美国西奈山伊坎医学院Dusan Bogunovic课题组发现，人类TBK1缺失导致TNF诱导型细胞死亡驱动的自体炎症。该研究于2021年8月6日在线发表于国际一流学术期刊《细胞》。
据研究人员介绍，TANK结合激酶1（TBK1）调节IFN-I、NF-κB和TNF诱导的RIPK1依赖性细胞死亡（RCD）。在小鼠中，TBK1的双等位缺失在胚胎期是致命的。
研究人员发现了四名年龄分别为32岁、26岁、7岁和8岁的人类，他们来自三个没有血缘关系的近亲家庭，都有TBK1功能丧失的纯合突变。所有四个病人都患有慢性和系统性的自体炎症，但没有严重的病毒感染。研究人员证明TBK1的缺失导致通过RIG-I/MDA5诱导的IFN-I过低但足够，而该系统通过NF-κB诱导的IL-6几乎保持完整。自身炎症是由TNF诱导的RCD驱动的，因为患者衍生的成纤维细胞在体外经历了更高的坏死率，并且CC3在外周血中升高。抗TNF治疗抑制了基线循环炎症状况，并改善了体内的临床状况。
这些发现突出了IFN-I反应的可塑性，并强调了TBK1在调节RCD中的主要作用。
附：英文原文
Title: Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death
Author: Justin Taft, Michael Markson, Diana Legarda, Roosheel Patel, Mark Chan, Louise Malle, Ashley Richardson, Conor Gruber, Marta Martín-Fernández, Grazia M.S. Mancini, Jan A.M. van Laar, Philomine van Pelt, Sofija Buta, Beatrijs H.A. Wokke, Ira K.D. Sabli, Vanessa Sancho-Shimizu, Pallavi Pimpale Chavan, Oskar Schnappauf, Raju Khubchandani, Müerref Kasap Cüceolu, Seza zen, Daniel L. Kastner, Adrian T. Ting, Ivona Aksentijevich, Iris H.I. M. Hollink, Dusan Bogunovic
Issue&Volume: 2021-08-06
Abstract: TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependentcell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discoveredfour humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families withhomozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severeviral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficientIFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 inductionthrough NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblastsexperienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile andameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinalrole for TBK1 in the regulation of RCD.
DOI: 10.1016/j.cell.2021.07.026
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00885-0