6 Immunopathogenesis of viral hepatitis

More than 500 million people world-wide suffer from viral hepatitis which can be caused by a variety of distinct infectious agents. The spectrum of disease, which ranges from acute self-limited hepatitis to liver cirrhosis, not only reflects the different biological properties and pathogenicity of the hepatitis viruses, but is also the result of the specific interaction between each virus and the immune system of the infected host. The immune response plays a crucial role in the elimination of the infecting virus as well as in disease pathogenesis and is described in detail for acute and chronic hepatitis B and C virus infection. Acute hepatitis B virus infection is characterized by a vigorous, polyclonal cytotoxic T lymphocyte response against HBV that is not readily detectable in patients with chronic hepatitis B, suggesting that resolution of disease is mediated by the HBV-specific CTL response in these patients. Because traces of virus as well as HBVspecific CTL can perist for decades after clinical recovery, continuous priming of new CTL by minute traces of virus is thought to protect from reactivation of disease. In contrast, the hepatitis C virus causes chronic liver disease despite a polyclonal and multispecific immune response, suggesting that distinct immunological and viral mechanisms determine the different clinical outcome of HBV and HCV infection. Their implications for the development of immunomodulatory vaccines to cure patients with chronic viral hepatitis are discussed.     

New concepts in the immunopathogenesis of chronic hepatitis B: the importance of the innate immune response

Acute and chronic infection with hepatitis B virus (HBV) is associated with an increased risk of developing liver disease including cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The clinical presentation and natural history of HBV infection is mediated through complex interactions between the virus and the host immune response. HBV is not directly cytopathic to heptocytes; however, the interaction between the virus and the host immune response plays a central role in the pathogenesis of necroinflammation and liver fibrosis. Emerging data from immunopathogenesis studies in animal models and in vitro studies of liver biopsies from patients with chronic hepatitis B demonstrate a potentially important interaction between hepatitis B e antigen, HBV, and components of the innate immune response including Toll-like receptors, Kupffer cells, natural killer T-cells, and dendritic cells. These findings suggest that the innate immune response has an important role in influencing the outcome of acute and chronic HBV infection. The current knowledge regarding the interaction between HBV and components of the innate immune response during acute and chronic HBV infection is reviewed.     

Role of viral factors in the natural course and therapy of chronic hepatitis B

Hepatitis B virus (HBV) infection is a global health problem that causes a wide spectrum of liver disease, including acute or fulminant hepatitis, inactive carrier state, chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The pathogenesis of hepatocyte damage associated with HBV is mainly through immune-mediated mechanisms. On the basis of the virus and host interactions, the natural history of HBV carriers who are infected in early life can be divided into four dynamic phases. The frequency, extent, and severity of hepatitis flares or acute exacerbation in the second immune clearance and/or fourth reactivation phase predict liver disease progression in HBV carriers. In the past decade, hepatitis B viral factors including serum HBV DNA level, genotype, and naturally occurring mutants predictive of clinical outcomes have been identified. The higher the serum HBV DNA level after the immune clearance phase, the higher the incidence of adverse outcomes over time. In addition, high viral load, genotype C, basal core promoter mutation, and pre-S deletion correlate with increased risk of cirrhosis and HCC development. As to the treatment of chronic hepatitis B, patients with high HBV DNA level and genotype C or D infection are shown to have a worse response to interferon therapy. In conclusion, serum HBV DNA level, genotype, and naturally occurring mutants are identified to influence liver disease progression and therapy of chronic hepatitis B. More investigations are needed to clarify the molecular mechanisms of the viral factors involved in the pathogenesis of each stage of liver disease and the response to antiviral treatments.     

Molecular characteristics and stages of chronic hepatitis B virus infection

Hepatitis B virus （HBV） is a common viral pathogen that causes a substantial health burden worldwide. Remarkable progress has been made in our under- standing of the natural stages of chronic HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. Knowledge of the HBV genome organization and replication cycle can unravel HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. Most HBV infections are spontaneously resolved in immunocompetent adults, whereas they become chronic in most neonates and infants at a great risk of developing complications such as cirrhosis and hepatocellular carcinoma （HCC）. Those with chronic HBV infection may present in one of the four phases of infection： immune tolerance, immune clearance [hepatitis B e antigen （HBeAg）-positive chronic hepatitis B （CHB）], inactive carrier state, and reactivation （HBeAg-negative CHB）. Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers. Long-term monitoring and optimal timing of antiviral therapy for chronic HBV infection help to prevent progression of HBV-related liver disease to its later stage, particularly in patients with higher risk markers of HCC, such as serum DNA concentration, HBeAg status, serum aminotransferase, HBV genotypes, and pre-core or core mutants.     

Regulatory T cells in viral hepatitis

The pathogenesis and outcome of viral infections are significantly influenced by the host immune response. The immune system is able to eliminate many viruses in the acute phase of infection. However, some viruses, like hepatitis C virus (HCV) and hepatitis B virus (HBV), can evade the host immune responses and establish a persistent infection. HCV and HBV persistence is caused by various mechanisms, like subversion of innate immune responses by viral factors, the emergence of T cell escape mutations, or T cell dysfunction and suppression. Recently, it has become evident that regulatory T cells may contribute to the pathogenesis and outcome of viral infections by suppressing antiviral immune responses. Indeed, the control of HCV and HBV specific immune responses mediated by regulatory T cells may be one mechanism that favors viral persistence, but it may also prevent the host from overwhelming T cell activity and liver damage. This review will focus on the role of regulatory T cells in viral hepatitis.     

Crosstalk between innate and adaptive immunity in hepatitis B virus infection

Hepatitis B virus(HBV) infection is a major public healthproblem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is res-ponsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.     

Innate antiviral immune responses to hepatitis B virus

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis in humans. As HBV itself is currently viewed as a non-cytopathic virus, the liver pathology associated with hepatitis B is mainly thought to be due to immune responses directed against HBV antigens. The outcome of HBV infection is the result of complex interactions between replicating HBV and the immune system. While the role of the adaptive immune response in the resolution of HBV infection is well understood, the contribution of innate immune mechanisms remains to be clearly defined. The innate immune system represents the first line of defense against viral infection, but its role has been difficult to analyze in humans due to late diagnosis of HBV infection. In this review, we discuss recent advances in the field of innate immunity to HBV infection.     

Hepatitis B and the Immune System

As a persistent virus, hepatitis B virus (HBV) is believed to be noncytopathic in most circumstances, with its disease pathogenesis mediated by host innate and adaptive immune responses. Although HBV may initially avoid activating critical innate intracellular defenses (eg, type I interferons), T cells exert both cytopathic and noncytopathic antiviral effects toward resolution of HBV infection. With chronic HBV infection, various immune regulatory or tolerance mechanisms are induced with varying degrees of effector T-cell dysfunction and liver inflammation, which contributes to liver disease progression. This review highlights some components of host immune response relevant for HBV infection, including the more recent appreciation of immune regulatory mechanisms induced during chronic viral infection. Although therapeutic options are evolving for HBV, a better understanding of its immune pathogenetic and regulatory mechanisms may help develop better approaches to treat HBV infection and prevent disease progression.     

Hepatitis C in the HIV-Infected Person

Because of shared routes of transmission, hepatitis C virus (HCV) infection is common in HIV-infected persons, who have been experiencing increasing HCV-related morbidity and mortality since the advent of effective antiretroviral therapy. Infection with HIV appears to adversely affect the outcome of hepatitis C, leading to increased viral persistence after acute infection, higher levels of viremia, and accelerated progression of HCV-related liver disease. In addition, hepatitis C may affect the course and management of HIV infection. The medical management of hepatitis C in HIV-infected persons is complicated by immune suppression, potential drug interactions and toxicities, and other forms of liver disease. In addition, there is little published experience with the safety and efficacy of the best available anti-HCV medications in HIV-infected persons. Thus, current efforts must be directed at preventing HCV and HIV infections and applying the principles learned in treating persons with either infection to manage those with both. Future efforts should include studies of the pathogenesis of HCV infection in HIV-infected persons and large, prospective studies that demonstrate the optimal management of persons co-infected with HIV and HCV. Such efforts will help to eliminate HCV-related liver disease as an emerging threat to HIV-infected persons.     

Critical analysis of the immune tolerance phase of chronic HBV infection: Natural history and diagnosis

Hepatitis B virus (HBV) infection is the major cause of cirrhosis and hepatocellular carcinoma worldwide. Based on virus-host interactions, the natural history of HBV carriers can be divided into four phases. In the prolonged immune tolerance phase, HBV carriers are positive for hepatitis B e antigen (HBeAg) and have high HBV replication but minimal liver disease. Early termination of immune tolerance and subsequent HBeAg seroconversion usually confer a favorable outcome, whereas delayed HBeAg seroconversion may accelerate the progression of liver disease. In recent years, viral and host factors such as the rapid decline of serum HBV DNA level, HBV genotype, possible naturally occurring mutants, and specific HLA haplotypes have been shown to affect the loss of immune tolerance in chronic hepatitis B. HBV carriers with an immune tolerant phenotype may be defined as having HBeAg positivity, persistently low-normal serum alanine aminotransferase, and serum HBV DNA greater than 2 × 10⁷ IU/mL. These patients should be monitored; many have a rapid transition to an inactive carrier state with favorable outcomes.     

Immunology of hepatitis D virus infection: General concepts and present evidence

Infection with the hepatitis D virus induces the most severe form of chronic viral hepatitis, affecting over 12 million people worldwide. Chronic HDV infection leads to rapid development of liver cirrhosis and hepatocellular carcinoma in ~70% of patients within 15 years of infection. Recent evidence suggests that an interplay of different components of the immune system are contributing to viral control and may even be implicated in liver disease pathogenesis. This review will describe general concepts of antiviral immune response and elicit the present evidence concerning the interplay of the hepatitis D virus with the immune system.     

Immunopathogenesis: role of innate and adaptive immune responses

Hepatitis B virus (HBV) infection in immunocompetent adults usually results in a self-limited, transient liver disease and viral clearance, with only a small percentage (5 to 10%) developing chronic hepatitis associated with viral persistence. In contrast, when neonates are infected, more than 90% become persistently infected, suffering differing degrees of chronic liver disease. Activation of immunity plays a central role in host-virus interactions, greatly influencing viral replication and the clinical outcome of infection. Although all of the specific mechanisms and consequences of this interaction have not been elucidated, the purpose of this article is to describe the basic arms of the immune system as they interact with the HBV and describe the present state of knowledge in this area. These arms may be divided broadly into innate and specific immune responses, and they have different roles and responses in acute and chronic infection.     

The natural history of chronic hepatitis B virus infection

Three stages of chronic hepatitis B virus (HBV) infection are recognized: the immune tolerant phase, the chronic hepatitis B phase, and the inactive hepatitis B carrier phase. Active liver disease is most often found in persons with elevated aminotransferase levels and HBV DNA levels >10(5) copies/mL. Possible risk factors for developing liver disease include older age, male gender, presence of hepatitis B e antigen (HBeAg), HBV genotype, mutations in the precore and core promoter regions of the viral genome, and coinfection with hepatitis D (delta) virus. All persons chronically infected with HBV should be followed every 6 to 12 months with aminotransferase levels. Those with elevated levels should be tested for HBeAg and its antibody (anti-HBe) as well as HBV DNA levels to determine if they are in need of further evaluation with a liver biopsy and are candidates for antiviral therapy. Future research will help clarify the outcome of chronic HBV infection.     

A virological perspective on the need for vaccination

Superinfecton of chronic carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV) with hepatitis A virus (HAV) is often associated with more severe liver disease than infection with HAV alone. Superinfection commonly causes markers of HBV and HCV replication to fall to significantly lower levels. The pathogenesis of acute liver damage characteristic of viral hepatitis is thought to be mediated by host cytotoxic T-lymphocytes (CTLs) directed against virus-infected hepatocytes. It has been proposed that the more aggressive liver disease observed in individuals infected with HAV in addition to chronic HBV/HCV is a result of the induction of interferon (IFN)-alpha during acute HAV infection. This accounts for the antiviral effect on the active markers of HBV/HCV replication, and the enhanced CTL response against HBV/HCV-infected hepatocytes. Alternatively, HAV may indirectly stimulate the T helper 1 (Th1)-type cytokine responses, such as interleukin (IL)-2, IFN-gamma and tumour necrosis factor (TNF)-alpha, which directly promote the antiviral CTL response. Clearance of HBV infection, and possible HAV and HCV, is associated with a specific CTL response, while viral persistence in chronic HBV and HCV infection has been attributed to an imbalance in the Th1-Th2 arms of the immune response. Vaccination against hepatitis A should be considered for patients with chronic HBV/HCV infection, to minimize the risk of exacerbating underlying liver disease.     

Natural history: The importance of viral load, liver damage and HCC

Viral hepatitis is the main cause of liver disease. Progression of viral hepatitis leading to liver cirrhosis and hepatocellular carcinoma occurs frequently in chronic HBV- and HCV-infected patients. Viral and host-related factors and modifiable and non-modifiable factors associated with advanced liver disease can be distinguished. For hepatitis B, viral factors include HBeAg status, HBV genotype, naturally occurring mutations, and viral load. The level of serum HBV DNA, reflecting the concentration of intrahepatic HBV DNA, is positively correlated with the risk for liver cirrhosis and HCC. The continued presence of intracellular hepatitis B virus and the resulting immune response might be the driving force for the progression of HBV-related liver disease and HBV reactivation. However, little is known about the natural course of intrahepatic HBV DNA, and further studies are needed. Patients with HCV and/or HDV and/or HIV coinfections are at an increased risk for an adverse outcome of their liver disease. For hepatitis C, courses of the disease are variable. Viral factors seem to be less significant for disease progression, while host-related effects play a more important role. Among these are modifiable cofactors such as hepatic steatosis and insulin resistance which lead to a more severe disease and lower response to antiviral therapy with chronic hepatitis C. The precise interactions between HCV and host metabolic factors need further elucidation, especially as the rate of metabolic diseases is on the increase.     

Hepatitis B transplantation: special conditions

Patients with hepatitis B virus (HBV) infection may be coinfected with other viral diseases, such as hepatitis C virus (HCV) and/or D virus (HDV), or have serious diseases secondary to the hepatitis, such as hepatocellular carcinoma. These coexisting conditions have an impact on the success of treatment and of liver transplantation. Patients with HBV and HDV are at lower risk for HBV recurrence than are patients with HBV alone; likewise, patients with HBV/HCV coinfection appear to have a higher 5-year survival rate posttransplantation. Treatment of coinfection is similar to that used for HBV alone. Hepatitis B immune globulin and interferon have been found to be effective in varying degrees. Recurrence or reinfection of disease after liver transplantation presents many clinical problems that will require new therapeutic approaches. Future studies will help to begin solving these challenges.     

Drugs of Abuse and Their Impact on Viral Pathogenesis

Commonly misused substances such as alcohol, cocaine, heroin, methamphetamine, and opioids suppress immune responses and may impact viral pathogenesis. In recent years, illicit use of opioids has fueled outbreaks of several viral pathogens, including the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). This review focuses on the myriad of mechanisms by which drugs of abuse impact viral replication and disease progression. Virus–drug interactions can accelerate viral disease progression and lead to increased risk of virus transmission.     

Clinical immune characterization of hepatitis B virus infection and implications for immune intervention: Progress and challenges

The host immune response plays an important role in mediating hepatitis B virus (HBV) control and induction of liver damage, which determines the outcome of infection. However, interactions between HBV, the immune system, and the liver microenvironment, remain poorly understood. This review briefly outlines what we know about innate and adaptive immune responses to HBV, as well as the liver immunology in infected patients. It addresses how our knowledge of the anti-HBV immune response might aid the development of adoptive immune therapeutic strategies against HBV. This review also highlights the challenges we are facing in understanding the cellular and molecular mechanisms bywhich the innate, adaptive and liver immune responses exert a synergistic antiviral function and influence disease progression. It concludes by addressing future directions and unanswered questions regarding the use of clinical immunotherapy. We hope this review will help hepatologists and gastroenterologists to understand the anti-HBV immune response, as well as current challenges and potential immunotherapeutic strategies against this disease.