Title | Inherited IL-18BP deficiency in human fulminant viral hepatitis. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Belkaya S, Michailidis E, Korol CB, Kabbani M, Cobat A, Bastard P, Lee YSeung, Hernandez N, Drutman S, de Jong YP, Vivier E, Bruneau J, Béziat V, Boisson B, Lorenzo-Diaz L, Boucherit S, Sebagh M, Jacquemin E, Emile J-F, Abel L, Rice CM, Jouanguy E, Casanova J-L |
Journal | J Exp Med |
Volume | 216 |
Issue | 8 |
Pagination | 1777-1790 |
Date Published | 2019 Aug 05 |
ISSN | 1540-9538 |
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 , 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. |
DOI | 10.1084/jem.20190669 |
Alternate Journal | J. Exp. Med. |
PubMed ID | 31213488 |
PubMed Central ID | PMC6683989 |
Grant List | T32 GM066699 / GM / NIGMS NIH HHS / United States |
Submitted by bel2021 on December 2, 2019 - 10:15am