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Five ORAS patients have been reported, but how dysregulated M1\u2010linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN\u2010Gly281Arg mutation leads to reduced activity and stability\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    and in cells. In contrast to OTULIN\u2010deficient monocytes, in which TNF signalling and NF\u2010\u03baB activation are increased, loss of OTULIN in patient\u2010derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF. Interestingly, both patient\u2010derived fibroblasts and OTULIN\u2010deficient monocytes are sensitised to certain types of TNF\u2010induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS. Together, our data suggest that ORAS pathogenesis involves hyper\u2010inflammatory immune cells and TNF\u2010induced death of both leukocytes and non\u2010haematopoietic cells.\n                  <\/jats:p>","DOI":"10.15252\/emmm.201809324","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T13:55:12Z","timestamp":1551102912000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":124,"title":["OTULIN deficiency in ORAS causes cell type\u2010specific LUBAC degradation, dysregulated TNF signalling and cell death"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1709-6534","authenticated-orcid":false,"given":"Rune Busk","family":"Damgaard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R","family":"Elliott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirby N","family":"Swatek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn R","family":"Maher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Stepensky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Elpeleg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8092-4320","authenticated-orcid":false,"given":"David","family":"Komander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9823-4750","authenticated-orcid":false,"given":"Yackov","family":"Berkun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,2,25]]},"reference":[{"key":"BFEMMM201809324_CR1","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","volume":"7","author":"P Bankhead","year":"2017","unstructured":"Bankhead P, Loughrey MB, Fern\u00e1ndez JA, Dombrowski Y, McArt DG, Dunne PD, McQuaid S, Gray RT, Murray LJ, Coleman HG et\u00a0al (2017) QuPath: open source software for digital pathology image analysis. 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