Reduced hepatitis B virus surface antigen-specific Th1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen-specific antibodies in the Trimera mouse

Abstract

In chronic hepatitis B virus (HBV) infectionInfection with the hepatitis B virus (HBV) is one of the most common infectious diseases with an estimated 300 million chronic HBV carriers worldwide. 1 The high risk of patients with chronic hepatitis B (CHB) developing liver cirrhosis and hepatocellular carcinoma is associated with a high morbidity and mortality. Because HBV is a noncytopathic virus, liver injury is mainly mediated by the host immune response against virus-infected liver cells. 2 Strong HBV core/precore (HBc/e) specific T helper (Th) cell activities are detectable in acute self-limited hepatitis B or during exacerbations of the chronic disease in concert with strong HBV envelope, core, and polymerase-specific cytotoxic T lymphocyte reactivities, whereas such T-cell responses are weak in chronic disease. [3][4][5][6] This HBV-specific T-cell failure of chronic HBV carriers is believed to account for viral persistence.Furthermore, the B-and Th-cell response to the HBV surface antigen (HBsAg) seems to be insufficient in chronic hepatitis B. Whereas in patients with acute hepatitis B, the disappearance of HBsAg and the occurrence of anti-hepatitis B surface antigen (HBs) antibodies in serum mark viral elimination with subsequent development of protective immunity, in patients with CHB such antibodies are usually undetectable. Accordingly, low frequencies of anti-HBssecreting B cells are detected in the latter patients in contrast to very high B-cell numbers in patients with acute self-limited hepatitis B. 7 However, from current in vitro studies it remains unclear whether chronic HBV carriers exhibit an HBsAgspecific Th cell defect because proliferative T-cell responses to HBsAg are very weak or undetectable not only in chronic infection but also during acute hepatitis B or during acute exacerbations of the chronic disease. 4,5 Moreover, in a recent study, antienvelope antibodies were detected in immune complexes with HBsAg in sera of patients with chronic HBV infection. 8 However, the epitope specificity of such antibodies was not further specified (i.e., anti-preS1/2 or anti-HBs) and the antibody levels were not compared with those of HBVimmunized or HBs-vaccinated individuals. Thus, our current knowledge about the cellular and molecular mechanisms of the presumed HBs-specific B-and T-cell defect of chronic HBV carriers is controversial and limited.Anti-HBs antibodies might mediate important antiviral effector functions because anti-HBs antibodies are virus neutralizing, 9,10 HBsAg is expressed on the membrane of infected liver cells 11 and anti-HBs-mediated cytotoxicity has

Characteristics of Circulating T Cell Receptor γδ T Cells from Individuals Chronically Infected with Hepatitis B Virus (HBV): An Association between Vδ2 Subtype and Chronic HBV Infection

“…Until now, considerable evidence has suggested that the immune response is the key factor in the pathogenesis of CHB [1][2][3][4]. Numerous studies have investigated the adaptive immune response with CD4 ϩ or CD8 ϩ T cells, B cells, or dendritic cells and the innate immune response with NK cells, in HBV-transgenic mice or in the monkey infection model; the results demonstrated that strong antiviral immune responses during the early stages of HBV infection could induce sustained viral clearance, whereas deficient immune responses could sustain infection [5][6][7][8].…”

“…Every year, ϳ1 million people who are chronically infected with HBV die of liver failure, liver cirrhosis, or hepatocellular carcinoma [1,2]. It is known that HBV is not directly cytopathic for infected hepatocytes, and the clinical outcome of HBV infection or the degree of liver damage is the result of complicated interactions between the virus and the host immune response [3,4]. Some findings of studies of the immunopathogenesis of chronic HBV infection have suggested that CD8 ϩ T cells, CD4 ϩ T cells, and NK cells, as well as cytokines in the liver, participate in the process of liver pathology [5][6][7][8].…”

Concentrations of Cytokines, Soluble Interleukin-2 Receptor, and Soluble CD30 in Sera of Patients with Hepatitis B Virus Infection during Acute and Convalescent Phases

“…Some of these cytokines lead to activities against pathogens, activate effector cells involved in the cellular interactions that occur during inflammation, and are part of the acute and chronic stages of viral hepatitis (22,35). The antibody response in patients with HBV infection plays a critical role in viral clearance through the formation of complexes with viral particles and their removal from the circulation (6,8,29).…”

“…Studies carried out with cultures of peripheral blood mononuclear cells from patients with acute HBV infection showed a Th1-like cytokine pattern with increased levels of production of IFN-␥ and TNF-␣ (2,6). This high level of cytokine production stimulates the immune response, allowing the cure of HBV disease (21).…”

Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens

“…For HBV therapy, it has been used to study specific T-cell responses, vaccination strategies (Bocher et al, 2000;Bocher et al, 2001) and the therapeutic effect of monoclonal antibodies directed against HBV epitopes (Eren et al, 2000;Galun et al, 2002). In addition, concerning HCV, an inhibitor of the internal ribosomal entry site and an anti-HCV monoclonal antibody were demonstrated to act as HCV inhibitors (Ilan et al, 2002) using this model.…”