Inherited IL-18BP deficiency in human fulminant viral hepatitis
Inherited IL-18BP deficiency in human fulminant viral hepatitis
复制标题
DOI：
10.1084/jem.20190669
复制
发表时间：
2019-08-01
影响因子：
15.3
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
--
作者：
Belkaya, Serkan;Michailidis, Eleftherios;Casanova, Jean-Laurent
暴发性病毒性肝炎（FVH）是一种毁灭性的和无法解释的条件，打击其他健康的个人在原发性感染常见的嗜肝病毒。我们报告一个11岁时感染甲型肝炎病毒（HAV）死于FVH的儿童，他是编码IL-18结合蛋白（IL-18 BP）的IL-18 BP中40个核苷酸缺失的纯合子。这种突变是功能丧失，不像在公共数据库中纯合状态下发现的变体。我们表明，人IL-18和IL-18 BP都主要由肝脏中的肝细胞和巨噬细胞分泌。此外，在不存在IL-18 BP的情况下，IL-18过度激活NK细胞导致体外不受控制地杀死人肝细胞。因此，遗传性人IL-18 BP缺陷通过释放IL-18而成为暴发性HAV肝炎的基础。这些发现提供了FVH可以由选择性破坏肝脏特异性免疫的单基因先天性缺陷引起的原理证明。他们还表明，人IL-18对肝脏有毒，IL-18 BP是其解毒剂。
Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.