학술논문
Inherited IL-18BP deficiency in human fulminant viral hepatitis
Document Type
Article
Author
Belkaya, Serkan; Michailidis, Eleftherios; Korol, Cecilia B.; Kabbani, Mohammad; Cobat, Aurélie; Bastard, Paul; Lee, Yoon Seung; Hernandez, Nicholas; Drutman, Scott; de Jong, Ype P.; Vivier, Eric; Bruneau, Julie; Béziat, Vivien; Boisson, Bertrand; Lorenzo-Diaz, Lazaro; Boucherit, Soraya; Sebagh, Mylène; Jacquemin, Emmanuel; Emile, Jean-François; Abel, Laurent; Rice, Charles M.; Jouanguy, Emmanuelle; Casanova, Jean-Laurent
Source
The Journal of Experimental Medicine; August 2019, Vol. 216 Issue: 8 p1777-1790, 14p
Subject
Language
ISSN
00221007; 15409538
Abstract
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.