-
Journal of Multidisciplinary Healthcare 2021Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.
PubMed: 34992377
DOI: 10.2147/JMDH.S295386 -
European Journal of Immunology May 2021Analysis of serum cytokine levels in Wiskott-Aldrich syndrome patients pre- and post- treatment reveals IL-18 as a stable and reliable marker of inflammation. Definitive...
Analysis of serum cytokine levels in Wiskott-Aldrich syndrome patients pre- and post- treatment reveals IL-18 as a stable and reliable marker of inflammation. Definitive stem cell treatment with good myeloid correction correlates with resolution of inflammation and reduction of circulating IL-18, highlighting the importance of actin cytoskeletal regulation of myeloid cells in control of inflammation.
Topics: Biomarkers; Cytokines; Disease Susceptibility; Humans; Inflammation Mediators; Interleukin-18; Wiskott-Aldrich Syndrome
PubMed: 33448368
DOI: 10.1002/eji.202049024 -
JCI Insight Sep 2020Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein...
Dysregulated sensing of self-nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self-nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation.
Topics: Actins; Animals; Autoantibodies; Cells, Cultured; DNA; Dendritic Cells; Endosomes; Immunity, Innate; Interferons; Membrane Proteins; Mice; Mice, Inbred C57BL; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Wiskott-Aldrich Syndrome Protein
PubMed: 32721945
DOI: 10.1172/jci.insight.132857 -
Archivos Argentinos de Pediatria Jun 2015The Wiskott-Aldrich syndrome is a rare X-linked recessive immunodeficiency, with an estimated incidence of 3.5 to 5.2 cases per million males. It is characterized by...
The Wiskott-Aldrich syndrome is a rare X-linked recessive immunodeficiency, with an estimated incidence of 3.5 to 5.2 cases per million males. It is characterized by immunodeficiency, microthrombocytopenia and eczema. We present a 5-year-old Hispanic male, with a medical history of numerous infectious diseases, compromised health, chronic malnutrition, language delay and failure to thrive. An infrequent mutation in the Wiskott-Aldrich syndrome gene was found.
Topics: Child, Preschool; Humans; Male; Wiskott-Aldrich Syndrome
PubMed: 25996331
DOI: 10.5546/aap.2015.e137 -
Frontiers in Immunology 2022Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins,... (Review)
Review
Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.
Topics: Actin Cytoskeleton; Actins; Humans; Microfilament Proteins; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35371070
DOI: 10.3389/fimmu.2022.799309 -
Frontiers in Immunology 2015Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of... (Review)
Review
Over the last decades, research dedicated to the molecular and cellular mechanisms underlying primary immunodeficiencies (PID) has helped to understand the etiology of many of these diseases and to develop novel therapeutic approaches. Beyond these aspects, PID are also studied because they offer invaluable natural genetic tools to dissect the human immune system. In this review, we highlight the research that has focused over the last 20 years on T lymphocytes from Wiskott-Aldrich syndrome (WAS) patients. WAS T lymphocytes are defective for the WAS protein (WASP), a regulator of actin cytoskeleton remodeling. Therefore, study of WAS T lymphocytes has helped to grasp that many steps of T lymphocyte activation and function depend on the crosstalk between membrane receptors and the actin cytoskeleton. These steps include motility, immunological synapse assembly, and signaling, as well as the implementation of helper, regulatory, or cytotoxic effector functions. The recent concept that WASP also works as a regulator of transcription within the nucleus is an illustration of the complexity of signal integration in T lymphocytes. Finally, this review will discuss how further study of WAS may contribute to solve novel challenges of T lymphocyte biology.
PubMed: 25709608
DOI: 10.3389/fimmu.2015.00047 -
Genome Medicine Oct 2017The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell...
BACKGROUND
The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined.
METHODS
We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4 T cells.
RESULTS
WASp was enriched at genic and intergenic regions and associated with the transcription start sites of protein-coding genes. Thymocytes and spleen CD4 T cells showed 15 common WASp-interacting genes, including the gene encoding T cell factor (TCF)12. WASp KO thymocytes had reduced nuclear TCF12 whereas thymocytes expressing constitutively active WASp and WASp had increased nuclear TCF12, suggesting that regulated WASp activity controlled nuclear TCF12. We identify a putative DNA element enriched in WASp ChIP-seq samples identical to a TCF1-binding site and we show that WASp directly interacted with TCF1 in the nucleus.
CONCLUSIONS
These data place nuclear WASp in proximity with TCF1 and TCF12, essential factors for T cell development.
Topics: Animals; Binding Sites; CD4-Positive T-Lymphocytes; Cell Nucleus; Cells, Cultured; Chromatin Immunoprecipitation; DNA; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; T Cell Transcription Factor 1; T-Lymphocytes; Thymocytes; Transcription, Genetic; Wiskott-Aldrich Syndrome Protein
PubMed: 29078804
DOI: 10.1186/s13073-017-0481-6 -
Science Advances Apr 2023The higher-order assembly of Bin-amphiphysin-Rvs (BAR) domain proteins, including the FCH-BAR (F-BAR) domain proteins, into lattice on the membrane is essential for the...
The higher-order assembly of Bin-amphiphysin-Rvs (BAR) domain proteins, including the FCH-BAR (F-BAR) domain proteins, into lattice on the membrane is essential for the formation of subcellular structures. However, the regulation of their ordered assembly has not been elucidated. Here, we show that the higher ordered assembly of growth-arrested specific 7 (GAS7), an F-BAR domain protein, is regulated by the multivalent scaffold proteins of Wiskott-Aldrich syndrome protein (WASP)/neural WASP, that commonly binds to the BAR domain superfamily proteins, together with WISH, Nck, the activated small guanosine triphosphatase Cdc42, and a membrane-anchored phagocytic receptor. The assembly kinetics by fluorescence resonance energy transfer monitoring indicated that the GAS7 assembly on liposomes started within seconds and was further increased by the presence of these proteins. The regulated GAS7 assembly was abolished by Wiskott-Aldrich syndrome mutations both in vitro and in cellular phagocytosis. Therefore, Cdc42 and the scaffold proteins that commonly bind to the BAR domain superfamily proteins promoted GAS7 assembly.
Topics: Wiskott-Aldrich Syndrome Protein; Monomeric GTP-Binding Proteins; Wiskott-Aldrich Syndrome Protein, Neuronal; Nerve Tissue Proteins; Actins
PubMed: 37126564
DOI: 10.1126/sciadv.adf5143 -
Experimental & Molecular Medicine Jun 2023The WAVE regulatory complex (WRC), composed of five components-Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300-is essential for proper actin cytoskeletal... (Review)
Review
The WAVE regulatory complex (WRC), composed of five components-Cyfip1/Sra1, WAVE/Scar, Abi, Nap1/Nckap1, and Brk1/HSPC300-is essential for proper actin cytoskeletal dynamics and remodeling in eukaryotic cells, likely by matching various patterned signals to Arp2/3-mediated actin nucleation. Accumulating evidence from recent studies has revealed diverse functions of the WRC in neurons, demonstrating its crucial role in dictating the assembly of molecular complexes for the patterning of various trans-synaptic signals. In this review, we discuss recent exciting findings on the physiological role of the WRC in regulating synaptic properties and highlight the involvement of WRC dysfunction in various brain disorders.
Topics: Actins; Wiskott-Aldrich Syndrome Protein Family; Carrier Proteins; Neurons
PubMed: 37258575
DOI: 10.1038/s12276-023-01004-1 -
Journal of Medical Case Reports Jul 2022Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections,...
INTRODUCTION
Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.
CASE PRESENTATION
We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott-Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.
CONCLUSION
Despite Wiskott-Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.
Topics: Africa, Eastern; Aged; Child; Humans; Immunoglobulin G; Infant; Male; Mutation; Reinfection; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35897083
DOI: 10.1186/s13256-022-03517-1