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Frontiers in Immunology 2022Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have...
Wiskott-Aldrich Syndrome (WAS) is characterized by recurrent infections, thrombocytopenia, and eczema. Here, we show that WASp-deficient mice on a BALB/c background have dysregulated cutaneous immune homeostasis with increased leukocyte accumulation in the skin, 1 week after birth. Increased cutaneous inflammation was associated with epithelial abnormalities, namely, altered keratinization, abnormal epidermal tight junctional morphology and increased trans-epidermal water loss; consistent with epidermal barrier dysfunction. Immune and physical barrier disruption was accompanied by progressive skin dysbiosis, highlighting the functional significance of the disrupted cutaneous homeostasis. Interestingly, the dysregulated immunity in the skin preceded the systemic elevation in IgE and lymphocytic infiltration of the colonic lamina propria associated with WASp deficiency. Mechanistically, the enhanced immune cell accumulation in the skin was lymphocyte dependent. Elevated levels of both Type 2 (IL-4, IL-5) and Type 17 (IL-17, IL-22, IL-23) cytokines were present in the skin, as well as the 'itch' factor IL-31. Unexpectedly, the canonical WAS-associated cytokine IL-4 did not play a role in the immune dysfunction. Instead, IL-17 was critical for skin immune infiltration and elevation of both Type 2 and Type 17 cytokines. Our findings reveal a previously unrecognized IL-17-dependent breakdown in immune homeostasis and cutaneous barrier integrity in the absence of WASp, targeting of which may provide new therapeutic possibilities for the treatment of skin pathologies in WAS patients.
Topics: Animals; Cytokines; Homeostasis; Interleukin-17; Interleukin-4; Mice; Mice, Knockout; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35265075
DOI: 10.3389/fimmu.2022.817427 -
Biology of Blood and Marrow... Jul 2018Our initial experience with hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n = 12) or a haploidentical related donor (n = 6) with T...
A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαβ and CD19 Cell-Depleted Stem Cell Transplantation in Patients with Wiskott-Aldrich Syndrome.
Our initial experience with hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n = 12) or a haploidentical related donor (n = 6) with T cell receptor (TCR)αβ/CD19 graft depletion in patients with Wiskott-Aldrich syndrome (WAS) (n = 18) showed a dramatic decrease in the incidence of graft-versus-host disease (GVHD) and transplantation-related mortality, with an increased overall survival (OS) of 88.9%. Unfortunately, the treatment was associated with mixed myeloid donor chimerism and secondary graft dysfunction (severe thrombocytopenia, n = 2; graft rejection, n = 5). To improve the outcome, we hypothesized that the addition of G-CSF and plerixafor to the conditioning chemotherapy would result in more complete donor stem cell engraftment. This trial was registered at www.clinicaltrials.gov (NCT03019809). A study group of patients with WAS (n = 16) underwent TCRαβ/CD19-depleted HSCT (MUD, n = 6; haploidentical, n = 10). The conditioning regimen was treosulfan-fludarabine-rabbit antithymocyte globulin-melphalan (or thiophosphamide in 1 patient) with G-CSF (10 µg/kg/day for 5 days starting on day -8) and plerixafor (240 µg/kg/day for 3 days starting on day -6). The clinical outcomes in this study were compared to those in a historical dataset (n = 18). No patients had grade III/IV acute GVHD in either the study or the historical control group. Importantly, in the patients with WAS, there was no statistical significance in OS between those who underwent HSCT from haploidentical donors and those who underwent HSCT from MUDs (93.8% versus 88.5%; P = .612). All patients in the study group had full donor chimerism in whole blood and in the CD3 compartments. The OS was 93.8%, and there were no cases of graft dysfunction. This study demonstrates the efficacy of adding G-CSF/plerixafor to the conditioning regimen before HSCT with TCRαβ/C D19 graft depletion in patients with WAS.
Topics: Anti-HIV Agents; Antigens, CD19; Benzylamines; Child; Child, Preschool; Cyclams; Female; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Infant; Infant, Newborn; Male; Receptors, Antigen, T-Cell, alpha-beta; Transplantation Conditioning; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 29550630
DOI: 10.1016/j.bbmt.2018.03.006 -
British Journal of Haematology Jan 2021
Topics: Child; Humans; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin; Wiskott-Aldrich Syndrome
PubMed: 33280084
DOI: 10.1111/bjh.17171 -
The Journal of Experimental Medicine Apr 2009The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is...
The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was(-/-) mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was(-/-) mice as compared with wild-type controls. Moreover analysis of was(-/-) iNKT cell maturation revealed a complete arrest at the CD44(+) NK1.1(-) intermediate stage. Notably, generation of BM chimeras demonstrated a was(-/-) iNKT cell-autonomous developmental defect. was(-/-) iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon gamma upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology.
Topics: Animals; Cytokines; Flow Cytometry; Humans; Hyaluronan Receptors; Lymphocyte Activation; Mice; Mice, Knockout; Mutation; Natural Killer T-Cells; Phenotype; Wiskott-Aldrich Syndrome
PubMed: 19307326
DOI: 10.1084/jem.20081773 -
British Journal of Haematology Jan 2021Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the... (Observational Study)
Observational Study
Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the thrombocytopenia is of paramount importance for most WAS patients. We report a retrospective analysis of the safety and efficacy of romiplostim treatment in reducing thrombocytopenia and bleeding tendency in 67 children (median age 1·3 years) with genetically confirmed WAS, followed in eight months (range, 1-12 months). Complete or partial primary responses regarding platelet counts were observed in 22 (33%) and 18 (27%) subjects, respectively. Yet, even in the non-responder group, the risk of haemorrhagic events decreased significantly, to 21%, after the first month of treatment. The responses tended to be durable and stable over time, with no significant fluctuations in platelets counts. The results of this retrospective study of a large cohort of WAS patients demonstrates that romiplostim can be used to increase platelet counts and reduce the risks of life-threatening bleeding in WAS patients awaiting haematopoietic stem cell transplantation or forgoing the procedure for various reasons.
Topics: Adolescent; Child; Child, Preschool; Hemorrhage; Humans; Infant; Platelet Count; Receptors, Fc; Recombinant Fusion Proteins; Retrospective Studies; Thrombocytopenia; Thrombopoietin; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 33131064
DOI: 10.1111/bjh.17174 -
Medicine Apr 2021Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk...
RATIONALE
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk of autoimmunity and malignancies. X-linked thrombocytopenia (XLT), the milder phenotype of WAS, is always limited to thrombocytopenia with absent or slight infections and eczema. Here, we illustrated the clinical and molecular characteristics of 2 unrelated patients with WAS from Chinese minorities.
PATIENT CONCERNS
Patient 1, a 13-day-old male newborn of the Chinese Lahu minority, showed a classic WAS phenotype, including thrombocytopenia, small platelets, buttock eczema, and recurrent infections. Patient 2, an 8-year-and 8-month-old boy of the Chinese Zhuang minority, presented an XLT phenotype without eczema and repeated infections.
DIAGNOSIS
Next-generation sequencing was performed to investigate the genetic variations. Flow cytometry was used to quantify the expression of WAS protein and analyze the lymphocyte subsets. A novel frameshift WAS mutation (c.927delC, p.Q310Rfs∗135) and a known nonsense WAS mutation (c.1090C>T, p.R364X) were identified in Patient 1 and Patient 2, respectively. Both patients were confirmed to have WAS protein deficiency, which was more severe in Patient 1. Meanwhile, the analysis of lymphocyte subsets revealed an abnormality in Patient 1, but not in Patient 2. Combined with the above clinical data and genetic characteristics, Patient 1 and Patient 2 were diagnosed as classic WAS and XLT, respectively. In addition, many miliary nodules were accidentally found in abdominal cavity of Patient 2 during appendectomy. Subsequently, Patient 2 was confirmed with pulmonary and abdominal tuberculosis through further laboratory and imaging examinations. To our knowledge, there have been only a few reports about WAS/XLT with tuberculosis.
INTERVENTIONS
Both patients received anti-infection therapy, platelet transfusions, and intravenous immunoglobulins. Moreover, Patient 2 also received antituberculosis treatment with ethambutol and amoxicillin-clavulanate.
OUTCOMES
The clinical symptoms and hematological parameters of these 2 patients were significantly improved. Regrettably, both patients discontinued the treatment for financial reasons.
LESSONS
Our report expands the pathogenic mutation spectrum of WAS gene and emphasizes the importance of molecular genetic testing in diagnosing WAS. Furthermore, researching and reporting rare cases of WAS from different populations will facilitate diagnosis and treatment of this disease.
Topics: Asian People; Child; DNA Mutational Analysis; Genetic Diseases, X-Linked; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Male; Minority Groups; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33879693
DOI: 10.1097/MD.0000000000025527 -
Frontiers in Immunology 2021Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic... (Review)
Review
Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.
Topics: Agammaglobulinemia; Alleles; Biomarkers; Diagnosis, Differential; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Mosaicism; Mutation; Organ Specificity; Phenotype; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; Wiskott-Aldrich Syndrome
PubMed: 34868061
DOI: 10.3389/fimmu.2021.783022 -
Frontiers in Immunology 2022Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease with a predisposition towards autoimmunity and lymphoproliferative diseases. Non-Hodgkin... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency disease with a predisposition towards autoimmunity and lymphoproliferative diseases. Non-Hodgkin lymphoma (NHL) is reported to be the predominant form of malignant tumor in WAS sufferers. Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of NHL while it is uncommon to occur in paranasal sinuses and especially when associated with WAS. In this article, we report a unique case of WAS associated with DLBCL in paranasal sinuses and review the major publications of WAS-related lymphomas that occurred in the head and neck area. This study extends the available therapies for WAS-related lymphomas and emphasizes the significance of recognition for sinonasal lymphomas in WAS patients presenting with sinusitis.
Topics: Humans; Wiskott-Aldrich Syndrome; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Paranasal Sinus Neoplasms; Paranasal Sinuses
PubMed: 36713385
DOI: 10.3389/fimmu.2022.1062261 -
Blood Feb 2013On the basis of a nationwide database of 160 patients with Wiskott-Aldrich syndrome (WAS), we identified a subset of infants who were significantly more likely to be...
On the basis of a nationwide database of 160 patients with Wiskott-Aldrich syndrome (WAS), we identified a subset of infants who were significantly more likely to be attributed with an Ochs score of 5 before the age of 2 (n = 26 of 47 [55%], P = 2.8 × 10(−7)). A retrospective analysis revealed that these patients often had severe refractory thrombocytopenia (n = 13), autoimmune hemolytic anemia (n = 15), and vasculitis (n = 6). One patient had developed 2 distinct cancers. Hemizygous mutations predictive of the absence of WAS protein were identified in 19 of the 24 tested patients, and the absence of WAS protein was confirmed in all 10 investigated cases. Allogeneic hematopoietic stem cell transplantation (HSCT) was found to be a curative treatment with a relatively good prognosis because it was successful in 17 of 22 patients. Nevertheless, 3 patients experienced significant disease sequelae and 4 patients died before HSCT. Therefore, the present study identifies a distinct subgroup of WAS patients with early-onset, life-threatening manifestations. We suggest that HSCT is a curative strategy in this subgroup of patients and should be performed as early in life as possible, even when a fully matched donor is lacking.
Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; Cohort Studies; Humans; Infant; Infant, Newborn; Prognosis; Research Design; Severity of Illness Index; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 23264593
DOI: 10.1182/blood-2012-08-448118 -
Blood May 2001Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia are caused by mutations of the WAS protein (WASP) gene. WASP may be involved in the regulation of podosome,...
Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia are caused by mutations of the WAS protein (WASP) gene. WASP may be involved in the regulation of podosome, an actin-rich dynamic cell adhesion structure formed by various types of cells. The molecular links between WASP and podosomes or other cell adhesion structures are unknown. Platelets express an SH2-SH3 adapter molecule, CrkL, that can directly associate with paxillin, which is localized in podosomes. The hypothesis that CrkL binds to WASP was, therefore, tested. Results from coprecipitation experiments using anti-CrkL and GST-fusion proteins suggest that CrkL binds to WASP through its SH3 domain and that the binding was not affected by WASP tyrosine phosphorylation. The binding of GST-fusion SH3 domain of PSTPIP1 in vitro was also not affected by WASP tyrosine phosphorylation, suggesting that the binding of the SH3 domains to WASP is not inhibited by tyrosine phosphorylation of WASP. Anti-CrkL also coprecipitates a 72-kd protein, which was identified as syk tyrosine kinase, critical for collagen induced-platelet activation. CrkL immunoprecipitates contain kinase-active syk, as evidenced by an in vitro kinase assay. Coprecipitation experiments using GST-fusion CrkL proteins suggest that both SH2 and SH3 domains of CrkL are involved in the binding of CrkL to syk. WASP, CrkL, syk, and paxillin-like Hic-5 incorporated to platelet cytoskeleton after platelet aggregation. Thus, CrkL is a novel molecular adapter for WASP and syk and may potentially transfer these molecules to the cytoskeleton through association with cytoskeletal proteins such as Hic-5.
Topics: Adaptor Proteins, Signal Transducing; Blood Platelets; Enzyme Precursors; Humans; Intracellular Signaling Peptides and Proteins; Ligands; Nuclear Proteins; Phosphoproteins; Protein-Tyrosine Kinases; Proteins; Signal Transduction; Syk Kinase; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; src Homology Domains
PubMed: 11313252
DOI: 10.1182/blood.v97.9.2633