Immune response pattern varies with the natural history of chronic hepatitis B

Abstract

BACKGROUND 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). AIM To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B. METHODS 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. RESULTS 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 CD56 bright NK cells and CD69 in CD56 dim 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. CONCLUSION 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.

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

“…Some conflicting results have been reported due to the wide spectrum of different clinical conditions characterizing the natural history of HBV infection [3]. As compared with healthy donors, a high expression of some activation/proliferation markers and death ligands (TRAIL) was observed both on peripheral and intrahepatic NK cells from chronic patients [47,48,49], particularly in the active hepatitis stage [50,51,52,53,54,55,56]. Intrahepatic NKG2D up-regulation was proposed to mediate NK activation and liver inflammation, which was particularly amplified in patients with acute-on-chronic liver failure (ACLF) [57].…”

“…However, such an activated phenotype is not associated with a significant potentiation of the NK cell function [58,59]. The dichotomy of a decreased cytokine production in the presence of a conserved or improved cytotoxicity, which likely accelerates liver damage, has been described in treatment-naive patients [47,48,50,51,53,54,56]. Recent reports associate NK cell dysfunction to a downregulation of the IL-2/IL-15 receptor β chain CD122 [60], or to the reduced expression of STAT3, which exerts a positive regulatory effect on NKp46 transcription [61].…”

Significantly Decreased Islet β Cell Function and Increased Fasting Plasma Glucose in Patients With Chronic Hepatitis B: a Cross-sectional Study

“…Fundamental studies have found that hepatitis B virus infection could increase the production of tumor necrosis factor (TNF), especially in HBeAg-negative patients. 27 The overproduction of TNF could decrease the phosphorylation of insulin receptor substrates 1 and 2, inhibit phosphoinositol 3-kinase and protein kinase B, block the phosphorylation of glucose transporter 4, preventthecell uptake of glucose 28 and increase plasma glucose levels. Prostate six-transmembrane protein 2 (STAMP2) can be induced by cytokines, such as TNF alpha, which can inhibit IR in rats.…”

Significantly decreased islet β cell function and increased fasting plasma glucose in patients with chronic hepatitis B: a cross-sectional study

“…Fundamental studies have found that hepatitis B virus infection could increase the production of tumor necrosis factor (TNF), especially in HBeAg-negative patients. 27 The overproduction of TNF could decrease the phosphorylation of insulin receptor substrates 1 and 2, inhibit phosphoinositol 3-kinase and protein kinase B, block the phosphorylation of glucose transporter 4, prevent the cell uptake of glucose 28 and increase plasma glucose levels. Prostate six-transmembrane protein 2 (STAMP2) is a factor associated with in ammation and dietary adipocyte function and system metabolism.…”