Journal Article

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

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

2019

Overview

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.

• Publisher: National Academy of Sciences
• Subject: B-Lymphocytes - immunology / B-Lymphocytes - pathology / Biological Sciences / Cell death / Cell Differentiation - genetics / Cell Differentiation - immunology / Enzymes / Epithelial cells / Epithelial Cells - immunology / Epithelial Cells - pathology / Female / HCT116 Cells / HEK293 Cells / Homeostasis / Humans / Immune system / Immunity, Mucosal - genetics / Immunodeficiency / Immunology / Immunology and Inflammation / Inflammasomes / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Inflammatory Bowel Diseases - immunology / Inflammatory Bowel Diseases - pathology / Intestinal Mucosa - immunology / Intestinal Mucosa - pathology / Intestine / Kinases / Life Sciences / Lymphocytes B / Male / Mutation / NF-kappa B - genetics / NF-kappa B - immunology / NF-κB protein / Pathogenesis / Patients / Primary immunodeficiencies / Protein kinase / Proteins / Receptor-Interacting Protein Serine-Threonine Kinases - deficiency / Receptor-Interacting Protein Serine-Threonine Kinases - immunology / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - immunology / Severe Combined Immunodeficiency - pathology / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Therapeutic targets / Threonine / Tumor necrosis factor receptors