UMLS:C0024312 - FACTA Search

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Query: UMLS:C0024312 (lymphopenia)
4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wiskott-Aldrich syndrome (WAS) is an inherited disease involving defects of platelets (small size, severe thrombocytopenia due to accelerated destruction) and T lymphocytes (progressive immunodeficiency, lymphopenia). The best-characterized molecular defect is the deficiency and, in some cases, abnormal forms of the T-lymphocyte surface mucin molecule CD43; deficiency of the platelet surface mucin GPIb was observed previously in two of four patients. Neither of these defects is primary, since CD43 and GPIb are encoded by autosomal genes and the disease is X-linked. This study uses cellular biological approaches to explore the possibility that destruction of structurally defective WAS platelets, mimicked experimentally by sonication of normal platelets, plays a role by releasing protease and generating other cellular defects. We show that a protease of normal platelets, identified as Ca(2+)-dependent neutral protease (calpain), which is known to cleave platelet GPIb, also specifically cleaves CD43 on the surface of neighboring desialylated T lymphocytes. The identification of the CD43 cleaving protease was based on its requirement for Ca2+ and inhibition by leupeptin, but not by diisopropylfluorophosphate (DFP). The approximate site of CD43 cleavage was identified by the use of a rabbit antibody. Sensitivity of GPIb to calpain is shown to be sialylation-independent and that of CD43 to be sialylation-dependent, and these findings are explained in terms of molecular structures. These and previous findings are incorporated into a putative mechanism, which explains most of the defects in the WAS. The mechanism suggests that the primary defective molecule in the WAS is unlikely to be a surface glycoprotein, but rather a cytoplasmic molecule with a function in cytoskeletal interactions and/or calcium ion regulation and calpain activation.
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PMID:Effect of platelet calpain on normal T-lymphocyte CD43: hypothesis of events in the Wiskott-Aldrich syndrome. 155 70

In 1937, Wiskott described three brothers with congenital thrombocytopenia, bloody diarrhea, eczema, and recurrent ear infections. Seventeen years later, Aldrich showed X-linked (a gene carried on the X chromosome) inheritance. Subsequently, the characteristic immune defects of Wiskott-Aldrich syndrome (WAS) were reported, including lymphopenia, lymphocyte depletion in the thymus, T-dependent pericortical areas of lymph nodes, defective delayed type hypersensitivity, and failure to produce antibodies to polysaccharides and to a variety of bacterial, protein, and viral antigens. The consistent platelet abnormalities were explained by ineffective thrombocytopoiesis. The increased risk of autoimmune diseases and malignancies was recognized. In addition to the classic WAS phenotype, a milder form designated as hereditary X-linked thrombocytopenia (XLT) has been described. The genes for both WAS and XLT have been mapped to Xp11.22 and sequence analysis has identified mutations of the same gene in both phenotypes. The gene coding for the WAS protein (WASP) is composed of 12 exons containing 1,823 base pairs and encodes a 502-amino acid protein. WASP is expressed in the cytoplasm of all hematopoietic stem cell-derived lineages. Although the precise function of WASP is unknown, several unique binding domains have been identified, and WASP appears to play a critical role in signal transduction by interacting with SH3-containing molecules and in the regulation of the cytoskeletal reorganization. The identification of the WASP gene allows the diagnosis of WAS on a molecular basis, carrier detection, and prenatal diagnosis. Treatment is largely symptomatic and includes antibiotics, prophylactic intravenous immunoglobulin (i.v.IG) and splenectomy in selected cases to reduce hemorrhages. Stem cell transplantation corrects the defect and should be considered in younger patients.
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PMID:The Wiskott-Aldrich syndrome. 980 Dec 62

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia, eczema, and variable degrees of impaired cellular and humoral immunity. Age-dependent T-cell lymphopenia has been described in WAS, however, the diversity of the T-cell compartment over time in these patients has not been characterized. We have used complementarity-determining region 3 (CDR3) size distribution analysis to assess T-cell receptor (TCR) Vbeta repertoire in 13 patients with WAS. Diverse CDR3 size pattern was demonstrated in patients under 15 years of age regardless of the levels of WAS protein (WASP) expression. In contrast, older patients showed significantly higher skewing of TCRVbeta repertoire as compared with healthy adults. We did not find correlation between clinical score and complexity of TCRVbeta repertoire. These findings suggest that WASP deficiency does not limit thymic generation of a normal TCR and indicate that T-cell oligoclonality may contribute to the immunodeficiency in older patients with WAS.
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PMID:Analysis of T-cell repertoire diversity in Wiskott-Aldrich syndrome. 1609 49

The Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency syndrome caused by mutations in the WAS protein (WASP). This participates in signalling and cytoskeletal homoeostasis, and some of its activities are regulated by its binding to the WASP interacting protein (WIP). WIP deficiency, however, has not yet been shown to be of pathological significance in humans. Here we show that, in WIP null (WIP(-/-)) mice, it produces haematological alterations and anatomical abnormalities in several organs, most probably as a consequence of autoimmune attacks. Granulocytosis and severe lymphopenia are associated with a proportional increase in segmented cells and fewer bone marrow erythrocytes and lymphocytes. Splenomegaly is accompanied by an increase of haematopoietic tissue and red pulp, reduction of the white pulp, and fewer B (B220(+)) lymphocytes (also apparent in the lymph nodes and Peyer's patches). Ulcerative colitis, interstitial pneumonitis, glomerular nephropathy with IgA deposits, autoantibodies, and joint inflammation are also evident. These progressive immunological disorders closely mimic those seen in WAS. WIP deficiency may thus be implicated in some cases in which mutations in the gene encoding WASP are not detected.
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PMID:WIP null mice display a progressive immunological disorder that resembles Wiskott-Aldrich syndrome. 1708 54

Activated T cells rapidly assemble filamentous (F-) actin networks in response to ligation of the T cell receptor or upon interaction with adhesive stimuli in order to facilitate cell migration and the formation of the immune synapse. Branched filament assembly is crucial for this process and is dependent upon activation of the Arp2/3 complex by the actin nucleation-promoting factor Wiskott-Aldrich Syndrome protein (WASp). Genetic disruption of the WAS gene has been linked to hematopoietic malignancies and various cytopenias. Although the contributions of WASp and Arp2/3 to T cell responses are fairly well characterized, the role of the mammalian Diaphanous (mDia)-related formins, which both nucleate and processively elongate non-branched F-actin, has not been demonstrated. Here, we report the effects on T cell development and function following the knock out of the murine Drf1 gene encoding the canonical formin p140mDia1. Drf1(-/-) mice develop lymphopenia characterized by diminished T cell populations in lymphoid tissues. Consistent with a role for p140mDia1 in the regulation of the actin cytoskeleton, isolated Drf1(-/-) splenic T cells adhered poorly to extracellular matrix proteins and migration in response to chemotactic stimuli was completely abrogated. Both integrin and chemokine receptor expression was unaffected by Drf1(-/-) targeting. In response to proliferative stimuli, both thymic and splenic Drf1(-/-) T cells failed to proliferate; ERK1/2 activation was also diminished in activated Drf1(-/-) T cells. These data suggest a central role for p140mDia1 in vivo in dynamic cytoskeletal remodeling events driving normal T cell responses.
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PMID:T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice. 1759 62

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder characterized by eczema, recurrent infections, thrombocytopenia and small platelets. There is an increased incidence of autoimmune phenomena particularly autoimmune haemolytic anaemias and vasculitic disorders. Mutations in the WASP gene encoding the cytoskeleton regulatory protein WASp (Wiskott-Aldrich syndrome protein) result in abnormal protein activity with defective cytoplasmic signaling and actin polymerization. This accounts for abnormal T cell responses to proliferation and susceptibility to infections, but does not fully explain the autoimmune phenomena nor the progressive lymphopenia seen in these patients. Wiskott Aldrich patients also demonstrate abnormal O-glycosylation of a highly conserved transmembrane glycoprotein CD43 that is expressed on most haemopoeitic cells. The altered glycosylation pattern on WAS lymphocytes is due to increased beta1-->6 GlcNACtransferase activity which leads to branched core 2 glycans or lower molecular forms of CD43 glycoprotein. The clinical hypothesis put forward is that abnormal O-glycosylation of CD43 may underlie the development of the autoimmune disorders and the progressive lymphopenia observed in WAS patients. Regulation of glycosylation of CD43 is important in the selection process of T cells within the thymus and abnormalities of glycosylation may cause many immune perturbations, such as the escape of self-reactive T cells into the periphery and subsequent development of autoimmune disease in these patients.
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PMID:Abnormal O-glycosylation of CD43 may account for some features of Wiskott-Aldrich syndrome. 1766 47

Although T cell dysfunction and lymphopenia are key features of immunodeficient patients with the Wiskott-Aldrich syndrome and Wiskott-Aldrich syndrome protein (WASP)-deficient mice, T cell development appears relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homologue of WASP, may serve a redundant function with WASP. To examine the unique and redundant activities of WASP and N-WASP, we generated ES cells devoid of WASP and N-WASP [double knockout (DKO)] and used the RAG-2-deficient blastocyst complementation system to generate DKO lymphocytes. Moreover, we mated WASP KO mice with mice containing a conditionally targeted N-WASP allele and used the Cre-loxP system to generate mice lacking WASP and N-WASP in T cells [conditional DKO (cDKO)]. In both systems, N-WASP-deficient cells were indistinguishable from WT cells. In contrast, T cell development in DKO and cDKO mice was markedly altered, as shown by thymic hypocellularity and reduced numbers of peripheral T cells. We found that the combined activity of WASP and N-WASP was important for CD4(-)CD8(-) double-negative (DN)-to-CD4(+)CD8(+) double-positive (DP) cell transition, and this may be partly explained by reduced cycling DN3 cells. In addition, decreased migratory responses of CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) cells and increased percentage of CD69(low)CD24(low) and CD62L(low) SP cells in cDKO cells imply retention of SP cells in the thymus. In summary, this study suggests that, although WASP serves a unique role for peripheral T cell function, T cell development depends on the combined activity of WASP and N-WASP.
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PMID:Wiskott Aldrich syndrome protein (WASP) and N-WASP are critical for T cell development. 1787 99

The Wiskott-Aldrich syndrome protein is an essential cytoskeleton regulator found in cells of the hematopoietic lineage and controls the motility of leukocytes. The impact of WAS gene deficiency on the mobilization of hematopoietic progenitor/stem cells in circulation has remained unexplored but information would be pertinent in the context of autologous gene therapy of Wiskott-Aldrich syndrome. The response to granulocyte-colony stimulating factor mobilization was investigated in a murine WAS knock-out model of the disease, by measuring hematologic parameters, circulation and engraftment of hematopoietic progenitor/stem cells. In the steady-state, adult WAS knock-out mice have B-cell lymphopenia, marked neutrophilia, increased counts of circulating hematopoietic progenitor cells and splenomegaly, presumably caused by the retention of hematopoietic progenitor cells due to high levels of splenic CXCL12. In spite of these anomalies, the administration of granulocyte-colony-stimulating factor mobilizes progenitor/stem cells in WAS knock-out mice to the same level and with the same kinetics as in wild-type control mice. Mobilized peripheral blood cells from WAS knock-out mice can be transduced and are able to engraft into lethally-irradiated hosts reconstituting multiple lineages of cells and providing more effective radio-protection than mobilized cells from wild-type control mice. Surprisingly, the homing and the peripheral blood recovery of B lymphocytes was influenced by the background of the host. Thus, in the absence of Wiskott-Aldrich syndrome protein, effective mobilization is achieved but partial correction may occur as a result of an abnormal hematopoietic environment.
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PMID:Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor. 2344 77

A significant number of contributions to our understanding of primary immunodeficiencies (PIDs) in pathogenesis, diagnosis, and treatment were published in the Journal in 2013. For example, deficiency of mast cell degranulation caused by signal transducer and activator of transcription 3 deficiency was demonstrated to contribute to the difference in the frequency of severe allergic reactions in patients with autosomal dominant hyper-IgE syndrome compared with that seen in atopic subjects with similar high IgE serum levels. High levels of nonglycosylated IgA were found in patients with Wiskott-Aldrich syndrome, and these abnormal antibodies might contribute to the nephropathy seen in these patients. New described genes causing immunodeficiency included caspase recruitment domain 11 (CARD11), mucosa-associated lymphoid tissue 1 (MALT1) for combined immunodeficiencies, and tetratricopeptide repeat domain 7A (TTC7A) for mutations associated with multiple atresia with combined immunodeficiency. Other observations expand the spectrum of clinical presentation of specific gene defects (eg, adult-onset idiopathic T-cell lymphopenia and early-onset autoimmunity might be due to hypomorphic mutations of the recombination-activating genes). Newborn screening in California established the incidence of severe combined immunodeficiency at 1 in 66,250 live births. The use of hematopoietic stem cell transplantation for PIDs was reviewed, with recommendations to give priority to research oriented to establish the best regimens to improve the safety and efficacy of bone marrow transplantation. These represent only a fraction of significant research done in patients with PIDs that has accelerated the quality of care of these patients. Genetic analysis of patients has demonstrated multiple phenotypic expressions of immune deficiency in patients with nearly identical genotypes, suggesting that additional genetic factors, possibly gene dosage, or environmental factors are responsible for this diversity.
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PMID:Advances in basic and clinical immunology in 2013. 2458 42

The lack or marked reduction of recently formed T and B cells provides a basis for neonatal screening for severe combined immunodeficiencies (SCID) and X-linked agammaglobulinemia (XLA). Newborns with other conditions are also identified if a severe T or B cell lymphopenia is present at birth. We retrospectively analyzed Guthrie card samples from 11 children with Wiskott-Aldrich syndrome (WAS), a rare disease that requires early diagnosis and treatment, to determine whether combined T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) screening could identify these patients. 4 of 11 patients showed markedly reduced TREC or KREC copy numbers in their DBS as compared to storage-time matched controls and prospectively screened Swedish and German newborns. No correlation was observed between the WAS gene mutations, the clinical severity/course and the result of the screening assay. A diagnosis of WAS should thus be considered in newborns with positive TREC or KREC screening results.
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PMID:Newborn screening for severe T and B cell lymphopenia identifies a fraction of patients with Wiskott-Aldrich syndrome. 2521 81

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