Published online Apr 28, 2019. doi: 10.3748/wjg.v25.i16.1950
Peer-review started: February 17, 2019
First decision: March 5, 2019
Revised: March 12, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: April 28, 2019
Processing time: 69 Days and 22.4 Hours
Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG).
To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B.
The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.
The ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.
Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
Core tip: Chronic hepatitis B is a highly heterogeneous disease, which can be divided into four phases: immune tolerant, immune active (IA), inactive carrier and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). Natural killer (NK) and virus-specific T cells are two key effector cells of cellular immunity. Our study demonstrates the conversion of the immune response pattern along the natural history of chronic hepatitis B virus infection. NK cells were phenotypically activated in the clinical phases (IA and ENEG) with biochemical liver damage. NK, non-specific and virus-specific T cells were functionally impaired in immune tolerant and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T cell responses were partially restored in the inactive carrier phase, and the ENEG phase was primarily dominated by nonantigen-specific T cell responses.