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. [email protected].
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.