Inherited IL-18BP deficiency in human fulminant viral hepatitis

被引：89

作者：

Belkaya, Serkan ^{[1
]}

Michailidis, Eleftherios ^{[2
]}

Korol, Cecilia B. ^{[3
,4
]}

Kabbani, Mohammad ^{[2
]}

Cobat, Aurelie ^{[3
,4
]}

Bastard, Paul ^{[1
]}

Lee, Yoon Seung ^{[1
]}

Hernandez, Nicholas ^{[1
]}

Drutman, Scott ^{[1
]}

de Jong, Ype P. ^{[2
,5
]}

Vivier, Eric ^{[6
,7
,8
]}

Bruneau, Julie ^{[4
,9
]}

Beziat, Vivien ^{[1
,3
,4
]}

Boisson, Bertrand ^{[1
,3
,4
]}

Lorenzo-Diaz, Lazaro ^{[3
,4
]}

Boucherit, Soraya ^{[3
,4
]}

Sebagh, Mylene ^{[10
]}

Jacquemin, Emmanuel ^{[11
,12
]}

Emile, Jean-Francois ^{[13
]}

Abel, Laurent ^{[1
,3
,4
]}

Rice, Charles M. ^{[2
]}

Jouanguy, Emmanuelle ^{[1
,3
,4
]}

Casanova, Jean-Laurent ^{[1
,3
,4
,14
,15
]}

机构：

[1] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[2] Rockefeller Univ, Lab Virol & Infect Dis, 1230 York Ave, New York, NY 10021 USA

[3] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Necker Branch, INSERM U1163, Paris, France

[4] Paris Descartes Univ, Imagine Inst, Paris, France

[5] Weill Cornell Med Coll, Div Gastroenterol & Hepatol, New York, NY USA

[6] Aix Marseille Univ, INSERM, CNRS, Ctr Immunol Marseille Luminy, Marseille, France

[7] Hop la Timone, AP HM, Marseille Immunopole, Serv Immunol, Marseille, France

[8] Innate Pharma, Innate Pharma Res Labs, Marseille, France

[9] Necker Hosp Sick Children, AP HP, Dept Pathol, Paris, France

[10] Hop Paul Brousse, AP HP, Hepatobiliary Ctr, Dept Pathol, Villejuif, France

[11] Univ Paris Sud Saclay, Bicetre Univ Hosp, AP HP, Pediat Hepatol & Liver Transplantat Unit,Natl Ref, Le Kremlin Bicetre, France

[12] Univ Paris Sud Saclay, INSERM U1174, Orsay, France

[13] Ambroise Pare Hosp, AP HP, Dept Pathol, Boulogne, France

[14] Necker Hosp Sick Children, Pediat Immunol Hematol Unit, Paris, France

[15] Howard Hughes Med Inst, New York, NY 20815 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2019年 / 216卷 / 08期

基金：

美国国家卫生研究院;

关键词：

ACUTE LIVER-FAILURE; BINDING-PROTEIN; BIOLOGICAL-PROPERTIES; INBORN-ERRORS; INTERLEUKIN-18; MICE; PATHOGENESIS; EXPRESSION; CELLS; CYTOTOXICITY;

D O I：

10.1084/jem.20190669

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：1777 / 1790

页数：14

共 61 条

[1]

Cloning and expression of interleukin-18 binding protein [J].