TY - JOUR
T1 - Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation
AU - Cuchet-Lourenço, Delphine
AU - Eletto, Davide
AU - Wu, Changxin
AU - Plagnol, Vincent
AU - Papapietro, Olivier
AU - Curtis, James
AU - Ceron-Gutierrez, Lourdes
AU - Bacon, Chris M
AU - Hackett, Scott
AU - Alsaleem, Badr
AU - Maes, Mailis
AU - Gaspar, Miguel
AU - Alisaac, Ali
AU - Goss, Emma
AU - AlIdrissi, Eman
AU - Siegmund, Daniela
AU - Wajant, Harald
AU - Kumararatne, Dinakantha
AU - AlZahrani, Mofareh S
AU - Arkwright, Peter D
AU - Abinun, Mario
AU - Doffinger, Rainer
AU - Nejentsev, Sergey
PY - 2018/8/24
Y1 - 2018/8/24
N2 - 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.
AB - 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.
KW - Alleles
KW - Arthritis/genetics
KW - Cytokines/metabolism
KW - Female
KW - Fibroblasts/metabolism
KW - Humans
KW - Inflammatory Bowel Diseases/genetics
KW - Lymphopenia/genetics
KW - Male
KW - Mitogen-Activated Protein Kinases/metabolism
KW - Pedigree
KW - Receptor-Interacting Protein Serine-Threonine Kinases/genetics
KW - Severe Combined Immunodeficiency/genetics
U2 - https://doi.org/10.1126/science.aar2641
DO - https://doi.org/10.1126/science.aar2641
M3 - Article
C2 - 30026316
SN - 0036-8075
VL - 361
SP - 810
EP - 813
JO - Science
JF - Science
IS - 6404
ER -