Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage

Claire Dunn, Maurizia Brunetto, Gary Reynolds, Theodoros Christophides, Patrick T. Kennedy, Pietro Lampertico, Abhishek Das, A. Ross Lopes, Persephone Borrow, Kevin Williams, Elizabeth Humphreys, Simon Afford, David H. Adams, Antonio Bertoletti, Mala K. Maini

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatitis B virus (HBV) causes chronic infection in more than 350 million people worldwide. It replicates in hepatocytes but is non-cytopathic; liver damage is thought to be immune mediated. Here, we investigated the role of innate immune responses in mediating liver damage in patients with chronic HBV infection. Longitudinal analysis revealed a temporal correlation between flares of liver inflammation and fluctuations in interleukin (IL)-8, interferon (IFN)-α, and natural killer (NK) cell expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly ex vivo. A cross-sectional study confirmed these findings in patients with HBV-related liver inflammation compared with healthy carriers. Activated, TRAIL-expressing NK cells were further enriched in the liver of patients with chronic HBV infection, while their hepatocytes expressed increased levels of a TRAIL death-inducing receptor. IFN-α concentrations found in patients were capable of activating NK cells to induce TRAIL-mediated hepatocyte apoptosis in vitro. The pathogenic potential of this pathway could be further enhanced by the ability of the IFN-α/IL-8 combination to dysregulate the balance of death-inducing and regulatory TRAIL receptors expressed on hepatocytes. We conclude that NK cells may contribute to liver inflammation by TRAIL-mediated death of hepatocytes and demonstrate that this non-antigen-specific mechanism can be switched on by cytokines produced during active HBV infection. JEM

Original languageEnglish
Pages (from-to)667-680
Number of pages14
JournalJournal of Experimental Medicine
Volume204
Issue number3
DOIs
Publication statusPublished - Mar 19 2007

ASJC Scopus subject areas

  • Immunology

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