Annual Rate and Predictors of HBeAg, HBV DNA and HBsAg Seroclearance

把握当下

StephenW 发表于 2011-8-22 21:09
感谢您的解释。我同意您所有的观点。我不明白eAb的用途。通常情况下，小
三阳(eAg- ve，eAb+ve)意味病毒复 ...

我不明白eAb的用途。通常情况下，小三阳(eAg- ve，eAb+ve)意味病毒复制低，为什么呢？
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我的理解：
如果免疫反应比较充分+病毒量低（dna水平不高），这样免疫战斗力超过病毒复制能力，大三阳就能逐渐转为小三阳携带，这种小三阳就是复制低的，即“通常情况”

如果免疫反应没那么充分+病毒量高，或者虽然充分但是病毒量太高，那么免疫就打不赢病毒，病毒量大还造成病毒容易变异：逐渐使用不释放e抗原进行复制的方式，即变成小三阳
这种小三阳就是不太常见的病毒量复制“高”的，但也没大三阳高，因为这种小三阳变异病毒抗免疫能力变强之后复制能力变弱了

StephenW

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我在一本教科书，“Viral Hepatitis 3rd Edition 病毒性肝炎”, 看到一个“免疫耐受”的建议解释。

"In the neonate born to an HBV-infected mother, it has been suggested that HBeAg
crosses the placenta and induces tolerance. HBeAg may also have an immunomodulatory function duringinfection in adult life. Low molecular weight soluble proteins, such as HBeAg, induce a state of immune nonresponsiveness,
at the T-helper (Th) level. HBeAg-induced tolerance results in T-cell non-response to HBcAg,as well as HBeAg-derived epitopes, so that elimination
of HBV-infected cells does not occur."
在乙型肝炎病毒感染的母亲所生的新生儿，它一直建议，HBeAg 的通过胎盘和诱导耐受。 e抗原也可能在成年生活在感染过程中免疫调节功能。低分子量可溶性蛋白质，如e抗原，诱发免疫无反应状态，在辅助性T（TH）的水平。 e抗原诱导的T细胞的非反应HBcAg的，以及HBeAg衍生的抗原表位的宽容的结果，因此，消除 HBV感染的细胞不会发生。

把握当下

StephenW 发表于 2011-8-23 19:04
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我在一本教科书，“Viral Hepatitis 3rd Edition 病毒性肝炎”, 看到一个“免疫耐受 ...

恩，这个解释我在论坛上也看到一个，我觉得跟你看的基本一致（有兴趣可以搜索一下）：

“在以前的博客文章中，我讲过，乙肝病毒本身对肝细胞没有直接的细胞损伤作用，肝细胞的损伤是由于人体对病毒产生的免疫反应引起的。HBV感染肝细胞后，产生大量抗原，如上面提到的表面抗原(HBsAg)，核心抗原(HBcAg)，这些抗原存在于肝细胞内或表面，激活人体的免疫功能，对感染了病毒的肝细胞进行攻击，结果导致肝细胞的损伤。e抗原（HBeAg）与核心抗原(HBcAg)的氨基酸序列几乎一致，蛋白质组成基本相同。所不同的是，HBeAg的比HBcAg多了几个氨基酸，蛋白分子略大。核心抗原（HBcAg）用于组装病毒的内衣壳，包装病毒的DNA，e抗原（HBeAg）产生后即分泌到肝细胞外，进入血液和分布全身其它地方。

　　为什么两个差不多的蛋白质，一个（HBcAg）用于组装病毒，一个（HBeAg）用于分泌到肝细胞外呢？

　　推测这是乙肝病毒逃避人体免疫攻击的一种手段。在乙肝病毒感染的早期，或胎儿在出生期或在子宫内接触到有病毒的血液时，乙肝病毒在肝细胞内合成的e抗原（HBeAg）并释放到血液内，释放出的HBeAg先“麻痹”婴儿的免疫系统，由于HBeAg与HBcAg非常相似，这样，当免疫系统碰到HBcAg时，由于已经被麻痹，于是不再对病毒产生免疫反应，使人体处于免疫耐受状态，无法有效地消灭或清除病毒。乙肝病毒通过释放HBeAg达到逃避人体免疫攻击的目的。这就是为什么，乙肝病毒制造出HBeAg这么一个蛋白，只释放到血液内，而对病毒的复制没有作用。

　　当然，上面只是一种猜测，HBeAg的真正功能，还有待进一步研究和发现。在还没有完全明了它的功能之前，我们知道它是一个绝好的监测病毒的指标就可以了。知道如果HBeAg阳性，就表示病毒复制活跃，血中HBV DNA水平高，传染性强就可以了。”

StephenW

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很好，谢谢你。
同一本书，解释了我们如何从免疫耐受进行到免疫清除:

As the years go by, this immune-tolerant phase gives way to increased hepatitic
activity, presumably reflecting immune activation, perhaps as a result of viral antigenic variation caused by transcriptional errors as already mentioned. The role of CD4-positive lymphocytes in this process is supported by the observation of an increased response to the nucleocapsid proteins as HBeAg/anti-HBe seroconversion
approaches. These cells presumably provide help to CTLs and B lymphocytes. Either because of CTL lysis of infected cells, or of cytokine production by CD4-positive lymphocytes, which inhibit virion production, cells supporting productive HBV infection are cleared during the seroconversion hepatitis. About 5% of HBeAg-positive chronic infections may spontaneously seroconvert to anti-HBe per year. In the majority of these patients, HBs antigenaemia persists predominantly because of
the presence of small numbers of cells containing integrated HBV sequences. However, by PCR, it is possible to detect small amounts of HBV DNA in the serum of
these HBsAg-positive, anti-HBe-positive subjects with normal liver function tests, indicating that viral replication is still occurring at low level.

随着岁月的流逝，这种免疫耐受期增加肝炎活动，反映免疫激活，也许作为一个转录错误造成的，前面已经提到的病毒抗原变异的结果。在这个过程中的CD4阳性淋巴细胞的作用是支持增加e抗原/抗- HBe血清转换的核衣壳蛋白反应的观察
方法。这些细胞可能提供帮助的CTL和B淋巴细胞。要么是因为对感染细胞的CTL裂解，或细胞因子的CD4阳性淋巴细胞，从而抑制病毒粒子的生产，生产，配套生产乙肝病毒感染的细胞被清除在血清转换肝炎。抗- HBe，每年大约有5％的HBeAg阳性慢性感染可能自发seroconvert。在这些患者中的大多数，HBs antigenaemia 仍然存在主要是因为包含整合型HBV序列的细胞数量小的存在。然而，经PCR，可以检测到血清HBV - DNA少量这些HBsAg阳性，抗- HBe阳性，肝功能正常的测试，表明病毒复制，科目仍是发生在低水平。


这是，由于多年突变的积累，有一天我们的免疫系统有一个新抗原的目标。免疫系统清除一些受感染的细胞，因此降低eAg生产，因此，减少免疫系统抑制，因此免疫系统更杀死感染细胞, 因此降低eAg生产,因此......最终的平衡 - 少数受感染的细胞在免疫系统的控制下，[像你以前说的] ???

把握当下

StephenW 发表于 2011-8-23 23:49
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很好，谢谢你。

这是，由于多年突变的积累，有一天我们的免疫系统有一个新抗原的目标。
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恩，我觉得是这样的，根据书里的意思：
免疫耐受开始打破的原因可能是病毒抗原复制时发生了一些错误，这些错误引起了免疫系统的警觉，从而激发了免疫系统对hbv的识别和攻击，慢慢的免疫耐受被打破了

免疫系统清除一些受感染的细胞，因此降低eAg生产，因此，减少免疫系统抑制，因此免疫系统更杀死感染细胞, 因此降低eAg生产,因此......最终的平衡 - 少数受感染的细胞在免疫系统的控制下，[像你以前说的] ???
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恩，我是这个意思，只是免疫激发的后果即可能使病人进入第3期，也可能是第4期（免疫逃避escape，即病毒变异了，东山再起）

In the majority of these patients, HBs antigenaemia persists predominantly because of
the presence of small numbers of cells containing integrated HBV sequences. However, by PCR, it is possible to detect small amounts of HBV DNA in the serum of
these HBsAg-positive, anti-HBe-positive subjects with normal liver function tests, indicating that viral replication is still occurring at low level.
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这里解释了为什么e转换之后，血清表抗仍然很高：因为少许肝细胞已经整合了hbv（基因）序列，仍然在制造表面抗原。如果通过精确pcr定量可能会发现表抗阳性、e抗体阳性、肝功正常的人血清中仍有少量hbv dna，这说明病毒仍在低水平复制（将来可能东山再起）

StephenW

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我想补充：
HBsAg颗粒（这些都不会传染），比病毒颗粒（Dane颗粒）的生产多很多倍。这些
HBsAg颗粒流在血液中抑制了我们的免疫系统。

把握当下

StephenW 发表于 2011-8-27 16:30
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我想补充：

"HBsAg颗粒流在血液中抑制了我们的免疫系统。"
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关于这个论坛有个帖子我觉得很形象：http://www.hbvhbv.com/forum/thread-954135-1-1.html
“27。说说肝炎的原理，当完全的免疫耐受变为不那么完全的免疫耐受时。。。
有一点值得一提，就是乙肝表面抗原还会刺激T细胞大量增殖，而T细胞大量增殖会抑制B细胞的成熟，不成熟B细胞就产生不了表面抗体蛋白。。。。”

StephenW

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As zhongdong426 did not provide any references, I cannot verify his claim that increased proliferation of T cells suppresses maturation of B cells:"就是乙肝表面抗原还会刺激T细胞大量增殖，而T细胞大量增殖会抑制B细胞的成熟，不成熟B细胞就产生不了表面抗体蛋白。这点原理很复杂，如果你看不懂，或者我说的不够通俗，可以不必看。看到这里，你可能会怨恨T细胞，T细胞直接杀伤受感染的肝细胞使你的转氨酶升高还不算，增殖的T细胞还抑制B细胞的成熟，导致表面抗体蛋白生产的减少，你很怨恨它对不对？但是免疫系统真的是很复杂的，T细胞对B细胞的制衡有很大意义的，比如，人如果受了辐射导致T细胞受损的话，B细胞就会大量增殖释放大量抗体，就会导致一系列的免疫性疾病的发生，比如，红斑狼疮，自身免疫性的肝炎，风湿性关节炎等等，由此可见，身体中各类免疫反应，不论是细胞免疫还是体液免液，共同构成了一个极为精细、复杂而完善的防卫体系。不能说谁对谁错。"

But he is right that our immune system us very complex. Lifevendor translated a very recent paper about therapeutic vaccine  that talked about T-cell exhaustion
http://www.hbvhbv.com/forum/thread-1042667-1-1.html.

The following abstract also mentioned possible mechanism that HBsAg used to modulate our immune response. All too complicated to me.

http://mt.china-papers.com/2/?p=64955



HBsAg Interferes with the TLR Signaling Pathway in Macrophage-like Cells                              Posted on May 25, 2010 by China Papers0
                                       
Abstract: Hepatitis B virus(HBV),an enveloped virus with a partial circular double-stranded DNA genome,can cause viral necroinflammation with variable severity,resulting in transient acute hepatitis,prolonged chronic hepatitis,or even fatal fulminant hepatitis.It is widely believed that both viral clearance and the development of the liver diseases after infections are determined by host-virus interactions mediated by the immune response.Many studies have shown that the defects in effector functions of the cellular immune response to HBV were responsible for the establishment of HBV infection.However,the precise mechanism of such impaired cellular responses in HBV infection is still to be determined.It is proposed that impaired function of antigen presentation may be involved,since antigen presentation is the prerequisite for priming T cellular immune responses.Toll-like receptor family,the member of pattern recognition receptors,have been identified as crucial mediators of inate immune system by recognizing conservative molecules in pathogens.Studies have shown that activation of antigen presenting cells via TLR signaling is prerequisite for subsequent induction of vigorous T cell responses. Recently,it has been reported that some viruses can interact with TLRs or their downstream molecules to interfere with the signaling cascade.These results suggest that the modulation of TLR-mediated signals is one of the mechanisms for virus to regulate the immune response,which may contribute to viral escape of immune surveillance and the establishment of persistent viral infection.However,it remains unclear whether this kind of immune modulation also exists in HBV infection.In this study,THP-1 cells,a human monocytic cell line,as well as macrophage-like cells differentiated from THP-1 treated with PMA were choosen as cell model for antigen presenting cells.HBsAg was selected to study the effect of HBV on TLR signaling pathway as HBV envelope protein is the most aboundant protein during HBV infection.RT-PCR and Real-time PCR analysis were used to detect TLR mRNA expression.Results showed that macrophage-like cells have a higher TLRs expression profile than THP-1,among which,TLR1,TLR2,TLR4 and TLR6 mRNAs were highly expressed.To investigate the modulatory effects of HBsAg on TLR signaling pathway,pam3csk4 and LPS,which are the TLR1/2 and TLR4 ligands respectively, were used to activate TLR signaling pathway in macrophage-like cells.Results showed that HBsAg inhibited LPS and pam3csk4 induced expression of IL-10 and IL-12 in a dose-dependent manner,which suggests that HBsAg can interfere with TLR signaling pathway activation.In order to further understand the underlying mechanism,the regulatory effects of HBsAg on NF-κB and MARPK pathway,which are downstream of TLR signaling,were detected.Immunofluorescence stainning analysis was used to detect nuclear location of NF-κB p65 protein.Results showed that the number of cells positive for nuclear NF-κB p65 was significantly lower in HBsAg treated cells than in the control cells after pam3csk4 and LPS stimulation. Western blotting analysis showed that LPS and pam3csk4-induced IκB-a degration was also inhibited.All the above results suggest that HBsAg can inhibit LPS and pam3csk4 induced activation of the NF-κB signal pathway.However,no significant change in phosphorylated IκB-a was observed.Further study of the phosphorylated ERK in these cells showed that the induced phosphorylation of ERK by LPS and pam3csk4 were inhibited by HBsAg,indicating the inhibiting effect of HBsAg on the ERK pathway.To further understand the molecular mechanism of interfering with TLR signaling pathway by HBsAg,the TLR expression profiles of HBsAg treated macrophage-like cells were also detected by Real-time PCR.Result showed that there was no significant change of expression of TLRs after treatment with HBsAg, suggesting the inhibition effect is independent of down-regulation of TLRs level. Furthermore,result showed that HBsAg even upregulated TLR4 expression.In addition to interfereing with TLRs recognization,previous studies have demonstrated that some negative regulators were also involved in TLR signaling pathway,including MyD88s,IRAK3,Tollip,IRF family and SOCS family.We next examined the expression of these negative regulators in HBsAg treated macrophage-like cells. Results showed that HBsAg upregulated SOCS1 expression,suggesting the upregulating SOCS1 expression by HBsAg may be one of the mechanisms by which HBsAg interferes with TLR signaling pathway.In conlusion,our studies showed that the presence of large amounts of HBsAg in serum during HBV infection may not only affect adaptive immune response by T cell exhaustion,but also influence the innate immune response by interfering with TLR signaling pathway to arrest antigen presentation.The above studies may provide new insights into the mechanism of inadequate cell-mediated immune response in chronic HBV patients and help to develop novel antiviral therapies…
Key words: HBsAg;  Toll-like receptor;  macrophage-like cell;  THP-1;  SOCS1