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Blood Feb 2005The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic...
The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASp-deficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell-dependent and -independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germinal center reaction was reduced in WASp-deficient mice. Thus, WASp is crucial for optimal B-cell responses and plays a pivotal role in the primary humoral immune response.
Topics: Animals; B-Lymphocytes; Cell Adhesion; Cell Aggregation; Cell Movement; Flow Cytometry; Humans; Mice; Mice, Knockout; Phenotype; Proteins; Spleen; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15383456
DOI: 10.1182/blood-2004-03-1003 -
Cellular and Molecular Life Sciences :... Jan 2012Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea,... (Review)
Review
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn's disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system.
Topics: Colitis, Ulcerative; Crohn Disease; Genes, X-Linked; Granulomatous Disease, Chronic; Humans; Interleukin-10; Intestinal Mucosa; Receptors, Interleukin-10; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; X-Linked Combined Immunodeficiency Diseases
PubMed: 21997382
DOI: 10.1007/s00018-011-0837-9 -
The Journal of Clinical Investigation Nov 1971The Wiskott-Aldrich syndrome is an immune deficiency disorder with an impairment of both humoral and cellular immune responses. Metabolic turnover studies of IgG, IgA,...
The Wiskott-Aldrich syndrome is an immune deficiency disorder with an impairment of both humoral and cellular immune responses. Metabolic turnover studies of IgG, IgA, IgM, and albumin were conducted in seven patients with the Wiskott-Aldrich syndrome using purified radioiodinated proteins. The survival of each of the proteins studied was significantly shortened with a half-time of 7.5 days for IgG (normal 22.9 +/-4 SD), 3.0 days for IgA (normal 5.8 +/-1), 5.0 days for IgM (normal 10.1 +/-2.1), and 8.6 days for albumin (normal 17, range 13-20); the fractional catabolic rates were correspondingly elevated and the distribution of protein among the body compartments was normal. For three of the four proteins. IgG, IgA, and albumin, the steady-state synthetic rates were generally elevated leading to normal or even elevated serum proteins levels. Thus, in the case of IgA, the synthetic rate averaged five times normal while the fractional degradative rate was twice normal. The resulting serum concentration was, therefore, significantly elevated, IgM represented an exception to this pattern in that the increased rate of degradation was not counterbalanced by an increased synthetic rate and, therefore, the serum levels were low. Albumin clearance studies using albumin-(51)Cr showed gastrointestinal protein loss in these patients to be slightly greater than normal, but this could account for only a small fraction of the hypercatabolism observed. There was no proteinuria or abnormalities of thyroid, adrenal, renal, or liver function. Thus, none of the previously recognized causes of increased serum protein catabolism were present. Patients with the Wiskott-Aldrich syndrome, therefore, have a unique disorder of serum protein metabolism characterized by endogenous hypercatabolism of at least four major serum proteins. This phenomenon may be related to reticuloendothelial hyperfunction since the Wiskott-Aldrich syndrome is associated with reticuloendothelial hyperplasia and accelerated clearance of colloidal materials from the plasma.
Topics: Adolescent; Child; Child, Preschool; Chromium Isotopes; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Infant; Lymphatic Diseases; Male; Metabolic Clearance Rate; Mononuclear Phagocyte System; Protein-Losing Enteropathies; Serum Albumin; Wiskott-Aldrich Syndrome
PubMed: 5096517
DOI: 10.1172/JCI106731 -
Molecular Therapy : the Journal of the... Jun 2012The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and immunodeficiency. Hematopoietic cell transplantation can cure...
The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and immunodeficiency. Hematopoietic cell transplantation can cure the disease and gene therapy is being tested as an alternative treatment option. In this study, we assessed the use of foamy virus (FV) vectors as a gene transfer system for WAS, using a Was knockout (KO) mouse model. Preliminary experiments using FV vectors expressing the green fluorescent protein under the transcriptional control of the endogenous WAS promoter or a ubiquitously acting chromatin opening element allowed us to define transduction conditions resulting in high (>40%) and long-term in-vivo marking of blood cells after transplantation. In following experiments, Was KO mice were treated with FV vectors containing the human WAS complementary DNA (cDNA). Transplanted animals expressed the WAS protein (WASp) in T and B lymphocytes, as well as platelets and showed restoration of both T-cell receptor-mediated responses and B-cell migration. We also observed recovery of platelet adhesion and podosome formation in dendritic cells (DCs) of treated mice. These data demonstrate that FV vectors can be effective for hematopoietic stem cell (HSC)-directed gene correction of WAS.
Topics: Animals; B-Lymphocytes; Blood Platelets; Cell Line; Dendritic Cells; Disease Models, Animal; Female; Gene Expression; Gene Order; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hematopoietic Stem Cells; Humans; Male; Mice; Mice, Knockout; Spumavirus; T-Lymphocytes; Transduction, Genetic; Transgenes; Virus Integration; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 22215016
DOI: 10.1038/mt.2011.282 -
Oncogene Jan 2021Immunodeficiency is associated with cancer risk. Accordingly, hematolymphoid cancers develop in Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency...
Immunodeficiency is associated with cancer risk. Accordingly, hematolymphoid cancers develop in Wiskott-Aldrich syndrome (WAS), an X-linked primary immunodeficiency disorder (PID) resulting from the deficiency of WAS-protein (WASp) expressed predominantly in the hematolymphoid cell lineages. Despite the correlation between WASp deficiency and hematolymphoid cancers, the molecular mechanism underlying the oncogenic role of WASp is incompletely understood. Employing the WASp-sufficient and WASp-deficient cell-pair model of human T and B lymphocytes, we show that WASp deficiency differentially influences hyperactivation versus inhibition of both CDC42:ERK1/2 and NF-κB:AP-1 pro-oncogenic signaling pathways in nonmalignant versus malignant T and B lymphocytes. Furthermore, WASp deficiency induces a cell-type specific up/down-modulation of the DNA-binding activities of NF-κB, AP-1, and multiple other transcription factors with known roles in oncogenesis. We propose that WASp functions as a putative "tumor-suppressor" protein in normal T and B cells, and "oncoprotein" in a subset of established T and B cell malignancies that are not associated with the NPM-ALK fusion.
Topics: B-Lymphocytes; Cell Proliferation; Cells, Cultured; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Oncogene Proteins; Signal Transduction; T-Lymphocytes; Transcription Factor AP-1; Tumor Suppressor Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; cdc42 GTP-Binding Protein
PubMed: 33139832
DOI: 10.1038/s41388-020-01533-3 -
Blood Aug 2001Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells...
Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4-- and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells. (Blood. 2001;98:1086-1094)
Topics: Animals; B-Lymphocytes; CD40 Antigens; Cell Adhesion; Cell Movement; Cell Polarity; Cytoskeleton; Interleukin-4; Mice; Mice, Knockout; Microvilli; Nerve Tissue Proteins; Proteins; Signal Transduction; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein, Neuronal; cdc42 GTP-Binding Protein; rac1 GTP-Binding Protein; rho GTP-Binding Proteins
PubMed: 11493455
DOI: 10.1182/blood.v98.4.1086 -
Clinical and Experimental Immunology Feb 2005
Review
Topics: B-Lymphocytes; Humans; Mutation; Proteins; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15654814
DOI: 10.1111/j.1365-2249.2005.02707.x -
The Journal of Experimental Medicine Sep 2015Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS...
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)-deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell-intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.
Topics: Adolescent; Adult; Animals; B-Cell Activating Factor; B-Lymphocytes; Case-Control Studies; Child; Child, Preschool; Cytoprotection; High-Throughput Nucleotide Sequencing; Humans; Infant; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Differentiation Factor 88; Receptors, Antigen, B-Cell; Toll-Like Receptors; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Young Adult
PubMed: 26371186
DOI: 10.1084/jem.20150585 -
Seminars in Thrombosis and Hemostasis Oct 2004Platelet dense granules form using mechanisms shared by melanosomes in melanocytes and by subsets of lysosomes in more generalized cells. Consequently, disorders of... (Review)
Review
Platelet dense granules form using mechanisms shared by melanosomes in melanocytes and by subsets of lysosomes in more generalized cells. Consequently, disorders of platelet dense granules can reveal how organelles form and move within cells. Models for the study of new vesicle formation include isolated delta-storage pool deficiency, combined alphadelta-storage pool deficiency, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, thrombocytopenia absent radii syndrome, and Wiskott-Aldrich syndrome. The molecular bases of dense granule deficiency are known for the seven subtypes of HPS, as well as for Chediak-Higashi syndrome, Griscelli syndrome, and Wiskott-Aldrich syndrome. The gene products involved in these disorders help elucidate the generalized process of the formation of vesicles from extant membranes such as the Golgi.
Topics: Blood Platelet Disorders; Blood Platelets; Chediak-Higashi Syndrome; Exons; Gene Expression Regulation; Hair; Hermanski-Pudlak Syndrome; Humans; Lysosomes; Microscopy, Electron; Thrombocytopenia; Wiskott-Aldrich Syndrome
PubMed: 15497096
DOI: 10.1055/s-2004-835674 -
Haematologica Oct 2011T-cell activation relies on the assembly of the immunological synapse, a structure tightly regulated by the actin cytoskeleton. The precise role of the Wiskott-Aldrich...
BACKGROUND
T-cell activation relies on the assembly of the immunological synapse, a structure tightly regulated by the actin cytoskeleton. The precise role of the Wiskott-Aldrich syndrome protein, an actin cytoskeleton regulator, in linking immunological synapse structure to downstream signaling remains to be clarified.
DESIGN AND METHODS
To address this point, CD4(+) T cells from patients with Wiskott-Aldrich syndrome were stimulated with antigen-presenting cells. The structure and dynamics of the immunological synapse were studied by confocal and video-microscopy.
RESULTS
Upon stimulation by antigen-presenting cells, Wiskott-Aldrich syndrome protein-deficient T cells displayed reduced cytokine production and proliferation. Although Wiskott-Aldrich syndrome T cells formed conjugates with antigen-presenting cells at normal frequency and exhibited normal T-cell receptor down-regulation, they emitted actin-rich protrusions away from the immunological synapse area and their microtubule organizing center failed to polarize fully towards the center of the immunological synapse. In parallel, abnormally dispersed phosphotyrosine staining revealed unfocused synaptic signaling in Wiskott-Aldrich syndrome T cells. Time-lapse microscopy confirmed the anomalous morphology of Wiskott-Aldrich syndrome T-cell immunological synapses and showed erratic calcium mobilization at the single-cell level.
CONCLUSIONS
Taken together, our data show that the Wiskott-Aldrich syndrome protein is required for the assembly of focused immunological synapse structures allowing optimal signal integration and sustained calcium signaling.
Topics: Antigen-Presenting Cells; CD4-Positive T-Lymphocytes; Calcium; Cell Communication; Cell Line; Humans; Immunological Synapses; Lymphocyte Activation; Receptors, Antigen, T-Cell; Signal Transduction; Superantigens; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 21659358
DOI: 10.3324/haematol.2011.040204