免疫系统在乙型、丙型病毒性肝炎发病过程中作用研究进展

乙型病毒性肝炎和丙型病毒性肝炎分别由乙型肝炎病毒和丙型肝炎病毒感染所致。乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）感染呈全球分布,我国是高流行地区,由于HBV、HCV基因的高变性,容易逃避机体免疫系统的清除。HBV、HCV感染免疫系统细胞,造成机体对HBV、HCV感染的免疫应答异常,并引起组织的损伤,导致肝细胞的慢性持续性感染,并可进一步发展成肝硬化,甚至肝细胞肝癌。HBV、HCV主要经血液传播,包括输血与血制品传播、静脉吸毒、针刺、医源性传播、性接触和母婴垂直传播。     

丙型肝炎病毒感染发病机理研究现状

随着对丙型肝炎病毒(HCV)感染认识的加深,有关其发病机理的研究也日益受到重视。HCV的直接致病作用可能参与急性感染致肝损害过程,免疫功能紊乱可能是造成肝脏损害尤其是慢性损害的重要原因,而对HCV致肝细胞癌(HCC)的机理仍了解较少。本文就HCV的直接致病作用,HCV感染的免疫发病机理及HCV与HCC的相关性等研究现状作一综述。     

CD81在HCV致病机制中的重要意义

CD81是近年发现的HCV受体分子,具有极广泛的生物学功能。CD81与HCV E2分子结合,可辅助病毒的感染、成熟与包装,并调节机体免疫功能,与HCV持续性感染、免疫逃逸及免疫病理损伤关系密切,在HCV致病机制中具有重要的意义。     

CD81在HCV致病机制中的重要意义

CD81是近年发现的HCV受体分子，具有极广泛的生物学功能。CD81与HCV E2分子结合，可辅助病毒的感染、成熟与包装，并调节机体免疫功能，与HCV持续性感染、免疫逃逸及免疫病理损伤关系密切，在HCV致病机制中具有重要的意义。     

慢性丙型肝炎患者的自生抗体检测及临床意义

免疫系统主要功能是对异种抗原的识别并产生免疫应答,免疫耐受的调节控制着机体内免疫反应不致损害自身组织的正常成分,只有当机体自身耐受性因某种原因遭到破坏或丧失时,免疫系统对自身成分产生免疫应答。长久以来,病毒一直被疑为自身免疫性疾病的触发因子,自1989年Esterbam(1)首次在丙型肝炎患者血清中查出自身抗体后,HCV感染与自身免疫的关系受到众多学者所重视,本文作者检测了30例抗HCV阳性者自身抗体情况,现报告如下:     

丙型肝炎病毒和肝细胞抗病毒机制相互作用的研究进展

丙型肝炎病毒（hepatitis C virus,HCV）是引起慢性肝炎和肝癌的主要病因之一。HCV感染可刺激靶细胞（肝细胞）产生干扰素和干扰素刺激因子,后者能在HCV感染复制周期的不同阶段抑制病毒。因此,肝细胞自身的天然免疫对识别和阻断HCV感染复制至关重要,是机体抗HCV感染的重要防御机制之一。然而,HCV可通过多种机制逃逸肝细胞的天然免疫反应。本文主要描述肝细胞的抗病毒机制对HCV的识别、抑制以及HCV逃逸和拮抗肝细胞天然免疫机制的研究进展。     

丙型肝炎病毒全基因组感染细胞模型研究

HCV是导致慢性肝炎、肝纤维化、肝细胞癌的重要致病因子,建立HCV全基因组感染细胞模型对于研究HCV致病机制,研究抗HCV药物具有重要意义,此文试就该领域内目前研究成果进行综述。     

感染“乙肝、病毒后

乙型肝炎病毒进入人体后,经过血液的途径进入肝脏,并在肝内细胞里生长繁殖。由于每个人发生乙型肝炎病毒感染时的年龄、感染的程度以及当时身体的状况不同,身体的表现也会有所不同,大致有以下几种类型:第一种是强反应型,指的是机体的免疫系统对感染了病毒的肝细胞的免疫清除     

应用干扰素和强的松治疗自身抗体阳性的慢性丙型肝炎

丙型肝炎病毒(HCV)感染和自身免疫之间的关系仍存在争议,而确定HCV感染引起肝细胞损伤的致病机理对那些血清HCV RNA和自身抗体阳性患者的治疗是必要的。本文针对血清抗-HCV、HCV RNA和自身抗体阳性的慢性丙型肝炎患者在短期应用强的松治疗后无应答再用α-干扰素(IFNα)治疗的应答情况进行了评价。     

不同健身运动对中老年人唾液中SlgA含量影响的研究

正免疫老化是指随着年龄的增加,机体免疫细胞产生速度减缓,许多功能性细胞分子发生增龄性改变,导致机体免疫应答功能下降或出现异常,使老年人容易患肿瘤感染及自身免疫性疾病的过程。运动对免疫系统有双重作用,适度的运动能刺激免疫系统功能,有利于机体保持抵抗疾病的最佳状态;而剧烈或过度的运动可抑制免疫系统功能,使机体更容易感染疾病。因此寻找适合中老年的运动方式来抵消免疫系统功能的增龄性改变有非常重要的意义。     

Hepatitis C immunology

This review summarizes what is currently known about the cellular and humoral immune responses to hepatitis C virus. The results of viral protein immunogenicity studies reported so far are analyzed, and points of controversy about the immunology and immunopathology of hepatitis C are discussed. A body of evidence supports the existence in hepatitis C virus-infected subjects of strong humoral and cellular immune responses. HCV Core, NS3 and NS4 proteins are the most immunogenic antigens for B cells and HLA class II-restricted CD4+ T cells. For its part, liver-infiltrating CD8+ CTL recognize epitopes within the Core, E1, E2/NS1 and NS2 proteins in a HLA class I restricted manner. CTL responses to HCV Core, NS3, NS4 and NS5 have been detected in peripheral blood of patients chronically infected with HCV. Although these B and T cell responses may contribute to clear the virus, in most cases they are unable to resolve chronic HCV infections. No protective B or T cell epitope has been found yet. It is becoming clearer that the immune response plays a fundamental role in the pathogenesis of liver disease in hepatitis C patients.     

In vivo and in vitro evidence that cross-reactive antibodies to C-terminus of hypervariable region 1 do not neutralize heterologous hepatitis C virus

The hypervariable region 1 (HVR1) of hepatitis C virus (HCV) may contain neutralizing epitopes. A chimpanzee in whom cross-reactive anti-HVR1 antibodies had been induced by immunization was challenged with heterologous HCV for clarifying whether cross-reactive anti-HVR1 antibodies can neutralize heterologous HCV. Acute hepatitis C occurred in this chimpanzee after the challenge. Rechallenge with mixtures of the highest titer cross-reactive immune serum and heterologous HCV, after the chimpanzee had cleared the viremia, again resulted in HCV infection. Virus capture assay and inhibition of virus adsorption to susceptible cells, by the immune sera from the chimpanzee and highly cross-reactive monoclonal antibodies (mAbs) against the C-terminus of HVR1 of the challenge virus, showed that cross-reactive anti-HVR1 had no cross-neutralizing activity. The data imply that the HVR1 component is insufficient to develop an effective HCV vaccine.     

Immunology of HCV infection: the causes of impaired cellular immune response and the effect of antiviral treatment

BACKGROUND: The outcome of HCV infection and the response to antiviral treatment depend on both viral and host factors. Host immune response contributes not only to viral control, clinical recovery and protective immunity, but also to chronic hepatitis and liver cirrhosis. Establishing immunological status and identifying pretreatment immunological factors associated with better response to therapy might be of importance in the understanding of the successful immune response and in the future of combination therapy to HCV infection. AIMS: The authors delivered a review on the immunology of HCV infection and characterized the cause of impaired cellular immune response in chronic HCV infection. Natural killer (NK) cell activity, perforin and the inhibitory CD81 HCV co-receptor expression, and Th1/Th2 cytokine production of the monocytes and lymphocytes have been investigated. PATIENTS AND METHODS: 42 patients with chronic hepatitis C, out of them 25 being on interferon (PEG-IFN) + ribavirin (RBV) therapy, 12 sustained virological responders, 26 HCV carriers with normal transaminase values and 22 healthy controls were studied. NK cell activity, perforin and CD81 expression, the IFNgamma, TNFalpha, IL-2 (Th1) and IL-4, IL-6, IL-10 (Th2) production of LPS stimulated monocytes and PMA + ionomycine stimulated lymphocytes were measured by flow-cytometry. RESULTS: In patients with chronic hepatitis C we demonstrated decreased NK cell activity associated with increased CD81 expression. The perforin expression of lymphocytes was also impaired in HCV patients. The pretreatment capacity of the macrophages to produce TNFalpha was predictive for sustained virological response. This increased TNFalpha production of the monocytes counteracted the observed impaired Th1 type cytokine production of the lymphocytes. IL-10 and IL-4 production showed positive correlation with HCV RNA levels, and negative correlation with histological activity index was noted. PEG-IFN + RBV treatment increased NK activity, perforin expression, Th1 type cytokine production of thr lymphocytes and downregulated CD81 expression inducing effective cellular immune response against HCV. The author's results provide further data to understand the causes of impaired cellular immune response in chronic HCV hepatitis and may be useful in the developement of immunotherapy as an adjunctive treatment to cure patients with chronic hepatitis C.     

Vertical transmission of hepatitis C virus: A tale of multiple outcomes

Globally, hepatitis C virus (HCV) infection affects approximately 130 million people and 3 million new infections occur annually. HCV is also recognized as an important cause of chronic liver disease in children. The absence of proofreading properties of the HCV RNA polymerase leads to a highly error prone replication process, allowing HCV to escape host immune response. The adaptive nature of HCV evolution dictates the outcome of the disease in many ways. Here, we investigated the molecular evolution of HCV in three unrelated children who acquired chronic HCV infection as a result of mother-to-child transmission, two of whom were also coinfected with HIV-1. The persistence of discrete HCV variants and their population structure were assessed using median joining network and Bayesian approaches. While patterns of viral evolution clearly differed between subjects, immune system dysfunction related to HIV coinfection or persistent HCV seronegativity stand as potential mechanisms to explain the lack of molecular evolution observed in these three cases. In contrast, treatment of HCV infection with PegIFN, which did not lead to sustained virologic responses in all 3 cases, was not associated with commensurate variations in the complexity of the variant spectrum. Finally, the differences in the degree of divergence suggest that the mode of transmission of the virus was not the main factor driving viral evolution.     

Immune responses against hepatitis C virus genotype 3a virus-like particles in mice: A novel VLP prime-adenovirus boost strategy

Chronic hepatitis C virus (HCV) infection represents a major health threat to global population. In India, approximately 15–20% of cases of chronic liver diseases are caused by HCV infection. Although, new drug treatments hold great promise for HCV eradication in infected individuals, the treatments are highly expensive. A vaccine for preventing or treating HCV infection would be of great value, particularly in developing countries. Several preclinical trials of virus-like particle (VLP) based vaccine strategies are in progress throughout the world. Previously, using baculovirus based system, we have reported the production of hepatitis C virus-like particles (HCV-LPs) encoding structural proteins for genotype 3a, which is prevalent in India. In the present study, we have generated HCV-LPs using adenovirus based system and tried different immunization strategies by using combinations of both kinds of HCV-LPs with other genotype 3a-based immunogens. HCV-LPs and peptides based ELISAs were used to evaluate antibody responses generated by these combinations. Cell-mediated immune responses were measured by using T-cell proliferation assay and intracellular cytokine staining. We observed that administration of recombinant adenoviruses expressing HCV structural proteins as final booster enhances both antibody as well as T-cell responses. Additionally, reduction of binding of VLP and JFH1 virus to human hepatocellular carcinoma cells demonstrated the presence of neutralizing antibodies in immunized sera. Taken together, our results suggest that the combined regimen of VLP followed by recombinant adenovirus could more effectively inhibit HCV infection, endorsing the novel vaccine strategy.     

Pathogenesis of hepatitis C virus infection

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. Chronic hepatitis C is a mayor cause of cirrhosis and hepatocellular carcinoma and HCV-related end-stage liver disease is, in many countries, the first cause of liver transplantation. HCV infection is characterized by its propensity to chronicity. Because of its high genetic variability, HCV has the capability to escape the immune response of the host. HCV is not directly cytopathic and liver lesions are mainly related to immune-mediated mechanisms that are characterized by a predominant type 1 helper cell response. Co-factor influencing the outcome of the disease including age, gender and alcohol consumption are poorly understood and other factors such as immunologic and genetic factors may play and important role. Recent studies have shown that the combination therapy with alpha interferon and ribavirin induces a sustained virological response in about 40% of patients with chronic hepatitis C. The lack of animal models and of in vitro cultures systems hampers the understanding of the pathogenesis of chronic hepatitis C and the development of new antivirals. The conjugation of polyethyleneglycol improved the pharmacodynamics and the efficacy of alpha interferon. The development of an effective vaccine remains the most difficult challenge. Because of the high protein variability of HCV, protective vaccines could be extremely difficult to produce and therapeutic vaccines seem more realistic. Considerable progress has been made in the field of HCV since its discovery 10 years ago but a major effort needs to be made in the next decade to control HCV-related disease.     

Indications of immune protection from hepatitis C infection

Hepatitis C affects many millions of people worldwide and is at very high prevalence among people who inject drugs. In our study of hepatitis C virus (HCV) in the social networks of injecting drug users (IDUs), five IDUs with injecting careers of 9 years or more were HCV antibody and RNA negative. All injected frequently with HCV RNA-positive IDUs, and two had recently injected with the syringe of an RNA-positive IDU. Our data suggest the existence of immune protection from HCV infection.