Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

Science. 2018 Aug 24;361(6404):810-813. doi: 10.1126/science.aar2641.

Delphine Cuchet-Lourenço ¹, Davide Eletto ¹, Changxin Wu ¹, Vincent Plagnol ², Olivier Papapietro ¹, James Curtis ¹, Lourdes Ceron-Gutierrez ³, Chris M Bacon ⁴ ⁵, Scott Hackett ⁶, Badr Alsaleem ⁷, Mailis Maes ¹, Miguel Gaspar ¹, Ali Alisaac ¹ ⁸, Emma Goss ¹, Eman AlIdrissi ⁹, Daniela Siegmund ¹⁰, Harald Wajant ¹⁰, Dinakantha Kumararatne ³, Mofareh S AlZahrani ⁹, Peter D Arkwright ¹¹, Mario Abinun ¹², Rainer Doffinger ³, Sergey Nejentsev ¹³

Affiliations

1 Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
2 University College London Genetics Institute, University College London, London, UK.
3 Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge, UK.
4 Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
5 Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
6 Paediatric Immunology Department, Birmingham Heartland Hospital, Birmingham, UK.
7 Children's Hospital, King Fahad Medical City, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia.
8 Faculty of Applied Medical Sciences, Albaha University, Albaha, Kingdom of Saudi Arabia.
9 Children's Hospital, University of King Saud for Health Sciences, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia.
10 Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
11 University of Manchester, Royal Manchester Children's Hospital, Manchester, UK.
12 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
13 Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. sn262@cam.ac.uk.

PMID: 30026316 DOI: 10.1126/science.aar2641

Abstract

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to Necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

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