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Scandinavian Journal of Immunology Jan 2022Wiskott-Aldrich syndrome (WAS) also called the eczema-thrombocytopenia-immunodeficiency syndrome is a primary immunodeficiency disease with X-linked recessive...
Wiskott-Aldrich syndrome (WAS) also called the eczema-thrombocytopenia-immunodeficiency syndrome is a primary immunodeficiency disease with X-linked recessive inheritance caused by mutations in the WAS protein (WASp) gene and characterized by thrombocytopenia with reduced platelet volume, eczema, immunodeficiency, and increased risk of malignant tumours. The mutations will lead to separate WAS severity which can be typical severe 'classical' WAS or less severe 'non-classical' WAS. This article will review and analyse clinical and immune characteristics of five unrelated Chinese families harbouring classical and non-classical WAS. The expression of WASp was detected in the peripheral blood monocytes (PBMC) by flow cytometry, and five mutations were found by WAS gene sequencing, one of which had not been reported in the literature, namely frameshift mutation c.1240_1247delCCACTCCC (p. P414Sfs*41).
Topics: China; DNA Mutational Analysis; Eczema; Family; Female; Humans; Infant; Leukocytes, Mononuclear; Male; Mean Platelet Volume; Mutation; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 34758123
DOI: 10.1111/sji.13115 -
Pathogens (Basel, Switzerland) Mar 2023Inborn errors of immunity (IEI) can present with infections, autoimmunity, lymphoproliferation, granulomas, and malignancy. IEIs are due to genetic abnormalities that... (Review)
Review
Inborn errors of immunity (IEI) can present with infections, autoimmunity, lymphoproliferation, granulomas, and malignancy. IEIs are due to genetic abnormalities that disrupt normal host-immune response or immune regulation. The microbiome appears essential for maintaining host immunity, especially in patients with a defective immune system. Altered gut microbiota in patients with IEI can lead to clinical symptoms. Microbial dysbiosis is the consequence of an increase in pro-inflammatory bacteria or a reduction in anti-inflammatory bacteria. However, functional and compositional differences in microbiota are also involved. Dysbiosis and a reduced alpha-diversity are well documented, particularly in conditions like common variable immunodeficiency. Deranged microbiota is also seen in Wiskott-Aldrich syndrome, severe combined immunodeficiency, chronic granulomatous disease, selective immunoglobulin-A deficiency, Hyper IgE syndrome (HIGES), X-linked lymphoproliferative disease-2, immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome, and defects of IL10 signalling. Distinct gastrointestinal, respiratory, and cutaneous symptoms linked to dysbiosis are seen in several IEIs, emphasizing the importance of microbiome identification. In this study, we discuss the processes that maintain immunological homeostasis between commensals and the host and the disruptions thereof in patients with IEIs. As the connection between microbiota, host immunity, and infectious illnesses is better understood, microbiota manipulation as a treatment strategy or infection prevention method would be more readily employed. Therefore, optimal prebiotics, probiotics, postbiotics, and fecal microbial transplantation can be promising strategies to restore the microbiota and decrease disease pathology in patients with IEIs.
PubMed: 37111404
DOI: 10.3390/pathogens12040518 -
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 -
Frontiers in Immunology 2023The abnormal expression of the Wiskott-Aldrich syndrome protein (WASP) encoded by the Wiskott-Aldrich syndrome (WAS) gene has been implicated in tumor invasion and...
INTRODUCTION
The abnormal expression of the Wiskott-Aldrich syndrome protein (WASP) encoded by the Wiskott-Aldrich syndrome (WAS) gene has been implicated in tumor invasion and immune regulation. However, prognostic implications of WAS and its correlation tumor infiltrating in renal clear cell carcinoma (ccRCC) is not clear cut.
METHODS
The correlation between WAS expression, clinicopathological variables and clinical outcomes were evaluated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Tumor Immune Estimation Resource (TIMER), UALCAN, Gene Expression Profiling Interaction Analysis (GEPIA), Kaplan-Meier (KM) plotter and other databases. Furthermore, we assessed the transcription expression of WAS in renal cancer tissues, various renal carcinoma cell lines and human renal tubular cells (HK2) using quantitative polymerase chain reaction (qPCR). A comprehensive analysis of multiple databases including TIMER, GEPIA, TISIDB, ESTIMATE algorithm, and CIBERSORT algorithm were performed to determine the correlation between WAS and tumor infiltrating immune cells in ccRCC.
RESULTS
The results displayed an increase in WAS mRNA level in ccRCC compared to normal tissue. WAS protein level was found highly expressed in cancer tissues, particularly within renal tumor cells via the human protein atlas (HPA). Interestingly, we found that elevated WAS expression was significantly positively correlated with the infiltration of CD8+ T cells, B cells, Monocytes, Neutrophils, Macrophages, T cell regulation, NK cells, and Dendritic cells in ccRCC. Bioinformatics demonstrated a strong correlation between WAS expression and 42 immune checkpoints, including the T cell exhaustion gene PD-1, which is critical for exploring immunotherapy for ccRCC. We revealed that patients with high WAS expression were less sensitive to immunotherapy medications.
CONCLUSION
In conclusion, our study identified that WAS was a prognostic biomarker and correlated with immune infiltrates in ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Prognosis; Wiskott-Aldrich Syndrome; Carcinoma; Kidney Neoplasms; Biomarkers
PubMed: 37122750
DOI: 10.3389/fimmu.2023.1102824 -
Small GTPases May 2020Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and... (Review)
Review
Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and Cdc42 are major modulators of the cytoskeleton. (N-)WASP and WIP control Rho GTPase activity in various cell types, either by direct WIP/(N-)WASP/Cdc42 or potential WIP/RhoA binding, or through secondary links that regulate GTPase distribution and/or transcription levels. WIP helps to regulate filopodium generation and participates in the Rac1-mediated ruffle formation that determines cell motility. In neurons, lack of WIP increases dendritic spine size and filamentous actin content in a RhoA-dependent manner. In contrast, WIP deficiency in an adenocarcinoma cell line significantly reduces RhoA levels. These data support a role for WIP in the GTPase-mediated regulation of numerous actin-related cell functions; we discuss the possibility that this WIP effect is linked to cell proliferative status.
Topics: Humans; Wiskott-Aldrich Syndrome Protein; rho GTP-Binding Proteins
PubMed: 29172947
DOI: 10.1080/21541248.2017.1390522 -
Frontiers in Immunology 2021Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved...
BACKGROUND
Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India.
METHODS
Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed.
RESULTS
In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months).
CONCLUSIONS
We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.
Topics: Age Factors; Child, Preschool; Developing Countries; Disease-Free Survival; Female; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; India; Infant; Male; Mutation; Phenotype; Risk Assessment; Risk Factors; Time Factors; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33936041
DOI: 10.3389/fimmu.2021.627651 -
Diagnostics (Basel, Switzerland) Jun 2023The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by... (Review)
Review
The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature.
PubMed: 37443545
DOI: 10.3390/diagnostics13132151 -
Annals of Translational Medicine Jul 2020Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ,... (Review)
Review
Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than 90% of cancer-related deaths. WAVE3 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which regulate actin cytoskeleton remodeling as well as several aspects of cell migration, invasion, and metastasis. In fact, WAVE3 has been established as a driver of tumor progression and metastasis in cancers from several origins, including triple negative breast cancers (TNBCs), which are classified as the most lethal subtype of breast cancer, due to their resistance to standard of care therapy and highly metastatic behavior. In this review, we will attempt to summarize the recent advances that have been made to understand how WAVE3 contributes to the molecular mechanisms that control cancer progression and metastasis. We will also review the signaling pathways that are involved in the regulation of WAVE3 expression and function to identify potential therapeutic options targeted against WAVE3 for the treatment of patients with metastatic tumors.
PubMed: 32793744
DOI: 10.21037/atm.2020.02.16 -
Nature Communications Jun 2022The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient...
The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.
Topics: Alternative Splicing; Cell Nucleus; Humans; RNA Polymerase II; RNA Splicing Factors; RNA-Binding Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35752626
DOI: 10.1038/s41467-022-31220-8 -
Frontiers in Immunology 2022Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or... (Review)
Review
Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or non-infectious features, including autoimmunity, lymphoproliferative disease, granulomas, and/or malignancy, which contribute substantially to morbidity and mortality. Some data suggest a correlation between clinical manifestations of IEI and altered gut microbiota. Many IEI display microbial dysbiosis resulting from the proliferation of pro-inflammatory bacteria or a decrease in anti-inflammatory bacteria with variations in the composition and function of numerous microbiota. Dysbiosis is considered more established, mainly within common variable immunodeficiency, selective immunoglobulin A deficiency, severe combined immunodeficiency diseases, Wiskott-Aldrich syndrome, Hyper-IgE syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, IL-10 receptor deficiency, chronic granulomatous disease, and Kostmann disease. For certain IEIs, the specific predominance of gastrointestinal, respiratory, and cutaneous involvement, which is frequently associated with dysbiosis, justifies the interest for microbiome identification. With the better understanding of the relationship between gut microbiota, host immunity, and infectious diseases, the integration of microbiota modulation as a therapeutic approach or a preventive measure of infection becomes increasingly relevant. Thus, a promising strategy is to develop optimized prebiotics, probiotics, postbiotics, and fecal microbial transplantation to rebalance the intestinal microbiota and thereby attenuate the disease activity of many IEIs.
Topics: Dysbiosis; Gastrointestinal Microbiome; Humans; Immune System Diseases; Immunoglobulin A; Receptors, Interleukin-10
PubMed: 36177048
DOI: 10.3389/fimmu.2022.982772