Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 3, Pages 970-975Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1813582116
Keywords
primary immunodeficiency; inflammatory bowel diseases; rare diseases
Categories
Funding
- Leona M. and Harry B. Helmsley Charitable Trust
- DFG [SFB1054]
- PID-NET (BMBF)
- BioSysNet
- Care-for-Rare Foundation
- INSERM
- China Scholarship Council
- Landesgraduiertenforderungsgesetz
- Daimler und Benz Stiftung
- Reinhard-Frank Stiftung
- Else-Kroner-Fresenius Stiftung
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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-kappa B 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.
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