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)-alpha, 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-alpha 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-alpha/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.
Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage / C. Dunn, M. Brunetto, G. Reynolds, T. Christophides, P.T. Kennedy, P. Lampertico, A. Das, A.R. Lopes, P. Borrow, K. Williams, E. Humphreys, S. Afford, D.H. Adams, A. Bertoletti, M.K. Maini. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - 204:3(2007), pp. 667-680.
|Titolo:||Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage|
|Settore Scientifico Disciplinare:||Settore MED/12 - Gastroenterologia|
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1084/jem.20061287|
|Appare nelle tipologie:||01 - Articolo su periodico|