journal, 2016Co-Authors: Brant M Wagener, Scott B. Snapper, Anni Zheng, Xueke Zhao, Pulin Che, Angela Brandon, Naseem Anjum, Judy Creighton, Junlin Guan, Qimei HanAbstract:TGF-β1 induces an increase in paracellular permeability and actin stress fiber formation in lung microvascular endothelial and alveolar epithelial cells via small Rho GTPase. The molecular mechanism involved is not fully understood. Neuronal Wiskott-Aldrich Syndrome protein (N-WASP) has an essential role in actin structure dynamics. We hypothesized that N-WASP plays a critical role in these TGF-β1-induced responses. In these cell monolayers, we demonstrated that N-WASP down-regulation by short hairpin RNA prevented TGF-β1-mediated disruption of the cortical actin structure, actin stress filament formation, and increased permeability. Furthermore, N-WASP down-regulation blocked TGF-β1 activation mediated by IL-1β in alveolar epithelial cells, which requires actin stress fiber formation. Control short hairpin RNA had no effect on these TGF-β1-induced responses. TGF-β1-induced phosphorylation of Y256 of N-WASP via activation of small Rho GTPase and focal adhesion kinase mediates TGF-β1-induced paracellular permeability and actin cytoskeleton dynamics. In vivo, compared with controls, N-WASP down-regulation increases survival and prevents lung edema in mice induced by bleomycin exposure-a lung injury model in which TGF-β1 plays a critical role. Our data indicate that N-WASP plays a crucial role in the development of TGF-β1-mediated acute lung injury by promoting pulmonary edema via regulation of actin cytoskeleton dynamics.-Wagener, B. M., Hu, M., Zheng, A., Zhao, X., Che, P., Brandon, A., Anjum, N., Snapper, S., Creighton, J., Guan, J.-L., Han, Q., Cai, G.-Q., Han, X., Pittet, J.-F., Ding, Q. Neuronal Wiskott-Aldrich Syndrome protein regulates TGF-β1-mediated lung vascular permeability.
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neural Wiskott Aldrich Syndrome protein modulates wnt signaling and is required for hair follicle cycling in mice
Journal of Clinical Investigation, 2010Co-Authors: Anna Lyubimova, John J Garber, Geeta Upadhyay, Andrey A Sharov, Florentina Anastasoaie, Vijay Yajnik, George Cotsarelis, Gian Paolo Dotto, Vladimir A Botchkarev, Scott B. SnapperAbstract:The Rho family GTPases Cdc42 and Rac1 are critical regulators of the actin cytoskeleton and are essential for skin and hair function. Wiskott-Aldrich Syndrome family proteins act downstream of these GTPases, controlling actin assembly and cytoskeletal reorganization, but their role in epithelial cells has not been characterized in vivo. Here, we used a conditional knockout approach to assess the role of neural Wiskott-Aldrich Syndrome protein (N-WASP), the ubiquitously expressed Wiskott-Aldrich Syndrome-like (WASL) protein, in mouse skin. We found that N-WASP deficiency in mouse skin led to severe alopecia, epidermal hyperproliferation, and ulceration, without obvious effects on epidermal differentiation and wound healing. Further analysis revealed that the observed alopecia was likely the result of a progressive and ultimately nearly complete block in hair follicle (HF) cycling by 5 months of age. N-WASP deficiency also led to abnormal proliferation of skin progenitor cells, resulting in their depletion over time. Furthermore, N-WASP deficiency in vitro and in vivo correlated with decreased GSK-3beta phosphorylation, decreased nuclear localization of beta-catenin in follicular keratinocytes, and decreased Wnt-dependent transcription. Our results indicate a critical role for N-WASP in skin function and HF cycling and identify a link between N-WASP and Wnt signaling. We therefore propose that N-WASP acts as a positive regulator of beta-catenin-dependent transcription, modulating differentiation of HF progenitor cells.
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lymphocyte dependent and th2 cytokine associated colitis in mice deficient in Wiskott Aldrich Syndrome protein
Gastroenterology, 2007Co-Authors: Deanna D Nguyen, Michel H. Maillard, Cathryn R Nagler, Atul K Bhan, Vinicius Cotta De Almeida, Emiko Mizoguchi, Christoph Klein, Ivan J Fuss, Atsushi Mizoguchi, Scott B. SnapperAbstract:Background & Aims: Controversy exists as to whether patients with inflammatory bowel disease have an underlying immunodeficiency. We have focused on a murine model of the Wiskott-Aldrich Syndrome, an immunodeficiency in which autoimmunity can manifest in the form of an inflammatory bowel disease-like illness. Wiskott-Aldrich Syndrome protein (WASP) deficiency in mice results in similar clinical features. Herein, we characterized the colitis in WASP-deficient mice. Methods: WASP-deficient mice were followed clinically and histologically. Immunologic studies were performed to determine the pathogenic cell population(s), the predominant cytokine expression pattern, and the role of cytokine(s) in colitis pathogenesis. Results: All WASP-deficient mice develop colitis by 6 months of age. Lymphocytes are required for disease induction, and CD4+ T cells from WASP-deficient mice are sufficient to induce disease in lymphocyte-deficient hosts. Lamina propria preparations from WASP-deficient mice demonstrated elevations in interferon-γ, interleukin (IL)-4, and IL-13 levels but decreased IL-6 and no difference in IL-17 expression in comparison with wild-type controls. Treatment with neutralizing antibody to IL-4, but not to interferon-γ, abrogated colitis development. However, mice deficient in both WASP and IL-4 showed no difference in histologic colitis scores at 24 weeks of age compared with WASP-deficient mice. Conclusions: These results demonstrate a critical role for lymphocytes and a relative T helper 2 cytokine predominance in the colitis associated with WASP-deficient mice. This is the only model of colitis with elevated T helper 2 cytokines and aberrant natural regulatory T cell function and is unique in having a human disease counterpart with similar defects.
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Wiskott Aldrich Syndrome protein wasp and n wasp are critical for t cell development
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Vinicius Cottadealmeida, Lisa S. Westerberg, Michel H. Maillard, Dilek Onaldi, Heather Wachtel, Parool Meelu, Ung-il Chung, Ramnik J. Xavier, Frederick W. Alt, Scott B. SnapperAbstract:Although T cell dysfunction and lymphopenia are key features of immunodeficient patients with the Wiskott-Aldrich Syndrome and Wiskott-Aldrich Syndrome protein (WASP)-deficient mice, T cell development appears relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homologue of WASP, may serve a redundant function with WASP. To examine the unique and redundant activities of WASP and N-WASP, we generated ES cells devoid of WASP and N-WASP [double knockout (DKO)] and used the RAG-2-deficient blastocyst complementation system to generate DKO lymphocytes. Moreover, we mated WASP KO mice with mice containing a conditionally targeted N-WASP allele and used the Cre-loxP system to generate mice lacking WASP and N-WASP in T cells [conditional DKO (cDKO)]. In both systems, N-WASP-deficient cells were indistinguishable from WT cells. In contrast, T cell development in DKO and cDKO mice was markedly altered, as shown by thymic hypocellularity and reduced numbers of peripheral T cells. We found that the combined activity of WASP and N-WASP was important for CD4(-)CD8(-) double-negative (DN)-to-CD4(+)CD8(+) double-positive (DP) cell transition, and this may be partly explained by reduced cycling DN3 cells. In addition, decreased migratory responses of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) cells and increased percentage of CD69(low)CD24(low) and CD62L(low) SP cells in cDKO cells imply retention of SP cells in the thymus. In summary, this study suggests that, although WASP serves a unique role for peripheral T cell function, T cell development depends on the combined activity of WASP and N-WASP.
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Wiskott–Aldrich Syndrome protein (WASP) and N-WASP are critical for T cell development
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Vinícius Cotta-de-almeida, Lisa S. Westerberg, Michel H. Maillard, Dilek Onaldi, Heather Wachtel, Parool Meelu, Ung-il Chung, Ramnik J. Xavier, Frederick W. Alt, Scott B. SnapperAbstract:Although T cell dysfunction and lymphopenia are key features of immunodeficient patients with the Wiskott-Aldrich Syndrome and Wiskott-Aldrich Syndrome protein (WASP)-deficient mice, T cell development appears relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homologue of WASP, may serve a redundant function with WASP. To examine the unique and redundant activities of WASP and N-WASP, we generated ES cells devoid of WASP and N-WASP [double knockout (DKO)] and used the RAG-2-deficient blastocyst complementation system to generate DKO lymphocytes. Moreover, we mated WASP KO mice with mice containing a conditionally targeted N-WASP allele and used the Cre-loxP system to generate mice lacking WASP and N-WASP in T cells [conditional DKO (cDKO)]. In both systems, N-WASP-deficient cells were indistinguishable from WT cells. In contrast, T cell development in DKO and cDKO mice was markedly altered, as shown by thymic hypocellularity and reduced numbers of peripheral T cells. We found that the combined activity of WASP and N-WASP was important for CD4(-)CD8(-) double-negative (DN)-to-CD4(+)CD8(+) double-positive (DP) cell transition, and this may be partly explained by reduced cycling DN3 cells. In addition, decreased migratory responses of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) cells and increased percentage of CD69(low)CD24(low) and CD62L(low) SP cells in cDKO cells imply retention of SP cells in the thymus. In summary, this study suggests that, although WASP serves a unique role for peripheral T cell function, T cell development depends on the combined activity of WASP and N-WASP.
Fabio Candotti - One of the best experts on this subject based on the ideXlab platform.
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Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome
Journal of Clinical Immunology, 2018Co-Authors: Fabio CandottiAbstract:The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked disorder originally described by Dr. Alfred Wiskott in 1937 and Dr. Robert Aldrich in 1954 as a familial disease characterized by infections, bleeding tendency, and eczema. Today, it is well recognized that the Syndrome has a wide clinical spectrum ranging from mild, isolated thrombocytopenia to full-blown presentation that can be complicated by life-threatening hemorrhages, immunodeficiency, atopy, autoimmunity, and cancer. The pathophysiology of classic and emerging features is being elucidated by clinical studies, but remains incompletely defined, which hinders the application of targeted therapies. At the same time, progress of hematopoietic stem cell transplantation and gene therapy offer optimistic prospects for treatment options aimed at the replacement of the defective lymphohematopoietic system that have the potential to provide a cure for this rare and polymorphic disease.
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The expression of Wiskott–Aldrich Syndrome protein (WASP) is dependent on WASP-interacting protein (WIP)
International immunology, 2007Co-Authors: Akihiro Konno, Martha Kirby, Stacie A. Anderson, Pamela L. Schwartzberg, Fabio CandottiAbstract:The Wiskott-Aldrich Syndrome protein (WASP) is a key molecule for transduction of extracellular signals that induce a variety of critical biological events involving actin cytoskeleton rearrangement. Among the cellular partners of WASP, the Wiskott-Aldrich Syndrome protein-interacting protein (WIP) has been speculated to play a critical role in the pathophysiology of Wiskott-Aldrich Syndrome since WASP mutation hot spots map to the WIP-binding region. The notion that WIP promotes WASP function, however, conflicts with evidence that WIP inhibits WASP-mediated actin polymerization and IL-2 production and suggests a complex regulation of WASP function by WIP. Here we show that WASP gene transfer results in high WASP expression only when WIP is concomitantly expressed in K562 cells. Furthermore, WIP-knockdown experiments demonstrated that T cells with reduced WIP expression show a concordant reduction of WASP levels. Mapping studies using WIP mutants showed that the minimal WIP region able to rescue WASP expression in WIP-knockdown cells was the WASP-binding domain. However, expression of such a minimal domain of WIP failed to rescue WASP-dependent, nuclear factor of activated T-cells-mediated IL-2 transcriptional activity. These results demonstrate that expression of WIP is necessary for functional WASP expression in human cells and provide a new paradigm for understanding the function of these two molecules.
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lessons from the Wiskott Aldrich Syndrome
The New England Journal of Medicine, 2006Co-Authors: Jennifer M Puck, Fabio CandottiAbstract:The Wiskott–Aldrich Syndrome is a well-recognized triad of eczema, bleeding diathesis, and recurrent infections that occurs in boys. Drs. Jennifer Puck and Fabio Candotti write that although it is rare, the Syndrome offers rich historical, clinical, and scientific lessons.
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Prenatal molecular diagnosis of Wiskott–Aldrich Syndrome by direct mutation analysis
Prenatal Diagnosis, 1999Co-Authors: Silvia Giliani, Patrizia Mella, Fabio Candotti, Richard Fabian Schumacher, Georg S. Wengler, Faustina Lalatta, Anders Fasth, Raffaele Badolato, Maurilia Fiorini, Alberto G. UgazioAbstract:We have performed prenatal diagnosis for Wiskott-Aldrich Syndrome (WAS) in two unrelated families by direct gene analysis. Using a combined non-radioactive analysis of single-strand conformational polymorphism (SSCP) and heteroduplex formation (HD), followed by automated sequencing, we studied DNA from chorionic villus sampling (CVS), allowing the diagnosis of one affected and one healthy male at the 12th week of gestation. Copyright © 1999 John Wiley & Sons, Ltd.
Maria Dolores Gallego - One of the best experts on this subject based on the ideXlab platform.
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wip is a chaperone for Wiskott Aldrich Syndrome protein wasp
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Yoji Sasahara, Miguel Angel De La Fuente, Marco Calamito, Ines M Anton, Abdallah Elkhal, Maria Dolores GallegoAbstract:Wiskott–Aldrich Syndrome protein (WASP) is in a complex with WASP-interacting protein (WIP). WASP levels, but not mRNA levels, were severely diminished in T cells from WIP−/− mice and were increased by introduction of WIP in these cells. The WASP binding domain of WIP was shown to protect WASP from degradation by calpain in vitro. Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP−/− mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding. The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP−/− mice. Despite its ability to increase WASP levels proteasome inhibition did not correct the impaired IL-2 gene expression and low F-actin content in T cells from the R86H WAS patient. These results demonstrate that WIP stabilizes WASP and suggest that it may also be important for its function.
