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      Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration

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          Abstract

          Badran et al. demonstrate an essential contribution of biallelic RELA expression in protecting stromal and epithelial cells from TNF-mediated cell death in patients with chronic mucocutaneous ulceration.

          Abstract

          The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8–mediated apoptosis as well as nuclear factor κB (NF-κB)–dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients’ fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB–dependent antiapoptotic genes. Rela +/− mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate–induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease.

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          NF-kappaB in inflammatory bowel disease.

          Apart from genetic and environmental factors, the mucosal immune system of the gut plays a central role in the pathogenesis of inflammatory bowel disease (IBD). In the healthy gut, the mucosal immune system ensures the balance between pro- and anti-inflammatory mediators and thereby allows an effective defence against luminal pathogens but at the same time prevents an overwhelming immune reaction directed against the huge amount of harmless luminal antigens (for example, components of food or nonpathological bacteria). In both entities of IBD (Crohn's disease and ulcerative colitis) this immunological balance is severely impaired and shifted towards the pro-inflammatory side. The chronic mucosal inflammation in IBD is caused by hyperactivation of effector immune cells, which produce high levels of pro-inflammatory cytokines like tumour necrosis factor-alpha, interleukin-6 and interferon-gamma, resulting in colonic tissue damage. The nuclear transcription factor kappaB (NF-kappaB) was identified as one of the key regulators in this immunological setting. Its activation is markedly induced in IBD patients and through its ability to promote the expression of various pro-inflammatory genes, NF-kappaB strongly influences the course of mucosal inflammation. Considering the different cell-type specific effects which are mediated by NF-kappaB, this review aims at describing the complex role of NF-kappaB in IBD and discusses existing pharmacological attempts to block the activation of NF-kappaB to develop new therapeutic strategies in IBD.
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            Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B.

            NF-kappa B, which consists of two polypeptides, p50 (M(r) 50K) and p65/RelA (M(r) 65K), is thought to be a key regulator of genes involved in responses to infection, inflammation and stress. Indeed, although developmentally normal, mice deficient in p50 display functional defects in immune responses. Here we describe the generation of mice deficient in the RelA subunit of NF-kappa B. Disruption of the relA locus leads to embryonic lethality at 15-16 days of gestation, concomitant with a massive degeneration of the liver by programmed cell death or apoptosis. Embryonic fibroblasts from RelA-deficient mice are defective in the tumour necrosis factor (TNF)-mediated induction of messenger RNAs for I kappa B alpha and granulocyte/macrophage colony stimulating factor (GM-CSF), although basal levels of these transcripts are unaltered. These results indicate that RelA controls inducible, but not basal, transcription in NF-kappa B-regulated pathways.
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              Immunodeficiency, auto-inflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency

              We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic auto-inflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1, a component the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin-1β (IL-1β) was compromised in the patients’ fibroblasts. By contrast, the patients’ mononuclear leukocytes, particularly monocytes, were hyperresponsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of auto-inflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types.
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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                03 July 2017
                : 214
                : 7
                : 1937-1947
                Affiliations
                [1 ]Division of Immunology, Boston Children’s Hospital, Boston, MA
                [2 ]Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA
                [3 ]Department of Pathology, Boston Children’s Hospital, Boston, MA
                [4 ]Department of Molecular Biology, Massachusetts General Hospital, Boston, MA
                [5 ]Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA
                Author notes
                Correspondence to Janet Chou: janet.chou@ 123456childrens.harvard.edu
                [*]

                Y.R. Badran and F. Dedeoglu contributed equally to this paper.

                Author information
                http://orcid.org/0000-0002-7516-0848
                http://orcid.org/0000-0001-7394-4457
                http://orcid.org/0000-0003-4566-1307
                http://orcid.org/0000-0002-6019-3751
                http://orcid.org/0000-0002-4610-2657
                Article
                20160724
                10.1084/jem.20160724
                5502421
                28600438
                3e171808-2b2e-402e-9c08-59f0cd37dde4
                © 2017 Badran et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 18 May 2016
                : 25 February 2017
                : 09 May 2017
                Funding
                Funded by: Perkins Fund
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: 1K08AI116979-01
                Funded by: Jeffrey Modell Foundation, DOI http://dx.doi.org/10.13039/100001245;
                Categories
                Research Articles
                Brief Definitive Report
                310
                319
                316

                Medicine
                Medicine

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