Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation

• Published in: Science (American Association for the Advancement of Science) Vol. 361; no. 6404; pp. 810 - 813
• Main Authors: Cuchet-Lourenço, Delphine, Eletto, Davide, Wu, Changxin, Plagnol, Vincent, Papapietro, Olivier, Curtis, James, Ceron-Gutierrez, Lourdes, Bacon, Chris M, Hackett, Scott, Alsaleem, Badr, Maes, Mailis, Gaspar, Miguel, Alisaac, Ali, Goss, Emma, AlIdrissi, Eman, Siegmund, Daniela, Wajant, Harald, Kumararatne, Dinakantha, AlZahrani, Mofareh S, Arkwright, Peter D, Abinun, Mario, Doffinger, Rainer, Nejentsev, Sergey
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 24.08.2018
• Subjects: Age; Alleles; Animal models; Apoptosis; Arthritis; Arthritis - genetics; Arthritis - immunology; Cell death; Cytokines; Cytokines - metabolism; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Hematopoietic stem cells; Humans; Immune system; Immunodeficiency; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Intestine; Kinases; Lymphopenia; Lymphopenia - genetics; Male; MAP kinase; Mice; Mitogen-Activated Protein Kinases - metabolism; Mutation; Necroptosis; Organs; Patients; Pedigree; Polyarthritis; Protein-serine/threonine kinase; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; Signal transduction; Signaling; Stem cell transplantation; Stem cells; Transplantation
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aar2641

RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.