Inherited IL-18BP deficiency in human fulminant viral hepatitis

J Exp Med. 2019 Aug 5;216(8):1777-1790. doi: 10.1084/jem.20190669. Epub 2019 Jun 18.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genetic Diseases, Inborn / complications*
  • Hep G2 Cells
  • Hepatitis A / genetics*
  • Hepatitis A / virology
  • Hepatitis A Virus, Human
  • Hepatocytes / metabolism
  • Homozygote
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Interleukin-18 / metabolism
  • Killer Cells, Natural / immunology
  • Liver / metabolism
  • Loss of Function Mutation
  • Lymphocyte Activation / genetics
  • Macrophages / metabolism
  • Male
  • Massive Hepatic Necrosis / genetics*
  • Massive Hepatic Necrosis / virology
  • Pedigree
  • Whole Exome Sequencing


  • IL18 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • interleukin-18 binding protein