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Proc Natl Acad Sci U S A. 2019 Jan 15;116(3):970-975. doi: 10.1073/pnas.1813582116. Epub 2018 Dec 27.

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases.

Author information

1
Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, 80337 Munich, Germany.
2
The Institute for Transfusion Medicine, University of Ulm, 89081 Ulm, Germany.
3
Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, 04730 Warsaw, Poland.
4
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115.
5
SickKids Inflammatory Bowel Disease Center, Research Institute, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
6
Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
7
Pediatric Gastroenterology, Hadassah University Hospital, Jerusalem 91120, Israel.
8
The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem 91031, Israel.
9
VEO-IBD Consortium, University Hospital, LMU Munich, 80337 Munich, Germany.
10
Pediatric Department, University Hospital Center Mustapha Bacha, 16000 Algiers, Algeria.
11
Institute of Pathology, Faculty of Medicine, LMU Munich, 80336 Munich, Germany.
12
Gene Center, LMU Munich, 81337 Munich, Germany.
13
Department of Biochemistry, LMU Munich, 81377 Munich, Germany.
14
Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany.
15
Allergy and Immunology Section, King Fahad Medical City, Children Specialized Hospital, 11525 Riyadh, Saudi Arabia.
16
Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France.
17
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, 75015 Paris, France.
18
Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Necker Medical School, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
19
Department of Pediatrics, University Medical Center Ulm, 89081 Ulm, Germany.
20
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G1X8, Canada.
21
Department of Biochemistry, University of Toronto, Toronto, ON M5G1A8, Canada.
22
Department of Medicine, Harvard Medical School, Boston, MA 02115.
23
Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115.
24
Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, 89081 Ulm, Germany.
25
Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität (LMU) Munich, 80337 Munich, Germany; daniel.kotlarz@med.uni-muenchen.de.

Abstract

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 RIPK1 presenting with primary immunodeficiency and/or intestinal inflammation. Mutations in RIPK1 were associated with reduced NF-κB 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.

KEYWORDS:

inflammatory bowel diseases; primary immunodeficiency; rare diseases

PMID:
30591564
DOI:
10.1073/pnas.1813582116

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