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Cellular and Molecular Life Sciences :... Sep 2004The Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by a variety of mutations in the gene encoding the WAS protein (WASp). WASp is expressed in... (Review)
Review
The Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by a variety of mutations in the gene encoding the WAS protein (WASp). WASp is expressed in hematopoetic cells and facilitates the reorganization of the actin cytoskeleton in response to many important cell stimuli. Extensive study of WAS and more recently WASp has given great insight into the relevance of this molecule and related molecules to both basic cell biology and human immune defenses.
Topics: Animals; Blood Platelets; Eczema; Genetic Therapy; Humans; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15378206
DOI: 10.1007/s00018-004-4086-z -
The Journal of Allergy and Clinical... Mar 2019
Topics: Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infant; Platelet Count; Splenectomy; Wiskott-Aldrich Syndrome
PubMed: 30048768
DOI: 10.1016/j.jaip.2018.07.009 -
Turkish Journal of Haematology :... Nov 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate...
OBJECTIVE
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort.
MATERIALS AND METHODS
We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019.
RESULTS
Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined.
CONCLUSION
All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Infant; Infant, Newborn; Male; Patient Outcome Assessment; Phenotype; Prognosis; Reinfection; Symptom Assessment; Treatment Outcome; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 32812413
DOI: 10.4274/tjh.galenos.2020.2020.0334 -
Clinical and Translational Medicine Apr 2022
Topics: Genetic Therapy; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35437889
DOI: 10.1002/ctm2.815 -
Indian Pediatrics Dec 2014Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder with a variable phenotype.
BACKGROUND
Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder with a variable phenotype.
CASE CHARACTERISTICS
3.5-year-old boy diagnosed with Wiskott-Aldrich syndrome.
OBSERVATION
Unusual and persistent thrombocytopenia with increased platelet volume (>10fL). He did not exhibit characteristic clinical and laboratory finding for the syndrome.
OUTCOME
Maternally inherited causative mutation in the exon 2 of the WAS gene was disclosed.
MESSAGE
This is a need for multidisciplinary assessment of patients with congenital or early infantile thrombocytopenia, including testing for mutations of the WAS gene in all unexplained cases even in the absence of characteristic microthrombocytopenia.
Topics: Humans; Infant; Male; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 25560165
DOI: 10.1007/s13312-014-0550-5 -
The Journal of Allergy and Clinical... Sep 2019Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and...
BACKGROUND
Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients.
OBJECTIVE
We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction.
METHODS
We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis.
RESULTS
We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up.
CONCLUSIONS
Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.
Topics: Adolescent; Adult; Blood Platelets; Child; Child, Preschool; Female; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lentivirus; Male; Microscopy, Electron, Transmission; Phenotype; Platelet Activation; Platelet Count; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 30926529
DOI: 10.1016/j.jaci.2019.03.012 -
Nature Communications May 2023Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we... (Clinical Trial)
Clinical Trial
Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.
Topics: Humans; Child; Animals; Mice; Bone Marrow; Hematopoietic Stem Cells; Hematopoietic Stem Cell Transplantation; Genetic Therapy; Wiskott-Aldrich Syndrome; Granulocyte Colony-Stimulating Factor
PubMed: 37244942
DOI: 10.1038/s41467-023-38448-y -
The Journal of Allergy and Clinical... Nov 2018Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal...
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined.
OBJECTIVE
Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS.
METHODS
We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens.
RESULTS
Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase.
CONCLUSIONS
These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.
Topics: Adolescent; Adult; Animals; Autoantibodies; B-Lymphocytes; Child, Preschool; Dendritic Cells; Extracellular Traps; Female; Gene Expression; Humans; Infant; Interferon Type I; Male; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 29447842
DOI: 10.1016/j.jaci.2017.11.063 -
Scandinavian Journal of Immunology Jun 2015The Wiskott-Aldrich syndrome protein (WASp) is an important regulator of the actin cytoskeleton and is required for immune cell function. WASp deficiency causes a marked...
The Wiskott-Aldrich syndrome protein (WASp) is an important regulator of the actin cytoskeleton and is required for immune cell function. WASp deficiency causes a marked reduction in major mature peripheral B cell subsets, particularly marginal zone (MZ) B cells. We hypothesized that WASp deficiency may also lead to a reduction of regulatory B cells (known as B10 cells) belonging to a novel subset of B cells. And in consideration of the key role of B10 cells play in maintaining peripheral tolerance, we conjectured that a deficit of these cells could contribute to the autoimmunity in patients with Wiskott-Aldrich syndrome (WAS). The effects of WASp deficiency on B10 cells have been reported by only one group, which used an antigen-induced arthritis model. To add more information, we measured the percentage of B10 cells, regulatory T cells (Tregs) and Th1 cells in WASp knockout (WASp KO) mice. We also measured the percentage of B10 cells in patients with WAS by flow cytometry. Importantly, we used the non-induced autoimmune WASp KO mouse model to investigate the association between B10 cell frequency and the Treg/Th1 balance. We found that the percentage of B10 cells was reduced in both mice (steady state and inflammatory state) and in humans and that the lower B10 population correlated with an imbalance in the Treg/Th1 ratio in old WASp KO mice with autoimmune colitis. These findings suggest that WASp plays a crucial role in B10 cell development and that WASp-deficient B10 cells may contribute to autoimmunity in WAS.
Topics: Animals; Autoimmune Diseases; B-Lymphocytes, Regulatory; Child; Child, Preschool; Colitis; Flow Cytometry; Humans; Infant; Interleukin-10; Lymphocyte Count; Mice, Inbred C57BL; Mice, Knockout; T-Lymphocytes, Regulatory; Th1 Cells; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 25728049
DOI: 10.1111/sji.12282 -
Blood Jun 2016Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most...
Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4(+) T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4(+) T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6(+) Tfh cells, but the frequency of ICOS(+) Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS(+) Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS(+) Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4(+) naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6.
Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Case-Control Studies; Cell Differentiation; Cells, Cultured; Germinal Center; Humans; Inducible T-Cell Co-Stimulator Protein; Interleukins; Lymph Nodes; Mice; Mice, Knockout; Positive Regulatory Domain I-Binding Factor 1; Receptors, CXCR5; Repressor Proteins; T-Lymphocytes, Helper-Inducer; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 27170596
DOI: 10.1182/blood-2015-06-652636