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Li, Yue; Fuehrer, Marita; Bahrami, Ehsan; Socha, Piotr; Klaudel-Dreszler, Maja; Bouzidi, Amira; Liu, Yanshan; Lehle, Anna S.; Magg, Thomas; Hollizeck, Sebastian; Rohlfs, Meino; Conca, Raffaele; Field, Michael; Warner, Neil; Mordechai, Slae; Shteyer, Eyal; Turner, Dan; Boukari, Rachida; Belbouab, Reda; Walz, Christoph; Gaidt, Moritz M.; Hornung, Veit; Baumann, Bernd; Pannicke, Ulrich; Al Idrissi, Eman; Alghamdi, Hamza Ali; Sepulveda, Fernando E.; Gil, Marine; Basile, Genevieve de Saint; Honig, Manfred; Koletzko, Sibylle; Muise, Aleixo M.; Snapper, Scott B.; Schwarz, Klaus; Klein, Christoph; Kotlarz, Daniel (2019): Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 3: pp. 970-975
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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-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.