A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes 2 phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome, however the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. Median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores (2 (23%), 3 (30%), 4 (23%) and 5 (19%)). Most patients received HLA mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. Cumulative incidence of neutrophil recovery at day-60 was 89% and day-100 acute graft-versus-host disease grade II-IV was 38%; use of methotrexate for graft-versus- host disease prophylaxis delayed engraftment (p=0.02), but decreased acute graft-versus-host disease (p=0.03). At 5-year, overall survival and event-free survival were 75% and 70%, respectively. Estimated 5 year- event-free survival was 83%, 73% and 55% for patients with clinical score 2, 4-5 and 3, respectively. In multivariate analysis, age<2years at umbilical cord blood transplantation and clinical phenotype X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be improved after 2007 (p=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor

Evaluation of Classic Wiskott Aldrich Syndrome with Mild Symptoms in Two Cousins: A Case Report

Introduction: Wiskott–Aldrich syndrome (WAS) is characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity. Commonly, classicWAS is presented with severe clinical symptoms. Case Presentation:We report a new phenotype of classic Wiskott–Aldrich syndrome with mild symptoms in two cousins who were 7 years old. They had not severe infections or hemorrhage, in spite of having genetic mutation in WAS gene. The symptoms and infections of the patients responded to treatment with IVIG and antibiotics. Conclusions: This report is presenting a novel clinical phenotype of classicWAS with milder symptoms

A Clinical Diagnosis of Wiskott Aldrich Syndrome in an Ethiopian Boy with Recurrent Sinopulmonary Infections: A Case Report

BACKGROUND፡ Wiskott Aldrich syndrome is a primary immunodeficiency notable for eczema, recurrent infections, bleeding diathesis and microcytic thrombocytopenia.CASE: A 4½ year old boy presented with recurrent sinopulmonary infections, repeated treatment for severe eczema since infancy, thrombocytopenia with low platelet volume. His brother and uncles died during childhood due to repeated illnesses. We outline ways to diagnose and manage children in resource limited settings.CONCLUSION: Wiskott Aldrich syndrome can be diagnosed by its clinical triad of syndromes. Mutation of the WASP gene confirms diagnosis. Increasing reports of primary immune deficiencies in Ethiopia call for improved education and care for clinical immunology

WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts

The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3-dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability

Characterization of the pathophysiology of Wiskott-Aldrich transgenic mice

Wiskott-Aldrich syndrome (WAS) is an X-Iinked recessive disease in which affected patients have any combination of the triad of classical symptoms of thrombocytopenia, eczema and immunodeficiencies. The gene has been cloned and sequenced, but its function is unknown. In order to determine the pathophysiology of the disease, transgenic animals have been generated which overexpress the normal Wiskott-Aldrich syndrome protein (WASP) in T lymphocytes. By characterizing the pathobiology and immunology of these mice, we will better understand the normal function of Wiskott Aldrich syndrome protein (WASP). The WASP transgenic mice have a profound phenotype that is characterized most prominently by splenomegaly and lymphadenopathy. Peripheral blood leukocytes are mildly, but significantly reduced, with all lineages being affected. WASP transgenic mice also have a mild thrombocytosis and megakaryocytosis. Histologically, the animals have enlarged germinal centers and increased numbers of germinal centers and lymphoproliferation in lymph nodes and spleens. This is reflected by elevated in vitro proliferative responses by both B and T cells. Signal transduction experiments show increased phosphorylation of several proteins in WASP transgenic cells versus cells from non-transgenic littermates. Based on these findings, it is believed that overexpression of WASP protein either in an antigen dependent or independent manner upregulates the immune response of B and T cells to various mitogens and pathogens. As a result, WASP transgenic mice develop chronic splenomegaly and lymphadenopathy due to the activated status of their immune cells. The differential phosphorylation of several proteins involved in signal transduction, even in the resting state, suggests that the immune systems of the WASP transgenic animals may be non-specifically activated. These same signal transduction proteins, which are affected by overexpression of the WASP protein are likely involved in the pathophysiology of WAS. Further efforts will be taken to identify these proteins and elucidate their role in both the pathophysiology of these transgenic mice as well as Wiskott-Aldrich syndrome. In the future, further experiments will be done to determine if this is an antigen dependent or independent response

Platelet actin nodules are podosome-like structures dependent on Wiskott-Aldrich syndrome protein and ARP2/3 complex

The actin nodule is a novel F-actin structure present in platelets during early spreading. However, only limited detail is known regarding nodule organization and function. Here we use electron microscopy, SIM and dSTORM super-resolution, and live-cell TIRF microscopy to characterize the structural organization and signalling pathways associated with nodule formation. Nodules are composed of up to four actin-rich structures linked together by actin bundles. They are enriched in the adhesion-related proteins talin and vinculin, have a central core of tyrosine phosphorylated proteins and are depleted of integrins at the plasma membrane. Nodule formation is dependent on Wiskott-Aldrich syndrome protein (WASp) and the ARP2/3 complex. WASp(-/-) mouse blood displays impaired platelet aggregate formation at arteriolar shear rates. We propose actin nodules are platelet podosome-related structures required for platelet-platelet interaction and their absence contributes to the bleeding diathesis of Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome

Departamentul Pediatrie, Universitatea de Stat de Medicină și Farmacie „Nicolae Testemițanu”, IMSP Institutul Mamei și Copilului, IMSP Institutul de Ftiziopneumologie, IMSP Spitalul Clinic Republican, Conferința Științifică cu participare internațională ”Imunitatea copilului și imunodeficiențele primare” în cadrul Proiectului Academiei de Științe a Moldovei și Proiectului din Europa de Est și Centrală în imunodeficiențe primare J Project 3 noiembrie 2017Sindromul Wiskott-Aldrich este o patologie rară, X-linkată recisivă, caracterizată prin triada: trombocitopenie, dermatită și infecții recurente. Este prezentat un caz clinic precedat de analiză bibliografică. Diagnosticul a fost suspectat precoce prin simptomatologia clasică cu manifestări hemoragice, pe fondal de trombocitopenie, dermatită cu marcherul atopiei la valori foarte crescute și afectări respiratorii severe. Afectarea pulmonară în imunodeficiența primară Wiskott-Aldrich evoluează cu riscuri de recidive, prin complicații pleuro-pulmonare, generalizate severe, care sunt cauzate de infecții polirezistente cu Stafilococcus aureus, Streptococcus ß-haemolyticus, Klebsiella pneumonia, Candida albicans și Pneumocistis jiroveci. Prognosticul în imunodeficiența primară Wiskott-Aldrich se raportează la gradul de afectare, caracterul complicațiilor și la prezența altor maladii concomitente. Wiskott-Aldrich syndrome is a rare, recurrent X-linked pathology, characterized by the triad: thrombocytopenia, dermatitis and recurrent infections. A clinical case, preceded by the bibliographic review, is presented. Diagnosis was suspected early by classical symptomatology with haemorrhagic manifestations on the background of thrombocytopenia, dermatitis with atopic marker at very high values and severe respiratory impairment. Pulmonary infections in the primary immunodeficiency Wiskott-Aldrich evolve with relapse risks through severe generalized pleuro-pulmonary complications that are caused by infections with Staphylococcus aureus, Streptococcus b-haemolyticus, Klebsiella pneumonia, Candida albicans and Pneumocistis jiroveci. The prognosis in primary immunodeficiency Wiskott-Aldrich is related to the degree of impairment, the nature of the complications and the presence of other concomitant diseases

Wiskott-Aldrich Syndrome

The Wiskott-Aldrich syndrome (WAS) could be a rare X-linked primary immunodeficiency disorder characterized by recurrent infections, eczema, and bleeding following thrombocytopenia. Despite the rarity of this syndrome, today our understanding of the cellular and molecular basis of the pathogenesis of this disease has increased and it’s well established that this disorder encompasses a wide range of clinical disorders including immunodeficiency, atopy, autoimmunity, and cancer. Wiskott–Aldrich Syndrome protein (WASP) mutations are located throughout the gene and inhibit or regulate the conventional function of WASP. Thus classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur within the Cdc42-binding site. Developments within the use of diagnostic tools, supportive care, and advances in allogeneic hematopoietic cell transplantation have remarkably reduced the mortality related to this disorder. Besides, gene therapy has provided optimistic perspectives on the treatment approaches of those patients

Computational Analysis of Binding of the GBD Domain of WASP to Different Binding Partners

The GTP-ase binding domain (GBD) of the signaling protein Wiskott-Aldrich Syndrome Protein (WASP) is intrinsically disordered and mutations in it have been linked with Wiskott-Aldrich Syndrome (WAS), an X-linked disorder characterized by thrombocytopenia, eczema and recurrent infections. Here, we use molecular dynamics simulations and the semi-empirical GROMOS 45A3 force field to study interaction of the GBD domain of WASP with a fragment of the protein EspFU as well as with the VCA domain of WASP (auto-inhibited state). EspFU is secreted and used by enterohaemorrhagic Escherichia coli to hijack eukaryotic cytoskeletal machinery, and it does so by competitively disrupting the auto-inhibitory interaction between GBD and VCA domains of WASP. In addition, naturally occurring mutations in the VCA domain cause different variants of WAS. Our simulations confirm that the EspFU domain binds the GBD domain similarly to the VCA domain, which explains why these two binding partners are competitive binders of the GBD domain. Furthermore, we propose a possible mechanism to explain the higher affinity of EspFU for the GBD domain. Finally, we show that the mutations in the VCA domain responsible for Wiskott-Aldrich syndrome can cause formation of β-sheets in the VCA domain. This effect, combined with the mutation-induced rearrangement of the salt bridge network, consequently disables tight binding between GBD and VCA domains. Overall, our results provide a microscopic, dynamic picture behind the two main ways through which the interactions involving the GBD domain of WASP participate in different disease processes.(doi: 10.5562/cca1806

WAS (Wiskott-Aldrich syndrome)

Review on WAS (Wiskott-Aldrich syndrome), with data on DNA, on the protein encoded, and where the gene is implicated