Activated natural killer cells accelerate liver damage in patients with chronic hepatitis B virus infection

Abstract

SummaryEmerging evidence indicates that natural killer (NK) cells may contribute to liver injury in patients with hepatitis B virus (HBV) infection. Because HBV infection progresses through various disease phases, the cytolytic profiles of peripheral and intrahepatic NK cells in HBV-infected patients remain to be defined. In this study, we comprehensively characterized intrahepatic and peripheral NK cells in a cohort of HBV-infected individuals, and investigated their impact on liver pathogenesis during chronic HBV infection. The study population included 34 immuneclearance (IC) patients, 36 immune-tolerant (IT) carriers and 10 healthy subjects. We found that the activity of peripheral NK cells from IC patients was functionally elevated compared to IT carriers and controls, and NK cell activation was indicated by an increased expression of CD69, CD107a, interferon (IFN)-g and tumour necrosis factor (TNF)-a. Further analysis showed that the increased activity of both peripheral and hepatic NK cells was correlated positively with liver injury, which was assessed by serum alanine aminotransferase levels (ALT) and the liver histological activity index (HAI). Interestingly, the frequency of peripheral NK cells was reduced in IC patients (especially those with higher HAI scores of 3-4), but there was a concomitant increase in hepatic NK cells. The functionally activated NK cells are enriched preferentially in the livers of IC patients and skew towards cytolytic activity that accelerates liver injury in chronic hepatitis B (CHB) patients.

Natural Killer Cell–Derived Interferon‐Gamma Promotes Hepatocellular Carcinoma Through the Epithelial Cell Adhesion Molecule–Epithelial‐to‐Mesenchymal Transition Axis in Hepatitis B Virus Transgenic Mice

“…Alpha‐galactosylceramide‐triggered NKT cells induced the sensitive liver injury in HBs‐Tg mice, which was also dependent on NK cells . In humans, functionally activated NK cells were preferentially enriched in the livers of HBV immune‐clearance patients, and their increased IFN‐γ expression was positively correlated with liver injury in chronic hepatitis B patients . IFN‐γ plays an important role in mediating hepatic inflammation and injury by induction of chemokines, adhesive molecules, and proapoptotic proteins .…”

“…(11) In humans, functionally activated NK cells were preferentially enriched in the livers of HBV immune-clearance patients, and their increased IFN-γ expression was positively correlated with liver injury in chronic hepatitis B patients. (12) IFN-γ plays an important role in mediating hepatic inflammation and injury by induction of chemokines, adhesive molecules, and proapoptotic proteins. (13,14) Further, IFN-γ participates in cancer elimination (immunosurveillance), protecting mice against chemically induced, spontaneous, and transplantable tumors.…”

Role of natural killer cells in liver transplantation treatment of liver cancer

“…Considering that NK cells are the primary source of IFN-γ and account for the majority of liver innate immunocytes (25), the present study detected the number and expression of activation markers for NK cells six months post-LT by FACS flow cytometry. There was no significant difference between these two groups in the number of liver NK cells (P=0.3734; 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.…”