ISVHLD2012]甲型肝炎的流行病学、免疫应答和预防——Prof.F. Blai

StephenW

ISVHLD2012]甲型肝炎的流行病学、免疫应答和预防——Prof.F. Blaine Hollinger  专访                    

                        -----

                    
                    

                        来源： 作者：F.B.Hollinger 发布时间：2012-7-17 14:05:17   阅读：13

                    
                                                                他们之间存在某种联系。丙肝有些推理很有趣。病毒在感染早期逃避免疫的途径可以被其他病毒利用，但是由于某种原因，他们逃避免疫的方式却不相同。丙肝和甲肝的途径相似，但是丙肝能够造成慢性感染而甲肝不能，这很令人不解。
                    
                                                                                       

　　Hepatology Digest: Your presentation is on hepatitis A entitled， “Epidemiology， Immune Response and Prophylaxis”. In Asia， we generally talk about HBV and HCV. What will be the main focus of your talk?
　　《国际肝病》：您的报告是关于甲型肝炎，题目为“流行病学、免疫反应和预防”。但是在亚洲，大家讨论的话题一般都是HBV和HCV。您报告的主要内容将是什么？
　　Dr Hollinger: I will talk more about immunopathogenesis of the disease first of all because it has some relevance as it relates to hepatitis C; also the receptors， its life cycle， the kind of particle it is， a little bit about how it enters the cell. The receptor is actually a similar receptor to what the Ebola and Marburg agents use which is kind of interesting. That receptor， even when altered because it is not tissue specific and is found in other tissues， enhances the uptake of virus and triggers NK cells to destroy the hepatocytes that are infected with HAV. There are a lot of interesting things in the pathogenesis. I will have a bit about epidemiology and I want to bring up particularly prophylaxis because， although you say it doesn’t have much relevance to China， there have been more than a million doses of hepatitis A vaccine given in China with live attenuated vaccine which we don’t use. I think the Chinese are the only ones using it. They also have two inactivated vaccines which are just used in China although now I think they are probably going to be used in India and maybe Thailand but at least not worldwide. So there are vaccines that are useful and can be of benefit. I will talk about the clinical disease. This is an international meeting and while the fact is that the majority of attendees will be from China， there will be people there from countries where this disease is quite prevalent. One thing about this meeting， I was in this group from the beginning when we put together the International Symposium of Viral Hepatitis and Liver Disease and I chaired the meeting in 1990， is that there is a strong push for public health and that all five agents would be discussed primarily as well as other things rather than just talk about treatment and other things like AASLD and EASL do. HBV and HCV are important in the United States also; we have a large Vietnamese and Chinese population. Houston， Texas has the second largest Vietnamese population in the country and a very large Chinese population. We don’t see a lot of hepatitis A but the interest in HAV as a virologist has to do with the immunology， its immunopathogenesis and life cycle.
　　Dr Hollinger:首先，我将更多的讨论甲肝的免疫发病机理，因为这与丙肝有关所以显得重要；还会谈到病毒受体、生命周期、病毒颗粒种类，还会涉及到病毒如何进入细胞。有趣的是，甲肝病毒受体实际上与埃博拉病毒受体和马尔堡病毒受体相似。这种受体不具有器官特异性，其他组织中也表达，而且即使被改变，也会提高病毒颗粒的摄入，引发NK细胞破坏HAV感染的肝细胞。发病机制非常值得关注。但我还会谈一点流行病学，还会特别提到预防。尽管你讲到甲肝在中国已并不重要，但是中国已进行了一百多万次减毒活疫苗的接种，而这种疫苗我们并不应用。我觉得可能只有中国才用这种减毒活疫苗。目前还有两种灭活疫苗刚刚在中国应用，并且很可能会在印度还有泰国应用，但无论如何不会在全世界范围内广泛应用。可见还是存在有益的疫苗。临床方面我也会谈到。这是一次国际性的会议，参会者尽管大部分都是中国人，但也会有来自甲肝流行的国家。在国际性病毒性肝炎和肝病大会成立之初我就参与了大会，并且1990年是大会主席。还有一点就是迫切需要大会涉及公关健康问题。大会主要围绕五种病毒性肝炎展开。不仅仅像AASLD和EASL那样讨论治疗等方面的内容还会涉及到其他方面。在美国HBV和HCV同样很重要，美国的越南人和华人都很多。休斯顿的越南人数在美国居第2位，华裔人口数也很大。尽管甲肝患者并不多，但作为病毒学家研究甲肝必须涉及到免疫学、免疫发病机理和生命周期。
　　Hepatology Digest: You are also interested in this because it has a relationship to other forms of hepatitis or other diseases?
　　《国际肝病》：您还对甲肝与其它肝炎或其他疾病的相关性感兴趣？
　　Dr Hollinger: There are some relationships. There are some interesting corollaries with hepatitis C. The pathways that the virus uses to evade the immune response early are used by other viruses but for some reason they don’t seem to evade the immune response in the same way. Hepatitis C and A have very similar pathways but C causes chronic disease and A doesn’t. So there is some real interest there. China is really a transitional country at the moment if you look at serum prevalence of antibodies there today， the younger people are becoming more susceptible to hepatitis A. In fact， the largest outbreak of hepatitis A occurred in Shanghai associated with the hairy clams in the estuary around Shanghai with 200000 to 300000 cases of hepatitis A back in 1988. From that， a large percentage of patients who also had hepatitis B died and it was from that kind of outbreak that the recommendations were to vaccinate patients for both hepatitis A and B because if they have HBV or HCV and they have advanced fibrosis or cirrhosis， and they acquire hepatitis A on top of that， the probability of developing full-on hepatitis and dying is significant. Xu Zhiyi， a prominent epidemiologist in Shanghai， was one of the principle people involved in reporting that epidemic back in 1990 or so.
　　Dr Hollinger: 他们之间存在某种联系。丙肝有些推理很有趣。病毒在感染早期逃避免疫的途径可以被其他病毒利用，但是由于某种原因，他们逃避免疫的方式却不相同。丙肝和甲肝的途径相似，但是丙肝能够造成慢性感染而甲肝不能，这很令人不解。通过现在甲肝抗体的流行病学调查，我们可以看出中国其实处于过渡期。事实上，甲肝最大的流行发生于上海，在1988年共有200000 到300000 例甲肝患者，其中有很多同时患有乙肝的患者出现死亡。这次甲肝爆发后才开始推荐甲肝和乙肝均需进行疫苗接种。进展到晚期肝纤维化或肝硬化的乙肝或丙肝患者，如果感染甲肝，发生爆发性肝炎并死亡的几率很高。上海杰出的流行病学家Xu Zhiyi，是报道1990年甲肝大流行的主要作者之一。
　　Hepatology Digest: You mentioned similarities between the receptors of HAV and HCV also?
　　《国际肝病》：您还谈到甲肝和丙肝病毒受体的相似性？
　　Dr Hollinger: The receptors are not the same per se. There are two candidate receptors. One is probably IgA immunocomplexes that bind to a glycoprotein membrane receptor which takes IgA into the cell. The other one is HAVCR1. This receptor is really important because of the way it affects NK cells and the way it affects the receptor in the uncoating of the virus in the cell. What was recently found is that it appears to be the same receptor as the filoviruses which include Ebola virus and Marburg virus which potentially could be bioterrorism agents.
　　Dr Hollinger: 两者的受体本身并非一样。共有两个可用受体，其中一个可能是IgA免疫复合物，它能结合糖蛋白膜受体并将IgA摄入细胞内；另一个是HAVCR1，这个受体非常重要，因为它不仅能够影响NK细胞，还会影响病毒颗粒在细胞内脱衣壳的受体。最近发现包括有潜力成为生物武器的埃博拉、马尔堡病毒在内的filoviruse病毒的受体似乎与甲肝病毒受体相同。
　　Hepatology Digest: Does hepatitis A affect the receptor or is the receptor modified by some outside agent?
　　《国际肝病》：甲肝病毒能够影响受体吗？外源性的介质会更改受体吗？
　　Dr Hollinger: The receptor is on most of the cells. The issue then is why the agent binds to the hepatocyte because you find this receptor on many cells in the body; that is an area we don’t understand very well. Why it binds specifically to hepatocytes and is not taken up by anything else such as NK cells which have this receptor also， is an area that is just not known very well and we have to pursue it a little more thoroughly. The other thing is that there is a very interesting relationship between that receptor and atopy which is essentially an allergy. People who have acquired hepatitis A in childhood are less likely to have the allergy or allergic reactions such as asthma than children who do not have hepatitis A antibodies. So there are other interesting things about the hepatitis A virus. The similarities between hepatitis A and hepatitis C have to do with sharing similar life cycles in terms of what machinery they incorporate. They are both RNA viruses that replicate in the cytoplasm as RNA viruses do; they don’t get into the nucleus. The pathways seem to be similar. For example， the RIG-I pathway which is one pathway to express interferon initially; both viruses use that pathway because they both have double stranded RNA and double stranded RNA stimulates those pathways which ultimately lead up to the expression of interferon-beta and interferon-stimulated genes and so on. But hepatitis A also uses part of its genome to cleave certain areas there and block that interferon production whereas hepatitis C doesn’t. It seems to evade the immune response initially early in the course of infection and yet it doesn’t cause chronic disease whereas hepatitis C does. From a molecular standpoint， there are some interesting developments between these two viruses.
　　Dr Hollinger: 甲肝受体存在在于大部分细胞中。疑问是机体的许多细胞都表达这一受体，但病毒仅结合肝细胞上的受体，其中原因目前并不清楚。病毒仅能特异性的结合肝细胞中的受体而不是其他诸如NK细胞中的受体，我们也不清楚，需要更为详尽的研究。另一方面，病毒受体与过敏反应中的特应性存在关联，这点很有趣。儿童期患甲肝的患者发生过敏或如哮喘样的过敏反应的几率低于无甲肝抗体的人。还有其他一些关注点，如甲肝和丙肝的相似处与他们生命周期中需要的细胞器有关。它们都是RNA病毒，在细胞质内复制，并不进入细胞核内，他们的途径似乎相似。例如，两种病毒均能够利用能够在早期表达干扰素的RIG-I通路；因为他们均有双链RNA。双链RNA能够活化这些通路，最终引发干扰素、干扰素活化基因等的表达。但是甲肝病毒能够利用自身的部分基因组切割部分区域从而阻断干扰素的产生，然而丙肝却不能。甲肝似乎仅仅在感染初期能够逃避免疫，并不能造成慢性感染，然而丙肝却能形成慢性感染。从分子角度看，两种病毒之间存在关联，值得关注。
　　Hepatology Digest: It seems like a contradiction. That it evades the immune response would seem to lend itself to a chronic infection.
　　《国际肝病》：这看起来矛盾。逃避免疫似乎应该造成慢性感染。
　　Dr Hollinger: It does not have a direct cytopathic effect. The reason we know the virus itself does not have a direct cytopathic effect is because the highest quantities of virus in the serum， the liver and the stool occur early in the course of the infection when there is no ALT abnormality. So the clinical disease is probably due to NK cells and CD8 and CD4 cells producing cytokines and other things. Early in the course of infection， we know from studies we have just completed in chimpanzees， that if these chimpanzees are infected， naturally or otherwise， the virus goes very quickly out of the blood within three to four weeks but it can remain in the feces and liver for up to 50 weeks or more. We didn’t know that. Not only is HAV RNA is found in the liver for up to 40 or 50 weeks but the HAV antigen is found in the liver too. Yet these chimps had cleared the infection and were fine. Why is that? Are they infectious? We don’t think so. Why aren’t they infectious? Probably because of antibodies circulating but we are not completely sure about that because the virus circulates in the blood often enclosed in a lipid envelope or vesicle. So molecularly there is still some strong interest in this. I think it is a fascinating agent myself. Along with Annette Martin from France， I have written the recent chapter on hepatitis A in Field’s Virology which is probably the bible on virology in the world. I think in China as things change， better hygiene and less contamination， there will be a lot of epidemics occur and that is why the vaccine is starting to be used there.
　　Dr Hollinger: 甲肝病毒没有直接杀伤细胞的能力。理由是感染早期患者ALT正常而患者的血清、肝脏、大便中病毒量最高。所以病变可能由产生细胞因子的NK细胞、CD8和CD4细胞造成。在我们刚刚完成的黑猩猩实验中发现，在黑猩猩感染病毒早期，或者自然感染或者其他原因造成干扰，血液中的病毒很快在3到4周内消失，但是粪便和肝脏内的病毒可以存在50周甚至更长时间。原因并不清楚。不仅甲肝RNA可以在肝内存在40或50周，甲肝抗原也存在于肝内。但是这些黑猩猩已经清除病毒，身体也很好。这是为什么？它们还具有传染性吗？我们认为没有。那么为什么没有传染性？可能因为存在于血液循环中的抗体，但是我们还不确定，因为血液循环中的病毒颗粒常常包被在脂质包膜或囊泡内。可见在分子水平上，甲肝仍旧有值得深入研究的地方。我个人认为甲肝是个很值得研究的病原体。我和法国的Annette Martin一起撰写了病毒学领域的圣经- Field病毒学中的甲肝部分。我觉得在中国，虽然卫生在改善、污染在减少，但是还会有许多甲肝患者，这就是中国正在启用新型甲肝疫苗的原因。