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
Chronic hepatitis B is a highly heterogeneous disease, which can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). Accordingly, clinical manifestations and disease progression markedly differ among these phases. Natural killer (NK) and hepatitis B virus (HBV)-specific T cells are two key effectors of cellular immunity, which play an important role in mediating liver damage and inhibiting viral replication. Therefore, the identification of immune features in clinical phases are helpful in better understanding the highly heterogeneous disease state of chronic HBV infection. However, the associations between host immunity and clinical phases are obscure.
The motivation of this study is to explore the immunological mechanisms underlying different clinical phases.
The objective of this study is to analyze the features of NK cells, nonantigen-specific and HBV-specific T cells in different clinical phases.
The frequency, subpopulation and phenotype of circulating NK cells were detected by flow cytometry through direct surface staining. NK cell functions, including cytokine production and cytotoxic activity, and nonantigen-specific T cell responses were measured by flow cytometry after stimulant incubation and intracellular staining. For HBV-specific T-cell responses, PBMCs were stimulated by HBV core or S peptide pools. After 10 d of in vitro expansion, HBV-specific T cell responses were determined by detecting the frequency of T cells producing IFN-γ or IL-2. In addition, clinical phases were assigned according to the available history and laboratory results, using classification criteria described in clinical practice guidelines.
NK cells were phenotypically activated in the clinical phases (IA and ENEG) with biochemical liver damage. Both NK and T cells were 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 were partially restored in the IC phase, and ENEG phase was primarily dominated by nonantigen-specific T cell responses.
In the cross-sectional analysis and longitudinal observation from several representative individuals, our findings depicted the shift of immune response pattern along the natural history of chronic HBV infection. Importantly, NK cells, nonantigen-specific and HBV-specific T cells may play a distinct role in different clinical phases. Our findings countered the previous opinion from the single perspective that innate and adaptive responses were synchronously inhibited or enhanced in some disease status. Our results emphasized the complicated roles of NK and T cells, which were extremely helpful in understanding the immunological mechanisms underlying different clinical stages in chronic HBV infection. Furthermore, the better understanding of immune features in different phases will lead towards individualized therapy.
Future research should be conducted to investigate the regulatory mechanisms of NK cells, nonantigen-specific and HBV-specific T cells in distinct phases of chronic HBV infection. In the future, virologic and immunological mechanisms under distinct phases will still be one of the most focused issues due to the highly heterogeneous disease profile until chronic HBV infection is completely solved. Virologic factors, such HBV-RNA, HBcAg, cccDNA and gene variation, and host factors, such as hepatocyte clone and other types of immune responses, are other perspectives for future research.