Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

Nishikomori, Ryuta; Izawa, Kazushi; Murata, Yuuki; Tanaka, Naoko; Sakai, Harumi; Saito, Megumu K.; Yasumi, Takahiro; Takaoka, Yuki; Nakahata, Tatsutoshi; Mizukami, Tomoyuki; Nunoi, Hiroyuki; Kiyohara, Yuki; Yoden, Atsushi; Murata, Takuji; Sasaki, Susumu; Ito, Etsuro; Akutagawa, Hiroshi; Kawai, Toshinao; Imai, Chihaya; Okada, Satoshi; Kobayashi, Masao; Heike, Toshio

doi:10.1182/blood-2011-05-354167

Cited by 30 publications

(18 citation statements)

References 39 publications

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“…The T cell counts are normal but TCR activation is impaired, especially NF-κB activation. In accordance with these studies, our simulation indicates that the NEMO and IKKB perturbations lead to inactivation of NF-κB, despite normal activation of AP1 and NFAT [24, 83, 84]. …”

Section: Discussionsupporting

confidence: 87%

Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells

Teku

Vihinen

2017

PLoS ONE

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Primary immunodeficiencies (PIDs) form a large and heterogeneous group of mainly rare disorders that affect the immune system. T-cell deficiencies account for about one-tenth of PIDs, most of them being monogenic. Apart from genetic and clinical information, lots of other data are available for PID proteins and genes, including functions and interactions. Thus, it is possible to perform systems biology studies on the effects of PIDs on T-cell physiology and response. To achieve this, we reconstructed a T-cell network model based on literature mining and TPPIN, a previously published core T-cell network, and performed semi-quantitative dynamic network simulations on both normal and T-cell PID failure modes. The results for several loss-of-function PID simulations correspond to results of previously reported molecular studies. The simulations for TCR PTPRC, LCK, ZAP70 and ITK indicate profound changes to numerous proteins in the network. Significant effects were observed also in the BCL10, CARD11, MALT1, NEMO, IKKB and MAP3K14 simulations. No major effects were observed for PIDs that are caused by constitutively active proteins. The T-cell model facilitates the understanding of the underlying dynamics of PID disease processes. The approach confirms previous knowledge about T-cell signaling network and indicates several new important proteins that may be of interest when developing novel diagnosis and therapies to treat immunological defects.

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Section: Discussionsupporting

confidence: 87%

Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells

Teku

Vihinen

2017

PLoS ONE

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“…Moreover, the ability of transfected NEMO mutants to support TNFα-induced phosphorylation of IκBα was consistent with their reported activities from previous papers. That is, mutants 9-SG, L153R, R173G, and R175P showed limited activity in 1.1 cells and in previous reports [22, 36, 37, 38], whereas mutants D113N, R123W, and Q183H were nearly as active as wild-type NEMO in both 1.1 cells and previous reports [39].…”

Section: Discussionsupporting

confidence: 66%

CRISPR/Cas9-based editing of a sensitive transcriptional regulatory element to achieve cell type-specific knockdown of the NEMO scaffold protein

et al. 2019

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The use of alternative promoters for the cell type-specific expression of a given mRNA/protein is a common cell strategy. NEMO is a scaffold protein required for canonical NF-κB signaling. Transcription of the NEMO gene is primarily controlled by two promoters: one (promoter B) drives NEMO transcription in most cell types and the second (promoter D) is largely responsible for NEMO transcription in liver cells. Herein, we have used a CRISPR/Cas9-based approach to disrupt a core sequence element of promoter B, and this genetic editing essentially eliminates expression of NEMO mRNA and protein in 293T human kidney cells. By cell subcloning, we have isolated targeted 293T cell lines that express no detectable NEMO protein, have defined genomic alterations at promoter B, and do not support activation of canonical NF-κB signaling in response to treatment with tumor necrosis factor. Nevertheless, non-canonical NF-κB signaling is intact in these NEMO-deficient cells. Expression of ectopic wild-type NEMO, but not certain human NEMO disease mutants, in the edited cells restores downstream NF-κB signaling in response to tumor necrosis factor. Targeting of the promoter B element does not substantially reduce NEMO expression (from promoter D) in the human SNU-423 liver cancer cell line. Thus, we have created a strategy for selectively eliminating cell type-specific expression from an alternative promoter and have generated 293T cell lines with a functional knockout of NEMO. The implications of these findings for further studies and for therapeutic approaches to target canonical NF-κB signaling are discussed.

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“…Between 2002 and 2016, 13 patients with XL-EDA-ID were reported to have undergone HSCT (Dupuis-Girod et al 2002;Orange et al 2004;Tono et al 2007;Mancini et al 2008;Pai et al 2008;Salt et al 2008;Fish et al 2009;Minakawa et al 2009;Permaul et al 2009;Imamura et al 2011;Kawai et al 2012;Abbott et al 2014;Carlberg et al 2014;Klemann et al 2016). A summary of patient characteristics prior to HSCT can be found in Table 1.…”

Section: X-linked Ectodermal Dysplasia With Immunodeficiencymentioning

confidence: 99%

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Scott

Grunebaum

2017

LymphoSign Journal

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The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations. Statement of novelty:This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.

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Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency

Cited by 30 publications

References 39 publications

Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells

Simulation of the dynamics of primary immunodeficiencies in CD4+ T-cells

CRISPR/Cas9-based editing of a sensitive transcriptional regulatory element to achieve cell type-specific knockdown of the NEMO scaffold protein

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

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