Deletion of Wiskott–Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells

Baptista, Marisa A. P.; Keszei, Márton; Oliveira, Mariana M.S.; Sunahara, Karen K. S.; Andersson, John; Dahlberg, Carin; Worth, Austen; Liedén, Agne; Kuo, I-Chun; Wallin, Robert P. A.; Snapper, Scott B.; Eidsmo, Liv; Scheynius, Annika; Karlsson, Mikael C. I.; Bouma, Gerben; Burns, Siobhan O.; Forsell, Mattias N.E.; Thrasher, Adrian J.; Nylén, Susanne; Westerberg, Lisa S.

doi:10.1038/ncomms12175

Cited by 28 publications

(53 citation statements)

References 60 publications

(95 reference statements)

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“…This regulates the actin cytoskeleton in most hematopoietic lineages and is consequently important for normal function of many immunological processes. [1][2][3][4] Clinical and biological manifestations of WAS include microthrombocytopenia, recurrent infections, and eczema. Patients also display an increased incidence of autoimmunity and are at risk of developing lymphoproliferative disorders and lymphoid malignancies.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Morris

Fox

Chakraverty

et al. 2017

Blood

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Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proinflammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242.

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Section: Introductionmentioning

confidence: 99%

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Morris

Fox

Chakraverty

et al. 2017

Blood

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“…Rac2 regulated the recruitment and assembly of NOX2 in cDC1s, but not in cDC2s [99]. Deletion of the Wiskott-Aldrich syndrome protein (WASp) increased Rac2 activity, which resulted in enhanced CP efficiency, both in cDC1s and cDC2s [110]. In contrast, the reduced activity of either gp91phox or p47phox impairs the CP ability of BMDCs [99].…”

Section: Protection Of Extracellular Proteins From Lysosomal Degradationmentioning

confidence: 99%

Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review

2020

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While the success of dendritic cell (DC) vaccination largely depends on cross-presentation (CP) efficiency, the precise molecular mechanism of CP is not yet characterized. Recent research revealed that endoplasmic reticulum (ER)-associated degradation (ERAD), which was first identified as part of the protein quality control system in the ER, plays a pivotal role in the processing of extracellular proteins in CP. The discovery of ERAD-dependent processing strongly suggests that the properties of extracellular antigens are one of the keys to effective DC vaccination, in addition to DC subsets and the maturation of these cells. In this review, we address recent advances in CP, focusing on the molecular mechanisms of the ERAD-dependent processing of extracellular proteins. As ERAD itself and the ERAD-dependent processing in CP share cellular machinery, enhancing the recognition of extracellular proteins, such as the ERAD substrate, by ex vivo methods may serve to improve the efficacy of DC vaccination.

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“…An abnormal DC:Tcell immune synapse results in impaired T cell and antibody responses leading to recurrent bacterial and viral infections and autoimmunity [109]. The reported increase in DC cross-presentation and expansion of CD8 + T cells in WASp knockout mice has not been observed in humans [110]. [111]).…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

Human dendritic cell immunodeficiencies

Cytlak

Collin

2019

Seminars in Cell & Developmental Biology

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The critical functions of dendritic cells (DCs) in immunity and tolerance have been demonstrated in many animal models but their non-redundant roles in humans are more difficult to probe. Human primary immunodeficiency (PID), resulting from single gene mutations, may result in DC deficiency or dysfunction. This relatively recent recognition illuminates the in vivo role of human DCs and the pathophysiology of the associated clinical syndromes. In this review, the development and function of DCs as established in murine models and human in vitro systems, discussed. This forms the basis of predicting the effects of DC deficiency in vivo and understanding the consequences of specific mutations on DC development and function. DC deficiency syndromes are associated with heterozygous GATA2 mutation, bi-allelic and heterozygous IRF8 mutation and heterozygous IKZF1 mutation. The intricate involvement of DCs in the balance between immunity and tolerance is leading to increased recognition of their involvement in a number of other immunodeficiencies and autoimmune conditions. Owing to the precise control of transcription factor gene expression by super-enhancer elements, phenotypic anomalies are relatively commonly caused by heterozygous mutations.

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Deletion of Wiskott–Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells

Cited by 28 publications

References 60 publications

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Endoplasmic Reticulum-Associated Degradation-Dependent Processing in Cross-Presentation and Its Potential for Dendritic Cell Vaccinations: A Review

Human dendritic cell immunodeficiencies

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