{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:58:33Z","timestamp":1792468713461,"version":"4.5.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"3","license":[{"start":{"date-parts":[[2019,6,27]],"date-time":"2019-06-27T00:00:00Z","timestamp":1561593600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,1,15]]},"abstract":"<jats:p>\n                    Receptor-interacting serine\/threonine-protein kinase 1 (RIPK1) is a critical regulator of cell death and inflammation, but its relevance for human disease pathogenesis remains elusive. Studies of monogenic disorders might provide critical insights into disease mechanisms and therapeutic targeting of RIPK1 for common diseases. Here, we report on eight patients from six unrelated pedigrees with biallelic loss-of-function mutations in\n                    <jats:italic>RIPK1<\/jats:italic>\n                    presenting with primary immunodeficiency and\/or intestinal inflammation. Mutations in\n                    <jats:italic>RIPK1<\/jats:italic>\n                    were associated with reduced NF-\u03baB activity, defective differentiation of T and B cells, increased inflammasome activity, and impaired response to TNFR1-mediated cell death in intestinal epithelial cells. The characterization of RIPK1-deficient patients highlights the essential role of RIPK1 in controlling human immune and intestinal homeostasis, and might have critical implications for therapies targeting RIPK1.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1813582116","type":"journal-article","created":{"date-parts":[[2018,12,27]],"date-time":"2018-12-27T19:25:14Z","timestamp":1545938714000},"page":"970-975","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":191,"title":["Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases"],"prefix":"10.1073","volume":"116","author":[{"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marita","family":"F\u00fchrer","sequence":"additional","affiliation":[{"name":"The Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehsan","family":"Bahrami","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Socha","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children\u2019s Memorial Health Institute, 04730 Warsaw, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Klaudel-Dreszler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children\u2019s Memorial Health Institute, 04730 Warsaw, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"Bouzidi","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanshan","family":"Liu","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Lehle","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Magg","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Hollizeck","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meino","family":"Rohlfs","sequence":"additional","affiliation":[{"name":"Dr. von Hauner Children\u2019s Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universit\u00e4t (LMU) Munich, 80337 Munich, 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Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachida","family":"Boukari","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital Center Mustapha Bacha, 16000 Algiers, Algeria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reda","family":"Belbouab","sequence":"additional","affiliation":[{"name":"Pediatric Department, University Hospital Center Mustapha Bacha, 16000 Algiers, Algeria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Walz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine, LMU Munich, 80336 Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz M.","family":"Gaidt","sequence":"additional","affiliation":[{"name":"Gene Center, LMU Munich, 81337 Munich, Germany;"},{"name":"Department of Biochemistry, LMU Munich, 81377 Munich, 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EMBO Mol Med 10, 1\u20133 (2018).","journal-title":"EMBO Mol Med"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature14191","article-title":"Necroptosis and its role in inflammation","volume":"517","author":"Pasparakis M","year":"2015","unstructured":"M Pasparakis, P Vandenabeele, Necroptosis and its role in inflammation. Nature 517, 311\u2013320 (2015).","journal-title":"Nature"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/j.cell.2014.04.019","article-title":"RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis","volume":"157","author":"Rickard JA","year":"2014","unstructured":"JA Rickard, , RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175\u20131188 (2014).","journal-title":"Cell"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.cell.2014.04.018","article-title":"RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3","volume":"157","author":"Dillon CP","year":"2014","unstructured":"CP Dillon, , RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189\u20131202 (2014).","journal-title":"Cell"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"7753","DOI":"10.1073\/pnas.1401857111","article-title":"RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition","volume":"111","author":"Kaiser WJ","year":"2014","unstructured":"WJ Kaiser, , RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc Natl Acad Sci USA 111, 7753\u20137758 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/nature13608","article-title":"RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis","volume":"513","author":"Dannappel M","year":"2014","unstructured":"M Dannappel, , RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90\u201394 (2014).","journal-title":"Nature"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/nature20558","article-title":"RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation","volume":"540","author":"Lin J","year":"2016","unstructured":"J Lin, , RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124\u2013128 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"737","DOI":"10.4049\/jimmunol.1701229","article-title":"Dendritic cell RIPK1 maintains immune homeostasis by preventing inflammation and autoimmunity","volume":"200","author":"O\u2019Donnell JA","year":"2018","unstructured":"JA O\u2019Donnell, , Dendritic cell RIPK1 maintains immune homeostasis by preventing inflammation and autoimmunity. J Immunol 200, 737\u2013748 (2018).","journal-title":"J Immunol"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/nature13706","article-title":"RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis","volume":"513","author":"Takahashi N","year":"2014","unstructured":"N Takahashi, , RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. 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