Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
University College London Genetics Institute, University College London, London, UK.
Science. 2018 Aug 24;361(6404):810-813. doi: 10.1126/science.aar2641. Epub 2018 Jul 19.
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.
RIPK1（受体相互作用丝氨酸/苏氨酸激酶 1）是导致炎症和细胞死亡的信号通路的主要调节因子，作为药物靶点具有医学意义。我们报告了三个不相关的家庭中的四名完全 RIPK1 缺乏症患者，这些患者由罕见的纯合突变引起。这些患者遭受复发性感染、早发性炎症性肠病和进行性多关节炎。他们的免疫缺陷伴有淋巴细胞减少和全血检测显示各种细胞因子的产生改变。体外，RIPK1 缺陷细胞显示有丝分裂原激活的蛋白激酶激活和细胞因子分泌受损，并且容易发生坏死性凋亡。造血干细胞移植在一名患者中逆转了细胞因子产生缺陷并解决了临床症状。因此，RIPK1 在人类免疫系统中发挥关键作用。
