Inherited IL-18BP deficiency in human fulminant viral hepatitis

Serkan Belkaya , Eleftherios Michailidis , Cecilia B. Korol , Mohammad Kabbani , Aurelie Cobat (1) , Paul Bastard , Yoon Seung Lee , Nicholas Hernandez , Scott Drutman , Ype P. De Jong , Eric Vivier (2) , Julie Bruneau (3) , Vivien Beziat (4) , Bertrand Boisson (5, 1) , Lazaro Lorenzo-Diaz , Soraya Boucherit (4) , Mylene Sebagh (6, 7) , Emmanuel Jacquemin (8) , Jean-Francois Emile (9) , Laurent Abel (10, 1) , Charles M. Rice (11) , Emmanuelle Jouanguy (12, 13, 4) , Jean-Laurent Casanova (10, 1, 14)

1 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
2 CIML - Centre d'Immunologie de Marseille - Luminy
3 Laboratoire d'anatomie et cythologie pathologique
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 St. Giles Laboratory of Human Genetics of Infectious Diseases
6 Département de Pathologie [Villejuif]
7 Physiopathogénèse et Traitement des Maladies du Foie
8 ICPH - Intéractions cellulaires et physiopathologie hépatique (Orsay, Essonne) UMRS 1174
9 BECCOH - Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
10 Inserm U980 - Génétique Humaine des Maladies Infectieuses
11 Laboratory of Virology and Infectious Disease [New York]
12 Hôpital Necker - Enfants Malades [AP-HP]
13 UPD5 - Université Paris Descartes - Paris 5
14 Service d'immuno-hématologie pédiatrique [CHU Necker]

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.

Domaines: Immunologie

Serkan Belkaya, Eleftherios Michailidis, Cecilia B. Korol, Mohammad Kabbani, Aurelie Cobat, et al.. Inherited IL-18BP deficiency in human fulminant viral hepatitis. Journal of Experimental Medicine, 2019, 216 (8), pp.1777-1790. ⟨10.1084/jem.20190669⟩. ⟨hal-02359432⟩