Inherited IL-18BP deficiency in human fulminant viral hepatitis.
J Exp Med
; 216(8): 1777-1790, 2019 08 05.
Article
em En
| MEDLINE
| ID: mdl-31213488
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos e Proteínas de Sinalização Intercelular
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Necrose Hepática Massiva
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Hepatite A
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Doenças Genéticas Inatas
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Risk_factors_studies
Limite:
Child
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Female
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Humans
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Male
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2019
Tipo de documento:
Article