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¹ Division of Infection and Immunity, ² Institute of Hepatology, and ³ Centre for Sexual Health and HIV Research, University College London, London W1T 4JF, UK
⁴ U.O. Gastroenterologia ed Epatologia, Spedali Riuniti di Santa Chiara, I-56124 Pisa, Italy
⁵ Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK
⁶ Gastroenterology Unit, Fondazione Policlinico, University of Milan, 20122 Milan, Italy
⁷ Nuffield Department of Clinical Medicine and The Jenner Institute, University of Oxford, Oxford OX3 9DU, UK

CORRESPONDENCE Mala K. Maini: m.maini{at}ucl.ac.uk

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)-, 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- 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-/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.

A. Bertoletti's present address is CMM, A*Star, Singapore 138668.

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