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.

PMID: 31213488 DOI: 10.1084/jem.20190669

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.

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