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Frontiers in Immunology 2020A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate... (Review)
Review
A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.
Topics: Actin Cytoskeleton; Animals; Autoimmunity; Genetic Predisposition to Disease; Humans; Immunologic Deficiency Syndromes; Inflammation; Mutation; Phenotype; Signal Transduction
PubMed: 33488606
DOI: 10.3389/fimmu.2020.604206 -
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 -
Biochemical Society Transactions Oct 2016Wiskott-Aldrich syndrome protein (WASP) family proteins have been extensively characterized as factors that promote the nucleation of actin through the activation of the... (Review)
Review
Wiskott-Aldrich syndrome protein (WASP) family proteins have been extensively characterized as factors that promote the nucleation of actin through the activation of the protein complex Arp2/3. While yeast mostly have a single member of the family, mammalian cells have at least six different members, often with multiple isoforms. Members of the family are characterized by a common structure. Their N-termini are varied and are considered to confer spatial and temporal regulation of Arp2/3-activating activity, whereas their C-terminal half contains a polyproline-rich region, one or more WASP homology-2 (WH2) actin-binding domains and motifs that bind directly to Arp2/3. Recent studies, however, indicate that the yeast WASP homologue Las17 is able to nucleate actin independently of Arp2/3 through the function of novel G-actin-binding activities in its polyproline region. This allows Las17 to generate the mother filaments that are needed for subsequent Arp2/3 recruitment and activation during the actin polymerization that drives endocytic invagination in yeast. In this review, we consider how motifs within the polyproline region of Las17 support nucleation of actin filaments, and whether similar mechanisms might exist among other family members.
Topics: Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Animals; Humans; Models, Biological; Peptides; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Wiskott-Aldrich Syndrome Protein
PubMed: 27911716
DOI: 10.1042/BST20160176 -
Indian Dermatology Online Journal 2017Primary immunodeficiency disorders (PIDs) are a group of disorders affecting the capability to fight against infection. These include defects in T cells and B cells... (Review)
Review
Primary immunodeficiency disorders (PIDs) are a group of disorders affecting the capability to fight against infection. These include defects in T cells and B cells affecting cell-mediated and humoral immunity, respectively, combined humoral and cell-mediated immunodeficiency, defects in phagocytosis, complement defects, and defects in cytokine or cytokine signalling pathways which are detrimental for immune function. Depending upon the type and severity, age at onset of symptoms can vary from neonatal period to late childhood. Clinically, this group of disorders can involve any organ system of an individual such as respiratory system, gastrointestinal system, skin and mucous membrane, bone and joints, endocrine organs, and nervous system. Common dermatological manifestations include eczema, warts, molluscum contagiosum, mucocutaneous candidiasis, recurrent nonhealing ulcers, skin abscesses, erythroderma, petechiae, and nail changes. The common skin manifestations of various PIDs include eczema (seen in Wiskott-Aldrich syndrome and autosomal dominant hyper IgE syndrome); erythroderma (in Omen syndrome); viral warts or molluscum contagiosum (in autosomal recessive hyper IgE syndrome); chronic mucocutaneous candidiasis (in hyper IgE syndrome, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome, Th17 cell defects); recurrent nonhealing ulcers (in leucocyte adhesion defect); skin abscesses (in antibody defects, hyper IgE syndrome, and chronic granulomatous disease); petechial or purpuric spots (in Wiskott-Aldrich syndrome).
PubMed: 29204384
DOI: 10.4103/idoj.IDOJ_189_17 -
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 -
Frontiers in Immunology 2015The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APCs) in the T cell area of secondary... (Review)
Review
The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APCs) in the T cell area of secondary lymphoid organs and the formation of highly organized intercellular junctions referred to as immune synapses (IS). In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells. The critical role of contact dynamics and synapse stability on the immune response is well illustrated by human immune deficiencies in which disease pathogenesis is linked to altered adhesion or defective cross-talk between the synaptic partners. The Wiskott-Aldrich syndrome (WAS) is a severe primary immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp), a scaffold that promotes actin polymerization and links TCR stimulation to T cell activation. Absence or mutations in WASp affects intercellular APC-T cell communications by interfering with multiple mechanisms on both sides of the IS. The warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is caused by mutations in CXCR4, a chemokine receptor that in mutant form leads to impairment of APC-T cell interactions. Present evidences suggest that other recently characterized primary immune deficiencies caused by mutation in genes linked to actin cytoskeletal reorganization, such as WIP and DOCK8, may also depend on altered synapse stability. Here, we will discuss in details the mechanisms of disturbed APC-T cell interactions in WAS and WHIM. Moreover, we will summarize the evidence pointing to a compromised conjugate formation in WIP, DOCK8, and X-linked lymphoproliferative syndrome.
PubMed: 26379669
DOI: 10.3389/fimmu.2015.00433 -
Scandinavian Journal of Immunology Jan 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of...
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by a mutation in the WAS gene that encodes the WAS protein (WASp); up to 5-10% of these patients develop inflammatory bowel disease (IBD). The mechanisms by which WASp deficiency causes IBD are unclear. Intestinal microbial dysbiosis and imbalances in host immune responses play important roles in the pathogenesis of polygenetic IBD; however, few studies have conducted detailed examination of the microbial alterations and their relationship with IBD in WAS. Here, we collected faecal samples from 19 children (all less than 2 years old) with WAS and samples from WASp-KO mice with IBD and subjected them to 16S ribosomal RNA sequencing. We found that microbial community richness and structure in WAS children were different from those in controls; WAS children revealed reduced microbial community richness and diversity. Relative abundance of Bacteroidetes and Verrucomicrobiain in WAS children was significantly lower, while that of Proteobacteria was markedly higher. WASp-KO mice revealed a significantly decreased abundance of Firmicutes. Faecal microbial dysbiosis caused by WASp deficiency is similar to that observed for polygenetic IBD, suggesting that WASp may play crucial function in microbial homoeostasis and that microbial dysbiosis may contribute to IBD in WAS. These microbial alterations may be useful targets for monitoring and therapeutically managing intestinal inflammation in WAS.
Topics: Animals; Biodiversity; Biomarkers; Case-Control Studies; Child, Preschool; Disease Models, Animal; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Humans; Infant; Inflammatory Bowel Diseases; Male; Metagenome; Metagenomics; Mice; Mice, Knockout; Mutation; RNA, Ribosomal, 16S; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 31267543
DOI: 10.1111/sji.12805 -
International Journal of Molecular... Apr 2021In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of... (Review)
Review
In the last decade, improvements in genetic testing have revolutionized the molecular diagnosis of inherited thrombocytopenias (ITs), increasing the spectrum of knowledge of these rare, complex and heterogeneous disorders. In contrast, the therapeutic management of ITs has not evolved in the same way. Platelet transfusions have been the gold standard treatment for a long time. Thrombopoietin receptor agonists (TPO-RA) were approved for immune thrombocytopenia (ITP) ten years ago and there is evidence for the use of TPO-RA not only in other forms of ITP, but also in ITs. We have reviewed in the literature the existing evidence on the role of TPO-RAs in ITs from 2010 to February 2021. A total of 24 articles have been included, 4 clinical trials, 3 case series and 17 case reports. A total of 126 patients with ITs have received TPO-RA. The main diagnoses were Wiskott-Aldrich syndrome, MYH9-related disorder and ANKRD26-related thrombocytopenia. Most patients were enrolled in clinical trials and were treated for short periods of time with TPO-RA as bridging therapies towards surgical interventions, or other specific approaches, such as hematopoietic stem cell transplantation. Here, we have carried out an updated and comprehensive review about the efficacy and safety of TPO-RA in ITs.
Topics: Disease Management; Genetic Diseases, Inborn; Hearing Loss, Sensorineural; Humans; Intercellular Signaling Peptides and Proteins; Myosin Heavy Chains; Platelet Transfusion; Receptors, Thrombopoietin; Thrombocytopenia; Treatment Outcome; Wiskott-Aldrich Syndrome
PubMed: 33919295
DOI: 10.3390/ijms22094330 -
Frontiers in Aging Neuroscience 2016The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological... (Review)
Review
The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. In most cases, the retromer acts as a core that interacts with associated proteins, including sorting nexin family member 27 (SNX27), members of the vacuolar protein sorting 10 (VPS10) receptor family, the major endosomal actin polymerization-promoting complex known as Wiskott-Aldrich syndrome protein and scar homolog (WASH), and other proteins. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. Here, we summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases.
PubMed: 26973516
DOI: 10.3389/fnagi.2016.00042 -
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