The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets

Ochs, Hans D.; Sj, Slichter; Harker, Lee A.; Behrens, W. E. Von; Clark, Robert A.; Wedgwood, RalphJ.

doi:10.1182/blood.v55.2.243.243

Cited by 293 publications

(101 citation statements)

References 52 publications

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“…Because WAS is primarily a paediatric disease [10,11,15,19,20] and lymphocyte numbers change substantially during normal childhood [21,22], data for patients (described in Table 1) and normal individuals were compared within the context of donor age. In the normal group, lymphocyte number was high in infants, declined during childhood and adolescence (2-16 years) and became approximately level in adults ( Fig.…”

Section: Early Lymphocyte Reduction In Was Patientsmentioning

confidence: 99%

“…Studies of small numbers of patients found reduced T cell number [10] (reviewed in [11,12]), decreased percent CD4 cells [13], and increased percent of activated and memory T cells [14]. The current view, based on a longitudinal study of four patients is that lymphocyte number is normal in infancy and declines progressively after age 6 due to decrease of T cells [15].…”

Section: Introductionmentioning

confidence: 99%

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Early deficit of lymphocytes in Wiskott–Aldrich syndrome: possible role of WASP in human lymphocyte maturation

Park

Kob

Продеус³

et al. 2004

Clinical and Experimental Immunology

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SUMMARYWiskott-Aldrich syndrome (WAS) is an X-linked platelet/immunodeficiency disease. The affected gene encodes WASP, a multidomain protein that regulates cytoskeletal assembly in blood cells. Patients have recurring infections, and their lymphocytes exhibit deficient proliferative responses in vitro . We report an evaluation of peripheral blood lymphocytes of 27 WAS patients, aged one month to 55 years. Whereas NK cells were normal, a significant deficit of T and B lymphocytes was observed. The number of lymphocytes was already decreased in infant patients, suggesting deficient output. Both CD4 and CD8 T lymphocytes were affected; the decrease was most pronounced for naïve T cells. Naïve CD4 lymphocytes of patients showed normal expression of Bcl-2, and Ki-67, and normal survival in vitro , suggesting that their in vivo survival and proliferation are normal . The collective data suggest that the patients' lymphocyte deficit results from deficient output, likely due to abnormal lymphocyte maturation in the thymus and bone marrow. We propose that WASP plays an important role not only in the function of mature T lymphocytes, but also in the maturation of human T and B lymphocytes and that impaired lymphocyte maturation is central to the aetiology of WAS immunodeficiency.

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Section: Early Lymphocyte Reduction In Was Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early deficit of lymphocytes in Wiskott–Aldrich syndrome: possible role of WASP in human lymphocyte maturation

Park

Kob

Продеус³

et al. 2004

Clinical and Experimental Immunology

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“…In normal individuals, WASP, which is expressed in haemopoietic cells (Parolini et al, 1997;Stewart et al, 1996) has been found at similar levels in neutrophils, mononuclear cells and platelets (unpublished observations). Whereas neutrophils are minimally affected in the WAS, lymphocyte defects are apparent and frequently severe in most patients after the age of 6 (Ochs et al, 1980). In comparison, platelet defects are found in all patients and in ,90% of cases at the time of diagnosis (Sullivan et al, 1994).…”

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confidence: 95%

Pathological events in platelets of Wiskott‐Aldrich syndrome patients

1999

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Summary. The Wiskott-Aldrich syndrome (WAS) is a severe X-linked platelet/immunological disorder arising from mutations of the gene WASP. At the clinical level, the major platelet abnormalities are small size and low number, both partially correctable by splenectomy. To identify underlying pathological events, we examined WAS platelets at various stages of their lifetime. In spleen sections from WAS patients, uorescence microscopy showed dramatic co-localization of markers of platelets (CD41) and macrophages (CD68) compared to non-thrombocytopenic controls, suggesting that WAS splenic macrophages are involved in platelet removal. Study of isolated WAS blood platelets by¯ow cytometry showed substantial enhancement of surface exposure of phosphatidylserine (PS), a signal for engulfment by macrophages. Isolated resting WAS platelets were also aberrantly susceptible to microparticle release, and plasma samples of WAS patients contained > 5 times normal numbers of platelet-derived microparticles which may explain the small size of circulating platelets. Measurements with the Ca 2+ sensitive dye¯uo-3 revealed signi®cantly increased Ca 2+ levels, 310 6 13 nmol/l for WAS platelets versus 106 6 12 nmol/l for normal platelets, and also prolongation of agonist-induced Ca 2+¯u x. Cumulatively, these studies identify abnormal events occurring in WAS platelets: increased Ca 2+ levels and enhancement of two Ca 2+ dependent processes, PS exposure and microparticle release; these abnormal events may contribute to the in vivo decrease of platelet number and reduction of platelet size in this disease.

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“…The pathogenesis of the platelet defect remains only partially understood and is thought to result from a combination of megakaryocyte dysfunction leading to small/abnormally formed platelets (Sabri et al, 2006;Ingrungruanglert et al, 2015) and increased platelet destruction in the spleen (Grottum et al, 1969). Megakaryocyte numbers in the bone marrow are typically normal (Grottum et al, 1969;Ochs et al, 1980). Recognition of WAS is important because curative stem cell and gene therapies are available, without which median survival is reduced to 10-15 years as a result of infections, severe bleeding, autoimmune complications and haematological malignancies (Sullivan et al, 1994).…”

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confidence: 99%

How I manage patients with Wiskott Aldrich syndrome

et al. 2019

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Summary Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X‐linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.

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The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets

Cited by 293 publications

References 52 publications

Early deficit of lymphocytes in Wiskott–Aldrich syndrome: possible role of WASP in human lymphocyte maturation

Early deficit of lymphocytes in Wiskott–Aldrich syndrome: possible role of WASP in human lymphocyte maturation

Pathological events in platelets of Wiskott‐Aldrich syndrome patients

How I manage patients with Wiskott Aldrich syndrome

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