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Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases.


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.

SUBMITTER: Li Y 

PROVIDER: S-EPMC6338855 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases.

Li Yue Y   Führer Marita M   Bahrami Ehsan E   Socha Piotr P   Klaudel-Dreszler Maja M   Bouzidi Amira A   Liu Yanshan Y   Lehle Anna S AS   Magg Thomas T   Hollizeck Sebastian S   Rohlfs Meino M   Conca Raffaele R   Field Michael M   Warner Neil N   Mordechai Slae S   Shteyer Eyal E   Turner Dan D   Boukari Rachida R   Belbouab Reda R   Walz Christoph C   Gaidt Moritz M MM   Hornung Veit V   Baumann Bernd B   Pannicke Ulrich U   Al Idrissi Eman E   Ali Alghamdi Hamza H   Sepulveda Fernando E FE   Gil Marine M   de Saint Basile Geneviève G   Hönig Manfred M   Koletzko Sibylle S   Muise Aleixo M AM   Snapper Scott B SB   Schwarz Klaus K   Klein Christoph C   Kotlarz Daniel D  

Proceedings of the National Academy of Sciences of the United States of America 20181227 3


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 <i>RIPK1</i> presenting with primary immunodeficiency and/or int  ...[more]

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