Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 8, Pages 1777-1790Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20190669
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Funding
- Investments for the future program (Agence Nationale de la Recherche) [ANR-10-IAHU-01]
- Institut National de la Sante et de la Recherche Medicale, Universite Paris Descartes
- St. Giles Foundation
- Rockefeller University
- Howard Hughes Medical Institute
- French National Agency for Research on AIDS [18265]
- International PhD program of Imagine Institute, Paris, France
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01-AI091707]
- Clinical and Translational Research Fellowship from the American Association for the Study of Liver Diseases Foundation
- Jeffrey Modell Foundation
- Rockefeller University Center for Basic and Translational Research on Disorders of the Digestive System
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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.
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