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Disease Markers 2010Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid... (Review)
Review
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.
Topics: Actins; Animals; Autoimmunity; Cytoskeleton; Eczema; Female; Genes, X-Linked; Humans; Mice; Mice, Knockout; Mutation; Protein Structure, Tertiary; Signal Transduction; Thrombocytopenia; Transcription, Genetic; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; cdc42 GTP-Binding Protein
PubMed: 21178275
DOI: 10.3233/DMA-2010-0735 -
European Journal of Immunology Nov 2017The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including... (Review)
Review
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.
Topics: Animals; Humans; Mice; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 28805251
DOI: 10.1002/eji.201646715 -
The Journal of Allergy and Clinical... Oct 2018Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia...
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.
Topics: Adolescent; Adult; Animals; Autoimmunity; Blood Platelets; CD40 Ligand; Child; Child, Preschool; Female; Humans; Infant; Inflammation; Mice, Inbred C57BL; Mice, Knockout; Platelet Count; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Young Adult
PubMed: 29421274
DOI: 10.1016/j.jaci.2017.12.1000 -
Clinical and Experimental Immunology Apr 2023Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of... (Review)
Review
Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation-ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes.
Topics: Humans; Mutation; Phenotype; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; RAC2 GTP-Binding Protein
PubMed: 36617178
DOI: 10.1093/cei/uxad001 -
Blood Mar 2022Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT...
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.
Topics: Busulfan; Child, Preschool; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 35100336
DOI: 10.1182/blood.2021014687 -
Allergology International : Official... Jun 2012Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease with unique and characteristic features. In 1994, the responsible gene for WAS, the WASP... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease with unique and characteristic features. In 1994, the responsible gene for WAS, the WASP gene on X-chromosome, was identified. Since then, renewed clinical and basic researches of WAS have started and remarkably developed. I will comment on recent progress in the clinical and basic researches of WAS, including some topics reported by our and other groups.
Topics: Animals; Eczema; Genes, X-Linked; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Immunity; Infant, Newborn; Male; Mutation; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 22361515
DOI: 10.2332/allergolint.11-RAI-0412 -
Nature Communications Nov 2017Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the...
Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. In a model of sterile inflammation utilizing TLR4 ligation followed by ATP or nigericin treatment, inflammasome activation is enhanced in monocytes from WAS patients and in WAS-knockout mouse dendritic cells. In ex vivo models of enteropathogenic Escherichia coli and Shigella flexneri infection, WASp deficiency causes defective bacterial clearance, excessive inflammasome activation and host cell death that are associated with dysregulated septin cage-like formation, impaired autophagic p62/LC3 recruitment and defective formation of canonical autophagosomes. Taken together, we propose that dysregulation of autophagy and inflammasome activities contribute to the autoinflammatory manifestations of WAS, thereby identifying potential targets for therapeutic intervention.
Topics: Actin Cytoskeleton; Animals; Autophagy; Bacterial Load; Cell Line, Tumor; Dendritic Cells; Enteropathogenic Escherichia coli; Humans; Immunity, Innate; Inflammasomes; Interferon Type I; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Nigericin; Septins; Shigella flexneri; THP-1 Cells; Toll-Like Receptor 4; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 29146903
DOI: 10.1038/s41467-017-01676-0 -
Biology of Blood and Marrow... Jan 2009Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder that has a variable clinical phenotype that correlates with the type of mutation in WASP, the... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder that has a variable clinical phenotype that correlates with the type of mutation in WASP, the gene encoding the WAS protein (WASP). WASP is a key regulator of actin polymerization in hematopoietic cells and has well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. Classic WAS often results from mutations that cause the absence of WASP expression, associated with thrombocytopenia with small platelets, sinopulmonary infections, and eczema in young males. Other phenotypes associated with expression of mutated WASP are X-linked thrombocytopenia and neutropenia. To date, the only curative therapy for WAS is hematopoietic cell transplantation (HCT) although gene therapy for WAS is under study. At least 2 retrospective studies of HCT for WAS have indicated that although HLA-matched sibling donors have the best outcomes (81% to 88%), when such a donor is not available, a matched unrelated donor should be considered (71% event free survival), although results are best in patients age < 5 years. Whereas most of the experience to date in Asia, Europe, and North America has been with myeloablative conditioning regimens, more recently, reduced-intensity conditioning (RIC) regimens also have been used with success. The issue of whether mixed chimerism post-HCT (which has a higher incidence in RIC transplantation) is associated with increased autoimmune manifestations in patients with WAS remains to be resolved.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Treatment Outcome; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 19147084
DOI: 10.1016/j.bbmt.2008.10.007 -
Frontiers in Immunology 2023The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp)...
The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. , their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR) CD4 CD8 double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8 SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.
Topics: Humans; Animals; Mice; Wiskott-Aldrich Syndrome Protein; Cell Lineage; Wiskott-Aldrich Syndrome; Receptors, Antigen, T-Cell; Cell Differentiation
PubMed: 37350958
DOI: 10.3389/fimmu.2023.1188099 -
The Journal of Allergy and Clinical... Aug 2020
Topics: Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cells; Humans; Male; Transplantation Conditioning; Wiskott-Aldrich Syndrome
PubMed: 32623069
DOI: 10.1016/j.jaci.2020.06.018