Characterization Of Peripheral NK Cells In HBV-infected Patients Reveals Their Potential Role In Liver Injury

Hepatitis B virus (HBV) is a hepadnavirus DNA virus, which does not directly cause liver damage. Therefore, liver damage in CHB patients is believed to be mediated by host immune responses. On one hand, inefficient control of viral replication occurs because specific anti-HBV immune response is inefficiently activated; on the other hand, non specific immune cells are persistently activated in a long period and will eventually mediate liver damages. Over the past decade, NK cells are gradually regarded as a very important player in the immunopathogenesis of various types of liver diseases. However, little is known about their immunological characteristics (including their phenotype and function details, especially during HBeAg-positive hepatic flare) as well as the immune-pathological mechanisms mediated by these cells.In present study, we conducted a comprehensive cross-sectional analysis of the immunological features (phenotype and functional characteristics) of peripheral NK cells in different phases of HBV-infected patients, including acute hepatitis, chronic HBV infection in immune tolerant phase and in immune activation phase. In order to explain the clinical significance of immunological changes and investigate mechanisms of NK cells activation and immune-mediated liver injury in CHB patients, clinical parameters (ALT, AST and viral load of HBV in serum) were also analyzed and correlated to these immunological features.We found that immune activated (IA) CHB patients displayed a large redistribution of peripheral NK cell subsets, indicated by decreased CD56^dimCD16^pos and increased CD56^brightCD16^neg subsets. More importantly, NK cells expressed significantly high levels of activation markers such as HLA-DR, CD38 and CD69 in IA patients rather than IT patients with chronic HBV infection. Interestingly, these activation molecules are simultaneously up-regulated on both T cells and NK cells in the patients at the early phase of acute resolved hepatitis B, which indicate that only NK cells are preferentially activated in IA patients. Functional analyses revealed that activated NK cells in IA patients secreted more cytokine IFN-y stimulated by IL-12/IL-15 and more CD 107a stimulated by K562 than IT patients and healthy controls. Also activated NK cells in IA patients could kill more target cells, including K562, HepG2, HepG2.2.15 and HuH7.5 cells, In addition, this hyper-activity of NK cells in IA patients was found to closely correlate with the higher level of serum ALT/AST.Our findings indicate that peripheral NK cells were highly activated in IA patients with CHB rather than IT subjects. Importantly, our data suggest that the over activities of NK cells are closely associated with the severity of liver damage in the CHB patients.