Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

Yue Li, Marita Führer, Ehsan Bahrami, Piotr Socha, Maja Klaudel-Dreszler, Amira Bouzidi, Yanshan Liu, Anna S. Lehle, Thomas Magg, Sebastian Hollizeck, Meino Rohlfs, Raffaele Conca, Michael Field, Neil Warner, Slae Mordechai, Eyal Shteyer, Dan Turner, Rachida Boukari, Reda Belbouab, Christoph WalzMoritz M. Gaidt, Veit Hornung, Bernd Baumann, Ulrich Pannicke, Eman Al Idrissi, Hamza Ali Alghamdi, Fernando E. Sepulveda, Marine Gil, Geneviève De Saint Basile, Manfred Hönig, Sibylle Koletzko, Aleixo M. Muise, Scott B. Snapper, Klaus Schwarz, Christoph Klein, Daniel Kotlarz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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.

Original languageAmerican English
Pages (from-to)970-975
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number3
DOIs
StatePublished - 15 Jan 2019

Bibliographical note

Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.

Keywords

  • Inflammatory bowel diseases |
  • Primary immunodeficiency |
  • Rare diseases

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