1. Intestinal Inflammation and Dysregulated Immunity in Patients With Inherited Caspase-8 Deficiency
- Author
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Scott B. Snapper, Veit Hornung, Hans Clevers, Moritz M. Gaidt, Nadine Yazbeck, Fabian Hauck, Rima Hanna-Wakim, Katja Lammens, Philip Bufler, Yue Li, Aleixo M. Muise, Maryam Ghalandary, Birgitta E. Michels, Anna S. Lehle, Henner F. Farin, Raffaele Conca, Thomas Magg, Batia Weiss, Yanshan Liu, Sibylle Koletzko, Atar Lev, Neil Warner, Olaf Groß, Daniel Kotlarz, Amos J. Simon, Christoph Walz, Christoph Klein, Sebastian Hollizeck, Benjamin Marquardt, Raz Somech, Dror S. Shouval, Meino Rohlfs, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
0301 basic medicine ,Heredity ,Inflammasomes ,Biopsy ,Ulcerative/genetics ,Apoptosis ,Lymphocytes/immunology ,Endoscopy, Gastrointestinal ,Mice ,0302 clinical medicine ,Lymphocytes ,Age of Onset ,Colitis, Ulcerative/genetics ,Autoimmune Lymphoproliferative Syndrome/genetics ,Mice, Knockout ,Caspase 8 ,Gastroenterology ,Inflammasome ,Colitis ,Acquired immune system ,Intestines ,Phenotype ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,Inflammation Mediators ,medicine.symptom ,medicine.drug ,Intestines/immunology ,Gastrointestinal ,Inflammasomes/immunology ,Caspase 8/genetics ,Knockout ,Necroptosis ,Inflammation ,03 medical and health sciences ,Germline mutation ,Immune system ,Immunity ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Inflammation Mediators/immunology ,Hepatology ,business.industry ,Autoimmune Lymphoproliferative Syndrome ,Epithelial Cells/immunology ,Epithelial Cells ,Endoscopy ,030104 developmental biology ,Mutation ,Cancer research ,Colitis, Ulcerative ,business - Abstract
Caspase-8 (CASP8) is a protease that initiates apoptosis and regulates inflammation and immune responses. We identified germline mutations in CASP8 in 3 unrelated patients with infant-onset inflammatory bowel disease: 2 patients were homozygous for the mutation 710A>G, p.Q237R, which resulted in reduced protein expression, and 1 patient carried the mutation 793C>T, p.R265W. We isolated peripheral blood mononuclear cells from our index patient and observed defects in T- and B-cell maturation, proliferation, and/or activation. Macrophages from 1 patient with CASP8 deficiency and monocytic BLaER1 cells with knockout of CASP8 or overexpression of CASP8 with the 710A>G mutation had altered inflammasome activity on stimulation with lipopolysaccharide. Patient-derived intestinal organoids and colon carcinoma cells with knockout of CASP8 had defects in cell death processes that involved loss of TRAIL signaling and increased necroptosis. These findings indicate that CASP8 controls inflammation, innate and adaptive immunity, and intestinal barrier integrity in humans.
- Published
- 2019