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

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.

• Authors: Delphine Cuchet-Lourenço, Davide Eletto, Changxin Wu, Vincent Plagnol, Olivier Papapietro, James Curtis, Lourdes Ceron-Gutierrez, Chris M Bacon, Scott Hackett, Badr Alsaleem, Mailis Maes, Miguel Gaspar, Ali Alisaac, Emma Goss, Eman AlIdrissi, Daniela Siegmund, Harald Wajant, Dinakantha Kumararatne, Mofareh S AlZahrani, Peter D Arkwright, Mario Abinun, Rainer Doffinger, Sergey Nejentsev
• Journal: Science (New York, N.Y.) (Science) Vol. 361 Issue 6404 Pg. 810-813 (08 24 2018) ISSN: 1095-9203 [Electronic] United States
• PMID: 30026316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Cytokines
• RIPK1 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases

Topics

• Alleles
• Arthritis (genetics, immunology)
• Cytokines (metabolism)
• Female
• Fibroblasts (metabolism, pathology)
• Humans
• Inflammatory Bowel Diseases (genetics, immunology)
• Lymphopenia (genetics)
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• Pedigree
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics)
• Severe Combined Immunodeficiency (genetics, immunology)