Inherited IL-18BP deficiency in human fulminant viral hepatitis PMID: 31213488

ADC Targets in Oncology

2026-04-10

Inherited IL-18BP deficiency in human fulminant viral hepatitis

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

Serkan Belkaya ¹ , Eleftherios Michailidis ^# ² , Cecilia B Korol ^# ³ ⁴ , Mohammad Kabbani ² , Aurélie Cobat ³ ⁴ , Paul Bastard ¹ , Yoon Seung Lee ¹ , Nicholas Hernandez ¹ , Scott Drutman ¹ , Ype P de Jong ² ⁵ , Eric Vivier ⁶ ⁷ ⁸ , Julie Bruneau ⁴ ⁹ , Vivien Béziat ¹ ³ ⁴ , Bertrand Boisson ¹ ³ ⁴ , Lazaro Lorenzo-Diaz ³ ⁴ , Soraya Boucherit ³ ⁴ , Mylène Sebagh ¹⁰ , Emmanuel Jacquemin ¹¹ ¹² , Jean-François Emile ¹³ , Laurent Abel ¹ ³ ⁴ , Charles M Rice ² , Emmanuelle Jouanguy ^# ¹ ³ ⁴ , Jean-Laurent Casanova ^# ¹⁴ ³ ⁴ ¹⁵ ¹⁶

Affiliations

1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY.
2. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY.
3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
4. Paris Descartes University, Imagine Institute, Paris, France.
5. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY.
6. Aix Marseille Université, INSERM, Centre National de la Recherche Scientifique, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
7. Service d'Immunologie, Marseille Immunopole, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
8. Innate Pharma Research Laboratories, Innate Pharma, Marseille, France.
9. Department of Pathology, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris, France.
10. Department of Pathology, Hepato-biliary Center, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Villejuif, France.
11. Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases, Assistance Publique-Hôpitaux de Paris, Bicêtre University Hospital, University of Paris Sud-Saclay, Le Kremlin Bicêtre, France.
12. INSERM U1174, University of Paris Sud-Saclay, Hepatinov, Orsay, France.
13. Department of Pathology, Assistance Publique-Hôpitaux de Paris, Ambroise Paré Hospital, Boulogne-Billancourt, France.
14. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY [email protected].
15. Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France.
16. Howard Hughes Medical Institute, New York, NY.
# Contributed equally.

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.