Publication: Inherited IL-18BP deficiency in human fulminant viral hepatitis

Publié dans: Journal of Experimental Medicine, 2019, 216 (8), pp.1777-1790. ⟨10.1084/jem.20190669⟩

Auteurs: Serkan Belkaya, Eleftherios Michailidis, Cecilia B. Korol, Mohammad Kabbani, Aurelie Cobat, Paul Bastard, Yoon Seung Lee, Nicholas Hernandez, Scott Drutman, Ype P. De Jong, Eric Vivier, Julie Bruneau, Vivien Beziat, Bertrand Boisson, Lazaro Lorenzo-Diaz, Soraya Boucherit, Mylene Sebagh, Emmanuel Jacquemin, Jean-Francois Emile, Laurent Abel, Charles M. Rice, Emmanuelle Jouanguy, Jean-Laurent Casanova

Résumé

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.

Lien vers HAL – hal-04831559

Lien vers le DOI – 10.1084/jem.20190669