Chronic hepatitis B: The interplay between intrahepatic lymphocyte population and viral antigens in relation to liver damage

Abstract

In Chronic hepatitis B (CHB) infection, virus and immune response interplay is thoughtto be responsible for pathogenesis. Yet, the impact of each immune cell population and viral protein expression in liver damage is still unknown. Our aim was to study the interplay between intrahepatic immune response and viral activity in relation to CHB liver damage. Immunostaining was performed in 29 liver biopsies from untreated CHB patients to characterize liver infiltrate [Th (CD4+), CTL (CD8+), Treg (FoxP3+), Th17 (IL-17A+) and Th1 (T-bet+)] and viral antigen expression (HBsAg and HBcAg).Inflammatory activity and fibrosis were assessed using the HAI and METAVIR scoring system. All studied populations were identified in the portal-periportal (P-P) areas with a CD4+ lymphocyte predominance, while only CD8+ and FoxP3+ cells were observed in the intralobular area. Both P-P CD4+ and intralobular CD8+ cell frequencies were increased among severe hepatitis cases. Concerning HBsAg and HBcAg expression, a mutually exclusive pattern was observed. HBcAg was mainly detected among HBeAg-positive patients and was associated with hepatitis severity and higher frequency of P-P FoxP3+, intralobular CD8+ and FoxP3+ cells. HBsAg was identified among HBeAg-negative cases with less severe hepatitis grade and lower frequency of P-P CD4+ and intralobular FoxP3+ lymphocytes. In conclusion, the HBV antigen profile expression seen during CHB infection may be reflecting different stages of viral replication which impacts the host immune response and liver damage process. While HBcAg might be an inducer of a regulatory microenvironment, the intralobular CTL population seemed to have a key role in hepatitis severity. K E Y W O R D Schronic hepatitis B, inflammatory infiltrate, liver damage, viral antigen

Identifying potential biomarkers in hepatitis B virus infection and its response to the antiviral therapy by integrated bioinformatic analysis

“…In the present study, intrahepatic immune response activation and chemokine signalling were detected, which might result in different immune cell infiltration in the liver microenvironment between responders and non‐responders. In addition, in previous studies, the immune infiltration characteristics in the liver microenvironment were also reported to be associated with hepatitis severity, the HBV‐related liver disease progression and the efficacy of antiviral treatments in previous studies 4,36 . Our chemokine assays in serum of CHB patients confirmed that 5 hub chemokines (CCL4, CCL5, CXCL9, CXCL10 and CXCL13) were significantly down‐regulated in antiviral treatment non‐responders comparing non‐responders.…”

“…In addition, in previous studies, the immune infiltration characteristics in the liver microenvironment were also reported to be associated with hepatitis severity, the HBV‐related liver disease progression and the efficacy of antiviral treatments in previous studies. 4 , 36 Our chemokine assays in serum of CHB patients confirmed that 5 hub chemokines (CCL4, CCL5, CXCL9, CXCL10 and CXCL13) were significantly down‐regulated in antiviral treatment non‐responders comparing non‐responders. The verified chemokines may have high potential values to be used as novel biomarkers in predicting treatment response.…”

Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection

“…Histopathological evaluation of the liver of infected patients demonstrated that mild leukocyte infiltration is observed in the IT and IC phases, whereas extensive infiltrates are observed in IA and ENEG patients, predominantly in the portal tract area [4]. These distinct characteristics were used by European Association for the Study of the Liver (EASL) to propose a revised nomenclature for HBeAg-positive and HBeAg-negative chronic HBV: chronic infection versus chronic hepatitis, which is thought to better describe the phases [3].…”

A GSVA based gene set synergizing with CD4+T cell bearing harmful factors yield risk signals in HBV related diseases via amalgamation of artificial intelligence

“…According to the previous studies (31,32,67,69)，we calculated ES of 28 LILs by cell marker gene based ssGSEA algorithm in HBV related diseases. A comprehensive view of LILs was provided and 21 out of 28 LILS showed closed correlations with CLST in liver tissues from CHB patients and several cell types including MDSC (70)(71)(72)(73) and Treg (74)(75)(76) previously reported as risk factors during progressive HBV related diseases. Moreover, CLST and the member genes were specifically enriched in patients at IA phases with inadequate immune clearance mediated liver damage when compared with those patients at any other phases.…”