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Inherited IL-18BP deficiency in human fulminant viral hepatitis

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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Contributor : Anita Dumenil <>
Submitted on : Tuesday, November 12, 2019 - 1:46:42 PM
Last modification on : Wednesday, November 25, 2020 - 2:52:09 PM

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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, Rockefeller University Press, 2019, 216 (8), pp.1777-1790. ⟨10.1084/jem.20190669⟩. ⟨hal-02359432⟩



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