{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T06:08:50Z","timestamp":1791094130622,"version":"4.1.0"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T00:00:00Z","timestamp":1398297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"German Federal Ministry of Education and Research","award":["BMBF 01 EO 0803"],"award-info":[{"award-number":["BMBF 01 EO 0803"]}]},{"name":"German Federal Ministry of Education and Research","award":["BMBF 01GM1111B"],"award-info":[{"award-number":["BMBF 01GM1111B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,24]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1\/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.<\/jats:p>","DOI":"10.1111\/cei.12306","type":"journal-article","created":{"date-parts":[[2014,2,26]],"date-time":"2014-02-26T08:08:47Z","timestamp":1393402127000},"page":"394-400","source":"Crossref","is-referenced-by-count":86,"title":["A new functional assay for the diagnosis of X-linked inhibitor of apoptosis (XIAP) deficiency"],"prefix":"10.1093","volume":"176","author":[{"given":"S","family":"Ammann","sequence":"first","affiliation":[{"name":"Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany"},{"name":"Faculty of Biology, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Elling","sequence":"additional","affiliation":[{"name":"Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany"},{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Gyrd-Hansen","sequence":"additional","affiliation":[{"name":"Ludwig Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"D\u00fcckers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Helios-Klinikum Krefeld, Krefeld, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Bredius","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S O","family":"Burns","sequence":"additional","affiliation":[{"name":"Institute of Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J D M","family":"Edgar","sequence":"additional","affiliation":[{"name":"Regional Immunology Service, The Royal Hospitals, Belfast, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Worth","sequence":"additional","affiliation":[{"name":"Centre for Immunodeficiency, Molecular Immunology Unit, Institute of Child Health, London, UK"},{"name":"Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Brandau","sequence":"additional","affiliation":[{"name":"Pediatric Gastroenterolgy, University Hospital Schleswig-Holstein, Luebeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Warnatz","sequence":"additional","affiliation":[{"name":"Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U","family":"zur Stadt","sequence":"additional","affiliation":[{"name":"University Medical Center Hamburg Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Hasselblatt","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University Hospital Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Institute of Transfusion Medicine, University Ulm, Ulm, Germany"},{"name":"Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wuerttemberg-Hessen, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Ehl","sequence":"additional","affiliation":[{"name":"Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany"},{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Speckmann","sequence":"additional","affiliation":[{"name":"Center of Chronic Immunodeficiency, University Medical Center, Freiburg, Germany"},{"name":"Department of Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,4,24]]},"reference":[{"key":"2021122010041726100_cei12306-bib-0001","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/nature05257","article-title":"XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome","volume":"444","author":"Rigaud","year":"2006","journal-title":"Nature"},{"key":"2021122010041726100_cei12306-bib-0002","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1182\/blood-2010-01-256099","article-title":"XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease","volume":"116","author":"Marsh","year":"2010","journal-title":"Blood"},{"key":"2021122010041726100_cei12306-bib-0003","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.clim.2013.07.004","article-title":"X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis","volume":"149","author":"Speckmann","year":"2013","journal-title":"Clin Immunol"},{"key":"2021122010041726100_cei12306-bib-0004","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1182\/blood-2010-07-298372","article-title":"Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1\/SAP deficiency) versus type 2 (XLP-2\/XIAP deficiency)","volume":"117","author":"Pachlopnik Schmid","year":"2011","journal-title":"Blood"},{"key":"2021122010041726100_cei12306-bib-0005","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s10875-011-9638-z","article-title":"Clinical and genetic characteristics of XIAP deficiency in Japan","volume":"32","author":"Yang","year":"2012","journal-title":"J Clin Immunol"},{"key":"2021122010041726100_cei12306-bib-0006","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-306474","article-title":"XIAP deficiency is a mendelian cause of late-onset IBD","author":"Speckmann","year":"2013","journal-title":"Gut"},{"key":"2021122010041726100_cei12306-bib-0007","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nrc2889","article-title":"IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer","volume":"10","author":"Gyrd-Hansen","year":"2010","journal-title":"Nat Rev Cancer"},{"key":"2021122010041726100_cei12306-bib-0008","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1002\/emmm.201303090","article-title":"Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signalling","volume":"5","author":"Damgaard","year":"2013","journal-title":"EMBO Mol Med"},{"key":"2021122010041726100_cei12306-bib-0009","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.molcel.2012.04.014","article-title":"The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity","volume":"46","author":"Damgaard","year":"2012","journal-title":"Mol Cell"},{"key":"2021122010041726100_cei12306-bib-0010","doi-asserted-by":"crossref","first-page":"14524","DOI":"10.1073\/pnas.0907131106","article-title":"XIAP mediates NOD signaling via interaction with RIP2","volume":"106","author":"Krieg","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122010041726100_cei12306-bib-0011","doi-asserted-by":"crossref","first-page":"e1000142","DOI":"10.1371\/journal.ppat.1000142","article-title":"XIAP regulates cytosol-specific innate immunity to Listeria infection","volume":"4","author":"Bauler","year":"2008","journal-title":"PLOS Pathog"},{"key":"2021122010041726100_cei12306-bib-0012","doi-asserted-by":"crossref","first-page":"21426","DOI":"10.1073\/pnas.1209673109","article-title":"RNAi screening identifies mediators of NOD2 signaling: implications for spatial specificity of MDP recognition","volume":"109","author":"Lipinski","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021122010041726100_cei12306-bib-0013","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1074\/jbc.C200651200","article-title":"Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection","volume":"278","author":"Girardin","year":"2003","journal-title":"J Biol Chem"},{"key":"2021122010041726100_cei12306-bib-0014","doi-asserted-by":"crossref","first-page":"5509","DOI":"10.1074\/jbc.C200673200","article-title":"Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease","volume":"278","author":"Inohara","year":"2003","journal-title":"J Biol Chem"},{"key":"2021122010041726100_cei12306-bib-0015","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1146\/annurev-genom-082908-150013","article-title":"The genetics of Crohn's disease","volume":"10","author":"Van Limbergen","year":"2009","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"2021122010041726100_cei12306-bib-0016","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1016\/S0140-6736(05)66582-8","article-title":"Muramyl dipeptide and Toll-like receptor sensitivity in NOD2-associated Crohn's disease","volume":"365","author":"van Heel","year":"2005","journal-title":"Lancet"},{"key":"2021122010041726100_cei12306-bib-0017","doi-asserted-by":"crossref","first-page":"4812","DOI":"10.1074\/jbc.M008072200","article-title":"Nod2, a Nod1\/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB","volume":"276","author":"Ogura","year":"2001","journal-title":"J Biol Chem"},{"key":"2021122010041726100_cei12306-bib-0018","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.it.2012.06.004","article-title":"Modulation of immune signalling by inhibitors of apoptosis","volume":"33","author":"Beug","year":"2012","journal-title":"Trends Immunol"},{"key":"2021122010041726100_cei12306-bib-0019","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1097\/GIM.0b013e3182088158","article-title":"Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease","volume":"13","author":"Worthey","year":"2011","journal-title":"Genet Med"},{"key":"2021122010041726100_cei12306-bib-0020","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1182\/blood-2011-08-374199","article-title":"A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes","volume":"119","author":"Bryceson","year":"2012","journal-title":"Blood"},{"key":"2021122010041726100_cei12306-bib-0021","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-62703-290-2_15","article-title":"Flow cytometric measurement of SLAM-associated protein and X-linked inhibitor of apoptosis","volume":"979","author":"Marsh","year":"2013","journal-title":"Methods Mol Biol"},{"key":"2021122010041726100_cei12306-bib-0022","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.clim.2009.03.517","article-title":"Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations","volume":"132","author":"Marsh","year":"2009","journal-title":"Clin Immunol"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.12306","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.12306","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/176\/3\/394\/41789662\/cei12306.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/176\/3\/394\/41789662\/cei12306.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:26:07Z","timestamp":1641054367000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/176\/3\/394\/6421247"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,24]]},"references-count":22,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,4,24]]},"published-print":{"date-parts":[[2014,4,24]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.12306","relation":{},"ISSN":["1365-2249","0009-9104"],"issn-type":[{"value":"1365-2249","type":"electronic"},{"value":"0009-9104","type":"print"}],"subject":[],"published-other":{"date-parts":[[2014,6]]},"published":{"date-parts":[[2014,4,24]]}}}