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

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.

Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells

“…We observed here a significant overrepresentation of the CD56 bright NK cell subset among NK cells in peritoneal effusions compared with peripheral blood. This finding is in agreement with a study by Belisle et al (28), and has also been described in several other tissues, including secondary lymphoid organs and the uterus of pregnant women, as well as in some human diseases (42)(43)(44)(45). Intriguingly, we found a clear correlation between the proportion of CD56 bright cells in peritoneal effusions and the loss of 2B4 in this compartment.…”

MicroRNA-146a Feedback Suppresses T Cell Immune Function by Targeting Stat1 in Patients with Chronic Hepatitis B

“…To understand how inflammation in CHB may influence miR-146a expression in T cells, we determined whether miR-146a is subject to regulation by TNF-a, IFN-a, and IL-6, which are the major proinflammatory cytokines involved in hepatic inflammations (27,28). The upregulation of miR-146a followed a dose-response curve and time course after treatment with TNF-a in Jurkat cells (Fig.…”

Immune therapy for hepatitis B

“…Toll-like receptor (TLR) agonists, cytokines and immune modulators reduced HBV DNA and induced HBV-specific immunity in HBV TM and DHBV-infected ducks (30)(31)(32). On the other hand, liver damages were documented when cells of innate immunity were activated in these animals (33)(34)(35). Thus, confusions prevailed about the clinical implications of non-antigenspecific immune therapy in animal models of chronic HBV infection.…”