{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:18:15Z","timestamp":1791274695646,"version":"4.1.0"},"reference-count":31,"publisher":"Rockefeller University Press","issue":"7","license":[{"start":{"date-parts":[[2019,9,20]],"date-time":"2019-09-20T00:00:00Z","timestamp":1568937600000},"content-version":"vor","delay-in-days":833,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"vor","delay-in-days":206,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"name":"Perkins Fund"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1K08AI116979-01"],"award-info":[{"award-number":["1K08AI116979-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001245","name":"Jeffrey Modell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,7,3]]},"abstract":"<jats:p>The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-\u03b1 (TNF). TNF activates opposing pathways leading to caspase-8\u2013mediated apoptosis as well as nuclear factor \u03baB (NF-\u03baB)\u2013dependent 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-\u03baB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients\u2019 fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-\u03baB activation, and defective expression of NF-\u03baB\u2013dependent antiapoptotic genes. Rela+\/\u2212 mice have similarly impaired NF-\u03baB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate\u2013induced 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.<\/jats:p>","DOI":"10.1084\/jem.20160724","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T14:10:09Z","timestamp":1497017409000},"page":"1937-1947","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":127,"title":["Human <i>RELA<\/i> haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration"],"prefix":"10.1084","volume":"214","author":[{"given":"Yousef R.","family":"Badran","sequence":"first","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7516-0848","authenticated-orcid":true,"given":"Fatma","family":"Dedeoglu","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7394-4457","authenticated-orcid":true,"given":"Juan Manuel","family":"Leyva Castillo","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Bainter","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro K.","family":"Ohsumi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athos","family":"Bousvaros","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Boston Children\u2019s Hospital, Boston, MA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4566-1307","authenticated-orcid":true,"given":"Jeffrey D.","family":"Goldsmith","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, MA 3"},{"name":"Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6019-3751","authenticated-orcid":true,"given":"Raif S.","family":"Geha","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4610-2657","authenticated-orcid":true,"given":"Janet","family":"Chou","sequence":"additional","affiliation":[{"name":"Division of Immunology, Boston Children\u2019s Hospital, Boston, MA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,6,9]]},"reference":[{"key":"2023072604080793300_bib1","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.4049\/jimmunol.167.3.1592","article-title":"Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-\u03baB in leukocyte recruitment","volume":"167","author":"Alcamo","year":"2001","journal-title":"J. Immunol."},{"key":"2023072604080793300_bib2","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/ibd.20753","article-title":"Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis","volume":"15","author":"Alex","year":"2009","journal-title":"Inflamm. Bowel Dis."},{"key":"2023072604080793300_bib3","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1111\/j.1365-2796.2008.01953.x","article-title":"NF-kappaB in inflammatory bowel disease","volume":"263","author":"Atreya","year":"2008","journal-title":"J. Intern. Med."},{"key":"2023072604080793300_bib4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/376167a0","article-title":"Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B","volume":"376","author":"Beg","year":"1995","journal-title":"Nature."},{"key":"2023072604080793300_bib5","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1038\/ni.2457","article-title":"Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency","volume":"13","author":"Boisson","year":"2012","journal-title":"Nat. Immunol."},{"key":"2023072604080793300_bib6","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1084\/jem.20141130","article-title":"Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia","volume":"212","author":"Boisson","year":"2015","journal-title":"J. Exp. Med."},{"key":"2023072604080793300_bib7","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s10875-016-0306-1","article-title":"NF-\u03baB1 haploinsufficiency causing Immunodeficiency and EBV-driven lymphoproliferation","volume":"36","author":"Boztug","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"2023072604080793300_bib8","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/nri3834","article-title":"Regulation of tumour necrosis factor signalling: live or let die","volume":"15","author":"Brenner","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2023072604080793300_bib9","doi-asserted-by":"publisher","first-page":"26041","DOI":"10.1074\/jbc.M602222200","article-title":"NF-\u03baB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages","volume":"281","author":"Cao","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2023072604080793300_bib10","doi-asserted-by":"publisher","first-page":"261","DOI":"10.2174\/09298673113206660303","article-title":"An update on autoinflammatory diseases","volume":"21","author":"Ciccarelli","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"2023072604080793300_bib11","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.cell.2016.07.019","article-title":"The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity","volume":"166","author":"Damgaard","year":"2016","journal-title":"Cell."},{"key":"2023072604080793300_bib12","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1016\/S0002-9440(10)65087-0","article-title":"Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity","volume":"156","author":"Diaz-Granados","year":"2000","journal-title":"Am. J. Pathol."},{"key":"2023072604080793300_bib13","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.4049\/jimmunol.166.3.1443","article-title":"Cutting edge: typhlocolitis in NF-\u03baB-deficient mice","volume":"166","author":"Erdman","year":"2001","journal-title":"J. Immunol."},{"key":"2023072604080793300_bib14","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/j.ajhg.2015.07.008","article-title":"Haploinsufficiency of the NF-\u03baB1 subunit p50 in common variable immunodeficiency","volume":"97","author":"Fliegauf","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"2023072604080793300_bib15","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1101\/gad.183434.111","article-title":"NF-\u03baB, the first quarter-century: remarkable progress and outstanding questions","volume":"26","author":"Hayden","year":"2012","journal-title":"Genes Dev."},{"key":"2023072604080793300_bib16","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature."},{"key":"2023072604080793300_bib17","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1016\/j.dld.2013.06.007","article-title":"Locally injected Infliximab ameliorates murine DSS colitis: differences in serum and intestinal levels of drug between healthy and colitic mice","volume":"45","author":"Lopetuso","year":"2013","journal-title":"Dig. Liver Dis."},{"key":"2023072604080793300_bib18","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/S0092-8674(00)80721-7","article-title":"Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes","volume":"97","author":"McDermott","year":"1999","journal-title":"Cell."},{"key":"2023072604080793300_bib19","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nature05698","article-title":"Epithelial NEMO links innate immunity to chronic intestinal inflammation","volume":"446","author":"Nenci","year":"2007","journal-title":"Nature."},{"key":"2023072604080793300_bib20","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1038\/nm0996-998","article-title":"Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-\u03baB abrogates established experimental colitis in mice","volume":"2","author":"Neurath","year":"1996","journal-title":"Nat. Med."},{"key":"2023072604080793300_bib21","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.pharmthera.2016.01.001","article-title":"Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases","volume":"159","author":"Olesen","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"2023072604080793300_bib22","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1056\/NEJMoa1309199","article-title":"Deficiency of innate and acquired immunity caused by an IKBKB mutation","volume":"369","author":"Pannicke","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"2023072604080793300_bib23","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1126\/science.1260791","article-title":"Autoimmunity by haploinsufficiency","volume":"345","author":"Rieux-Laucat","year":"2014","journal-title":"Science."},{"key":"2023072604080793300_bib24","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/S1074-7613(01)00207-2","article-title":"TRAF1 is a negative regulator of TNF signaling. enhanced TNF signaling in TRAF1-deficient mice","volume":"15","author":"Tsitsikov","year":"2001","journal-title":"Immunity."},{"key":"2023072604080793300_bib25","doi-asserted-by":"publisher","first-page":"939847","DOI":"10.1155\/2013\/939847","article-title":"Biological treatments: new weapons in the management of monogenic autoinflammatory disorders","volume":"2013","author":"Vitale","year":"2013","journal-title":"Mediators Inflamm."},{"key":"2023072604080793300_bib26","doi-asserted-by":"publisher","first-page":"3194","DOI":"10.4049\/jimmunol.171.6.3194","article-title":"IL-6 induces NF-\u03baB activation in the intestinal epithelia","volume":"171","author":"Wang","year":"2003","journal-title":"J. Immunol."},{"key":"2023072604080793300_bib27","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/nature05590","article-title":"Epithelial-cell-intrinsic IKK-\u03b2 expression regulates intestinal immune homeostasis","volume":"446","author":"Zaph","year":"2007","journal-title":"Nature."},{"key":"2023072604080793300_bib28","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2016.12.012","article-title":"30 Years of NF-\u03baB: a blossoming of relevance to human pathobiology","volume":"168","author":"Zhang","year":"2017","journal-title":"Cell."},{"key":"2023072604080793300_bib29","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.1038\/sj.onc.1206262","article-title":"Identification of NF-\u03baB\u2013regulated genes induced by TNF\u03b1 utilizing expression profiling and RNA interference","volume":"22","author":"Zhou","year":"2003","journal-title":"Oncogene."},{"key":"2023072604080793300_bib30","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/ng.3459","article-title":"Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease","volume":"48","author":"Zhou","year":"2016","journal-title":"Nat. Genet."},{"key":"2023072604080793300_bib31","doi-asserted-by":"publisher","first-page":"10127","DOI":"10.1073\/pnas.1612594113","article-title":"Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease","volume":"113","author":"Zhou","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/7\/1937\/1758714\/jem_20160724.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/7\/1937\/1758714\/jem_20160724.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T04:14:09Z","timestamp":1690344849000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/214\/7\/1937\/52188\/Human-RELA-haploinsufficiency-results-in-autosomal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,9]]},"references-count":31,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2017,7,3]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20160724","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,9]]}}}