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 language | American English |
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Pages (from-to) | 970-975 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 116 |
Issue number | 3 |
DOIs | |
State | Published - 15 Jan 2019 |
Bibliographical note
Funding Information:ACKNOWLEDGMENTS. We are grateful to the interdisciplinary medical staff. We acknowledge the assistance of the Flow Cytometry and Care-for-Rare Genomics Core Facility at the Dr. von Hauner Children’s Hospital, as well as the FACS facility of the Department of Pediatrics and Department of Molecular Diagnostics of the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm and the Genomics and Bioinformatics Core Facility at the Imagine Institute and UFR Necker. We thank Dr. T. Graf (Center for Genomic Regulation, Barcelona) for providing BLaER1 cells, and Genentech for supplying BV6. Further, we acknowledge bioinformatics support by Dr. Jacek Puchalka. The work has been supported by The Leona M. and Harry B. Helmsley Charitable Trust, DFG (Gottfried-Wilhelm-Leibniz Program, Collaborative Research Consortium SFB1054 project A05), PID-NET (BMBF), BioSysNet, the Care-for-Rare Foundation, and INSERM. Y. Li has been supported by the China Scholarship Council, E.B. received a scholarship from the Care-for-Rare Foundation, and M. Führer received a scholarship from the “Landesgraduiertenförderungsgesetz.” D.K. has been a scholar funded by the Daimler und Benz Stiftung, Reinhard-Frank Stiftung, and Else-Kröner-Fresenius Stiftung.
Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
Keywords
- Inflammatory bowel diseases |
- Primary immunodeficiency |
- Rare diseases