X-Linked Ectodermal Dysplasia With Immunodeficiency Caused by NEMO Mutation

Mancini, Anthony J.; Lawley, Leslie P.; Uzel, Gülbû

doi:10.1001/archderm.144.3.342

Cited by 59 publications

(33 citation statements)

References 25 publications

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“…5 Specifically, it revealed an insertion at 1167 (1167insC) of the IKBKG gene predicted to result in a frameshift at P389 (his mother was a carrier of the mutation, although his two sisters were not). 21 Secondary to recurrent infections, persistent diarrhea, failure to thrive and the known immunodeficiency-associated mutation, he was referred for an HLA-identical HSCT at 6 months of age (Table 2). Following HSCT, he achieved neutrophil engraftment (first day of ANC 4500/ml Â 3 days) at day þ 17, but subsequently developed rash and worsening diarrhea.…”

Section: Resultsmentioning

confidence: 99%

Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency

Fish

Duerst

Gelfand

et al. 2008

Bone Marrow Transplant

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Section: Resultsmentioning

confidence: 99%

Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency

Fish

Duerst

Gelfand

et al. 2008

Bone Marrow Transplant

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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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“…This clinical phenotype can be traced to defects in NF-κB signaling through a number of different receptors families, including TLR, TNF, and antigen receptors. However, inflammatory disease phenotypes, including arthritis, colitis, and graft versus host disease (GVHD)-like dermatitis have also been observed in some patients with NEMO syndrome (15)(16)(17). Inflammatory disorders mediated predominantly by cells and molecules of the innate immune system, without evidence of autoantibodies or autoreactive T cells, have been broadly termed "autoinflammatory" (18).…”

mentioning

confidence: 99%

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

Zilberman‐Rudenko

Shawver

Wessel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations. Individuals harboring these mutations develop inflammatory skin and intestinal disease in addition to ectodermal dysplasia with anhidrosis and immunodeficiency. Both primary cells from these patients, as well as reconstituted cell lines with this deletion, exhibited increased IκB kinase (IKK) activity and production of proinflammatory cytokines. Unlike previously described loss-of-function mutations, ΔCT-NEMO mutants promoted increased NF-κB activation in response to TNF and Toll-like receptor stimulation. Investigation of the underlying mechanisms revealed impaired interactions with A20, a negative regulator of NF-κB activation, leading to prolonged accumulation of K63-ubiquitinated RIP within the TNFR1 signaling complex. Recruitment of A20 to the C-terminal domain of NEMO represents a novel mechanism limiting NF-κB activation by NEMO, and its absence results in autoinflammatory disease.ctivation of the NF-κB family of transcription factors is required for normal development, innate and adaptive immunity, and the inflammatory response (1, 2). NF-κB-induced transcription of proinflammatory cytokines and chemokines amplifies immune-response programs and stimulates recruitment of inflammatory cells. Transcriptional activity of the classic NF-κB p65/p50 complex is regulated by the inhibitor of NF-κB kinase (IKK), consisting of the α-and β-catalytic subunits and the NEMO (NF-κB essential modulator, IKKγ) regulatory subunit. IKK activity leads to phosphorylation and K48-linked polyubiquitination of IκBα, the inhibitor of NF-κB. Ubiquitinated IκBα is then rapidly degraded, allowing nuclear translocation of NF-κB subunits and gene transactivation. NEMO functions as a scaffold within the IKK complex that is required for canonical IKK enzymatic activity and NF-κB activation (3).Activation of TNF, IL-1R, and Toll-like receptor (TLR) family receptors leads to K63 and linear (also termed M1) ubiquitination of cytosolic adapter proteins, such as receptor interacting protein 1 (RIP1). This in turn promotes recruitment of the IKK complex to the receptor signaling complex (4-8). A well-known negative regulator of NF-κB activation is A20 (encoded by the gene TNFAIP3). In the TNF-R1 complex, A20 removes K63-linked ubiquitin modifications on RIP1 through its deubiquitinase activity and converts these to K48-linked polyubiquitin chains through its E3 ligase activity (9). Editing of polyubiquitin linkages at the receptor complex in this manner results in rapid degradation of RIP1 and other signaling proteins, such as TRAF6, TRAF2, cIAP1, and cIAP2 (9, 10), promoting the termination of receptor-induced NF-κB activation. In addition, A20 directly inhibits IKK activity independently of its deubiquitinase activity in...

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X-Linked Ectodermal Dysplasia With Immunodeficiency Caused by NEMO Mutation

Cited by 59 publications

References 25 publications

Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency

Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency

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

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease

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