标题: Pathogenesis of Hepatitis B Virus [打印本页] 作者: StephenW 时间: 2012-3-11 11:12 标题: Pathogenesis of Hepatitis B Virus
本帖最后由 StephenW 于 2012-3-11 11:13 编辑
http://www.clinicaloptions.com/inPractice/Hepatology/Hepatology/ch3_Hep_B_Epidemiology_Pathogenesis_Diagnosis_and_Natural_History.aspx Pathogenesis of Hepatitis B Virus
Successful control of hepatitis B virus (HBV) is dependent on the complex interplay between the innate, cellular, and humoral responses to the infecting virus.[Chang 2007; Chisari 2010] At the same time, the immune response may be responsible for mediating clinical hepatitis and disease progression. The exact role of the innate response in acute HBV infection is unclear. The nonspecific innate immune response involves production of interferon, activation of natural killer cells, and activation of Kupffer cells, all of which may help to control viral replication and limit the spread of the virus during the early stages of infection.[Wieland 2000; Tang 2003; Webster 2002]
The roles of the cellular and humoral responses are better defined. The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response.[Ferrari 1990; Thimme 2003] Clinical hepatitis is associated with an influx of inflammatory cells, including both HBV-specific and non–HBV-specific T cells.[Thimme 2003] In particular, CD8+ T cells that mediate cytolytic activity against HBV-infected hepatocytes correlate with an increase in serum alanine aminotransferase level.[Thimme 2003] By contrast, the CD4+ and CD8+ response in chronic carriers is feeble or undetectable.[Rehermann 1995] However, their presence in the peripheral blood and liver of chronically infected persons with elevated alanine aminotransferase levels suggest a pathogenic role for the cellular immune response. Therefore, the cell-mediated immune response is a doubled-edged sword: a vigorous response leads to viral clearance, whereas an ineffective response leads to hepatocellular injury.
HBV-specific CD8+ cytotoxic T cells appear to be important for initiating liver injury. Upon activation, they secrete a number of cytokines, including interferons, that recruit a variety of nonspecific inflammatory cells in the liver, resulting in more extensive liver injury. Infiltrating macrophages probably mediate most of the hepatic damage.[Chang 2007]
Natural HistoryPrimary Infection and Acute Hepatitis
Following exposure to hepatitis B virus (HBV), two thirds of patients present with an asymptomatic, subclinical infection and one third present with an acute hepatitis with jaundice, of whom a minority (< 1%) develop fulminant hepatitis (Figure 3).[Kao 2008] The outcome of acute infection is largely dependent on age at exposure: 90% to 95% of individuals who acquire the infection as infants progress to chronic infection compared with 25% of those infected during childhood, and ≤ 5% of those infected as adults (Figure 3).[Hyams 1995]
Acute hepatitis B infection is more likely to resolve in patients who present with jaundice or who are not immunosuppressed at the time of infection compared with those who present with a subclinical infection or who are immunosuppressed. With sensitive assays for hepatitis B virus (HBV) DNA, low-level viral replication can be detected in up to 15% to 20% of persons who recover from acute HBV.[Yuki 2003] Indeed, it is now believed that low-level viral replication probably occurs throughout an individual’s lifetime and is held in check by the immune system.[Liang 2009] This explains why reactivation of hepatitis B might occur if the immune system becomes compromised by chemotherapy, bone marrow or stem cell transplantation, or HIV infection. Chronic Hepatitis and Its Sequelae
The outcome of chronic hepatitis B is variable and dependent on a complex interplay between the level of viral replication and the host immune response. Approximately one half of individuals transition to an inactive carrier state, 30% progress to cirrhosis, and the remainder have varying degrees of chronic hepatitis (Figure 3).[Kao 2008] Although all patients with chronic hepatitis B are at risk for hepatocellular carcinoma, the rate is highest for those with cirrhosis or persistently high viral replication.[McClune 2010; Chen 2006] Understanding the natural history of chronic hepatitis B virus (HBV) infection is crucial for determining who requires therapy, when to initiate treatment, and establishing realistic therapeutic goals.
细胞和体液反应的角色较容易定义。急性自限型乙肝感染中,t细胞反应强烈,繁殖快,具备多种特定毒性,t辅助细胞反应。(The T-cell response during acute, self-limited HBV infection is characterized by a strong, polyclonal, multispecific cytotoxic and helper T-cell response).
临床肝炎通常意味着出现大量炎症细胞、HBV相关/不相关T细胞。
特别是CD8+ T细胞,能通过升高alt水平调整针对感染乙肝病毒肝细胞的细胞溶解活动。相应的,病毒携带者的CD4+和CD8+反应比较小或检测不到。然而,它们在alt升高的感染患者的外周血和肝内仍然存在,说明仍会引起细胞免疫反应。因此细胞级免疫相应调整是双刃剑:强力反应导致病毒清除,但如果失败将导致肝损伤。HBV相关的CD8+ 毒性T细胞在开始导致肝损伤方面似乎非常重要。激活之后将分泌一些列毒素,包括干扰素。干扰素将在肝内吸引许多不相关的炎症细胞,导致出现更强烈的肝损伤。渗透巨噬细胞可能对肝损伤程度影响最大。