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

Park, J. Y.; Kob, M.; Продеус, А.П.; Rosen, Fred S.; Shcherbina, Anna; Remold‐O′Donnell, Eileen

doi:10.1111/j.1365-2249.2004.02409.x

Cited by 83 publications

(87 citation statements)

References 38 publications

(38 reference statements)

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“…We could show that WBD is capable not only of confirming the previously described hematopoietic alterations occurring in these individuals 4, 5, 6, 7, 9, 10, 17 but also of providing novel information on the hematopoietic landscape of these diseases. Indeed, together with the known defects in B cell contribution (Fig.…”

Section: Discussionsupporting

confidence: 73%

Multiparametric Whole Blood Dissection: A one‐shot comprehensive picture of the human hematopoietic system

et al. 2017

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Human hematopoiesis is a complex and dynamic system where morphologically and functionally diverse mature cell types are generated and maintained throughout life by bone marrow (BM) Hematopoietic Stem/Progenitor Cells (HSPC). Congenital and acquired hematopoietic disorders are often diagnosed through the detection of aberrant frequency or composition of hematopoietic cell populations. We here describe a novel protocol, called “Whole Blood Dissection” (WBD), capable of analyzing in a single test‐tube, hematopoietic progenitors and all major mature cell lineages composing either BM or peripheral blood (PB) through a multiparametric flow‐cytometry analysis. WBD allows unambiguously identifying in the same tube up to 23 different blood cell types including HSPC subtypes and all the major myeloid and lymphoid lineage compartments at different stages of maturation, through a combination of 17 surface and 1 viability cell markers. We assessed the efficacy of WBD by analyzing BM and PB samples from adult (n = 8) and pediatric (n = 9) healthy donors highlighting age‐related shift in cell composition. We also tested the capability of WBD on detecting aberrant hematopoietic cell composition in clinical samples of patients with primary immunodeficiency or leukemia unveiling expected and novel hematopoietic unbalances. Overall, WBD allows unambiguously identifying >99% of the cell subpopulations composing a blood sample in a reproducible, standardized, cost‐, and time‐efficient manner. This tool has a wide range of potential pre‐clinical and clinical applications going from the characterization of hematopoietic disorders to the monitoring of hematopoietic reconstitution in patients after transplant or gene therapy. © 2017 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC.

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Section: Discussionsupporting

confidence: 73%

Multiparametric Whole Blood Dissection: A one‐shot comprehensive picture of the human hematopoietic system

et al. 2017

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“…Although WASP deficiency affects the functions of both lymphoid and myeloid cells, results obtained from the follow-up of WAS patients who underwent HLAmatched hemopoietic stem cell transplant, and from the analysis of WAS patients with spontaneous genetic reversion, indicate that WASP expression confers a selective growth advantage to T cells only (20,21). Consistently, it has been shown that WAS patients have a reduction in the numbers of circulating T lymphocytes, especially within the naive compartment (22). WAS patients suffer from recurrent infections caused by encapsulated bacteria, viruses, and fungi (19), suggesting an impairment in cellular-mediated immunity.…”

Section: W Iskott-aldrich Syndrome (Was)mentioning

confidence: 80%

Defective Th1 Cytokine Gene Transcription in CD4+ and CD8+ T Cells from Wiskott-Aldrich Syndrome Patients

Trifari

Sitia

Aiuti

et al. 2006

The Journal of Immunology

101

110

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Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4+ and CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-γ, and TNF-α are strongly reduced in CD8+ T cells from WAS patients, compared with healthy donor CD8+ T cells. Furthermore, WAS CD4+ T cells secrete low levels of IL-2 and fail to produce IFN-γ and TNF-α, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-γ production persists after culture of naive WAS CD4+ T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4+ and CD8+ T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN-γ mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4+ T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8+ T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.

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“…This study showed that WASP expression is confined to a subset of the patient's memory T cells; his naive T cells are WASP-negative (M. I. Lutskiy et al, manuscript in preparation). For infants with WAS, although their lymphocyte numbers differ from normal, memory T cells are largely absent as in normal infants due to predominance of naive T cell populations (38). Further study of the mechanism of discordant WASP expression is needed particularly for the relatively frequent IVS 6 (ϩ5) gϾa genotype.…”

Section: Discussionmentioning

confidence: 99%

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Lutskiy

Rosen

Remold‐O′Donnell

2005

The Journal of Immunology

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Wiskott-Aldrich syndrome (WAS) is a platelet/immunodeficiency disease arising from mutations of WAS protein (WASP), a hemopoietic cytoskeletal protein. Clinical symptoms vary widely from mild (X-linked thrombocytopenia) to life threatening. In this study, we examined the molecular effects of individual mutations by quantifying WASP in peripheral lymphocytes of 44 patients and identifying the molecular variant (collectively called proteotype). Nonpredicted proteotypes were found for 14 genotypes. These include WASP-negative lymphocytes found for five missense genotypes and WASP-positive lymphocytes for two nonsense, five frameshift, and two splice site genotypes. Missense mutations in the Ena/VASP homology 1 (EVH1) domain lead to decreased/absent WASP but normal mRNA levels, indicating that proteolysis causes the protein deficit. Because several of the EVH1 missense mutations alter WIP binding sites, the findings suggest that abrogation of WIP binding induces proteolysis. Whereas platelets of most patients were previously shown to lack WASP, WASP-positive platelets were found for two atypical patients, both of whom have mutations outside the EVH1 domain. WASP variants with alternative splicing and intact C-terminal domains were characterized for eight nonsense and frameshift genotypes. One of these, a nonsense genotype in a mild patient, supports expression of WASP lacking half of the proline-rich region. With one notable exception, genotype and proteotype were linked, indicating that a genotype-proteotype registry could be assembled to aid in predicting disease course and planning therapy for newly diagnosed infants. Knowledge of the molecular effect of mutations would aid also in identifying disease-modifying genes.

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

Cited by 83 publications

References 38 publications

Multiparametric Whole Blood Dissection: A one‐shot comprehensive picture of the human hematopoietic system

Multiparametric Whole Blood Dissection: A one‐shot comprehensive picture of the human hematopoietic system

Defective Th1 Cytokine Gene Transcription in CD4+ and CD8+ T Cells from Wiskott-Aldrich Syndrome Patients

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

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