Cellular Immune Responses in HBV E Antigen Negative Chronic HBV
Cellular Immune Responses in HBV E Antigen Negative Chronic HBV
The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-γ (IFN-γ) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-γ producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-γ assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.
The course of chronic hepatitis B virus (HBV) infection is determined by the continuous interplay between viral replication and localized host immune responses in the liver. A number of studies over the last two decades have clearly defined the successive phases of chronic HBV infection. Most chronically infected HBV patients after the loss of hepatitis B e antigen (HBeAg), enter a phase of low viral replication and minimal liver inflammation, termed 'inactive HBsAg carrier state'. A subset of these HBeAg negative patients (20-30%), shortly after or, more commonly, years after HBeAg loss, demonstrate enhanced HBV replication (mainly form variants with decreased or absent capability of HBeAg production) associated with liver necroinflammation defined as 'HBeAg negative chronic hepatitis B (CHB)'.
Currently, HBeAg negative infection is the predominant form of chronic HBV infection worldwide. Despite the significant progress in our understanding of the epidemiology and clinical course of HBeAg negative chronic HBV infection, the immunopathogenetic mechanisms that are responsible for liver necro-inflammation, i.e. CHB, in approximately one third of chronically infected HBeAg negative patients have not been elucidated. Studies examining the immune responses either in the periphery or in the liver in this subset of patients are limited. Similarly, it is unclear how most HBsAg inactive carriers are able to maintain low HBV replication and minimal hepatocyte damage for decades and even a lifetime.
The primary aim of our study was to investigate the cellular immune responses in patients with HBeAg negative chronic HBV infection and compare these responses between patients with HBeAg negative CHB and HBsAg inactive carriers.
Summary and Introduction
Summary
The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-γ (IFN-γ) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-γ producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-γ assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.
Introduction
The course of chronic hepatitis B virus (HBV) infection is determined by the continuous interplay between viral replication and localized host immune responses in the liver. A number of studies over the last two decades have clearly defined the successive phases of chronic HBV infection. Most chronically infected HBV patients after the loss of hepatitis B e antigen (HBeAg), enter a phase of low viral replication and minimal liver inflammation, termed 'inactive HBsAg carrier state'. A subset of these HBeAg negative patients (20-30%), shortly after or, more commonly, years after HBeAg loss, demonstrate enhanced HBV replication (mainly form variants with decreased or absent capability of HBeAg production) associated with liver necroinflammation defined as 'HBeAg negative chronic hepatitis B (CHB)'.
Currently, HBeAg negative infection is the predominant form of chronic HBV infection worldwide. Despite the significant progress in our understanding of the epidemiology and clinical course of HBeAg negative chronic HBV infection, the immunopathogenetic mechanisms that are responsible for liver necro-inflammation, i.e. CHB, in approximately one third of chronically infected HBeAg negative patients have not been elucidated. Studies examining the immune responses either in the periphery or in the liver in this subset of patients are limited. Similarly, it is unclear how most HBsAg inactive carriers are able to maintain low HBV replication and minimal hepatocyte damage for decades and even a lifetime.
The primary aim of our study was to investigate the cellular immune responses in patients with HBeAg negative chronic HBV infection and compare these responses between patients with HBeAg negative CHB and HBsAg inactive carriers.
Source...