{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T02:09:03Z","timestamp":1777860543044,"version":"3.51.4"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"European Union Horizon 2020 research and innovation program","award":["667837"],"award-info":[{"award-number":["667837"]}]},{"name":"Heart Foundation Netherlands","award":["IN-CONTROL"],"award-info":[{"award-number":["IN-CONTROL"]}]},{"name":"Netherlands Organization for Scientific Research","award":["Spinoza"],"award-info":[{"award-number":["Spinoza"]}]},{"name":"NWO VIDI","award":["ZonMW"],"award-info":[{"award-number":["ZonMW"]}]},{"name":"ERC Consolidator Grant","award":["310372"],"award-info":[{"award-number":["310372"]}]},{"DOI":"10.13039\/100017732","name":"ERA-Net for Research Programmes on Rare Diseases","doi-asserted-by":"publisher","award":["EURO-CMC"],"award-info":[{"award-number":["EURO-CMC"]}],"id":[{"id":"10.13039\/100017732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,23]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Beh\u00e7et's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease\u00a0with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A&amp;gt;C, p.N44H) encoding for granulocyte\u2013macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-\u03b1 treatment, which may be linked to the capacity of TNF-\u03b1 to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease\u00a0and offer new opportunities for personalized treatment.<\/jats:p>","DOI":"10.1111\/cei.13568","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T20:32:33Z","timestamp":1608669153000},"page":"189-198","source":"Crossref","is-referenced-by-count":8,"title":["Mimicking Beh\u00e7et's disease: GM-CSF gain of function mutation in a family suffering from a Beh\u00e7et's disease-like disorder marked by extreme pathergy"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4810-2666","authenticated-orcid":false,"given":"B","family":"R\u00f6sler","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B","family":"Heinhuis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Silvestre","sequence":"additional","affiliation":[{"name":"Microbiology and Infection Research Domain, Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho , Braga, Portugal"},{"name":"ICVS\/3B's, PT Government Associate Laboratory , Guimar\u00e3es, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L A B","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M G","family":"Netea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"},{"name":"Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn , Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P","family":"Arts","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3284-4403","authenticated-orcid":false,"given":"T","family":"Mantere","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D J","family":"Lefeber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Translational Metabolic Laboratory, Radboud University Medical Centre , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Hoischen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"},{"name":"Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-4894","authenticated-orcid":false,"given":"F L","family":"Veerdonk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center , Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"2023081113532247800_cei13568-bib-0001","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10157-013-0869-6","article-title":"Overview of the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides","volume":"17","author":"Jennette","year":"2013","journal-title":"Clin Exp 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