A new role for an old marker, HBsAg

lin12345

Jnl of Hepatology
Volume 52, Issue 4, Pages 475-477 (April 2010)

Maurizia Rossana Brunetto
Liver Unit, University Hospital of Pisa, Italy

published online 01 February 2010.
Refers to article:
Hepatitis B surface antigen levels during the natural history of chronic
hepatitis B: A perspective on Asia , 17 February 2010
Tin Nguyen, Alexander J.V. Thompson, Scott Bowden, Catherine Croagh, Sally Bell, Paul V. Desmond, Miriam Levy, Stephen A. Locarnini
Journal of Hepatology
April 2010 (Vol. 52, Issue 4, Pages 508-513)
Abstract | Full Text | Full-Text PDF (758 KB)

Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: A European perspective , 15 February 2010
Jerzy Jaroszewicz, Beatriz Calle Serrano, Karsten Wursthorn, Katja Deterding, Jerome Schlue, Regina Raupach, Robert Flisiak, C.-Thomas Bock, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg
Journal of Hepatology
April 2010 (Vol. 52, Issue 4, Pages 514-522)
Abstract | Full Text | Full-Text PDF (1061 KB)

Detection in the serum of the "Australia antigen", namely hepatitis B surface antigen (HBsAg), was the Nobel prize discovery that identified hepatitis B virus (HBV) about 40years ago; to this day HBsAg remains the hallmark of overt HBV infection [1], [2]. HBsAg circulates in a wide array of particulate forms: competent virions (42nm, Dane particles), 20nm diameter filaments of variable length, and 20-22nm spherical defective particles, corresponding to empty viral envelopes [3]. Serum HBsAg results from the different combinations of three proteins (small, medium and large), either glycosylated or not, that are specified by a single open reading frame providing 3 carboxy-terminal colinear HBsAg proteins of different length. The small (S) protein (226 amino acids) is expressed at the highest levels, predominates in both virions and subviral particles and is secreted without cleavage of amino acid residues during translocation because of its self-assembling capacity with host-derived lipids in the cell ER [4]. The middle (M) protein (containing 55 extra residues of the pre-S2 domain) is regulated by the same promoter and is similarly secreted, whereas the transcription of the large protein (L) is regulated by a specific but weaker promoter (pre-S1) [5]. Hepatitis B virus large surface protein (L-HBs) containing both the pre-S2 region and the 108-119 additional residues of the pre-S1 domain, is an essential component of both virions and filaments, and represents 10-20% of their envelope proteins. In contrast, the L-HBs represents only 2% of the 22nm spherical particles [6], [7]. The complexity of HBsAg production and secretion is known since the early studies that showed a larger excess of both filaments and spherical subviral particles was present in highly viremic HBeAg positive carriers as compared to low viremic anti-HBe positive carriers, in whom the decline of filaments paralleled that of virions whereas spherical particles remained in moderate excess [8], [9]. Thus, subviral HBsAg particles exceed virions by a variable factor of 102-105 and can accumulate up to concentrations of several hundred micrograms per milliliter of serum [3].

Quantification of HBsAg was introduced more than 20years ago, but only recently has it been significantly improved by new automated quantitative assays [10]. Several studies suggest a new potential role of quantitative serum HBsAg in the prediction of virological response to antiviral therapy, at least in Peg-interferon treated patients [11], [12], [13]. HBsAg appears useful to identify non-responders as early as 12-24weeks after the beginning of treatment and to tailor treatment duration in responders [12], [13]. The correlations between HBsAg and HBV-DNA kinetics are complex and variable in the different treatment settings; the kinetics of the two parameters are dissociated in lamivudine treated patients and relapsers to Peg-interferon, but parallel in sustained responders to Peg-interferon [12], [13]. Preliminary reports on HBsAg and HBV-DNA serum levels in untreated acute and chronic hepatitis B cases confirm such a discrepancy, and little is known about their relative variations along the highly dynamic chronic HBV infection [14].

In this issue of the Journal, two manuscripts provide new insights into serum HBsAg levels during chronic HBV infection in Asian and European cohorts of HBV carriers. The novelty of the works of Nguyen et al. [15] and Jaroszewicz et al. [16] stems from their study on the correlations between HBsAg serum levels and the clinical and virologic features of chronic HBV carriers analysed in different phases of infection according to the most recent criteria. Overall, 434 chronic carriers were studied: 62 immune-tolerant carriers (IT), 103 HBeAg positive patients in the immune-clearance phase (IC), 118 HBeAg negative carriers in the non-/low replicative phase (LC), and 151 patients with HBeAg negative hepatitis (ENH). Two major findings are common in the two studies: (1) median HBsAg levels differ significantly during the 4 phases of HBV infection and decline progressively from IT (4.5-4.96log10IU/ml in Asian and European carriers) to LC (2.86-3.09log10IU/ml in Asian and European carriers); (2) HBsAg/HBV-DNA ratios are significantly higher in LC (1.05 Asian-1.17 European) as compared to all the others patients (ratios range 0.55-0.64). These findings entail that HBsAg secretion is highly dynamic and varies along chronic HBV infection both quantitatively and qualitatively. Accordingly, one intriguing and complex issue remains the correlation between HBsAg and HBV-DNA serum levels. In spite of an overall correlation in the European cohort (R=0.75, p<0.001), the two parameters show weaker or absent correlations when the different phases of HBV infection are analysed separately or by HBV genotype. A negative correlation is reported in genotype A HBeAg positive (IC, R=-0.24) and negative (ENH, R=-0.07) patients, a positive relation in genotype B, C and D ENH, in genotype B and C IT and in genotype A and D LC, but all the correlation coefficients are poor (R ranging from 0.29 to 0.57). On the contrary, in genotype B and C HBeAg positive patients (IC) HBsAg and HBV-DNA serum levels correlate significantly (p=0.0001) and with better coefficient (R=0.77), as well as in 12 European patients with acute hepatitis B (R=0.79). These data suggest direct interactions between HBV genotype, HBsAg serum level and viral load. Accordingly, genotype-specific patterns of expression of intracellular and extracellular viral DNA and antigens were shown by transfection of Huh7 [17]. In vitro, genotype A showed a sharp dissociation between HBsAg and HBV-DNA production, with the highest HBsAg secretion combined with the lowest HBV-DNA production in the culture medium [17]. Larger studies are needed to address the correlations between HBV genotypes and the dynamics of HBsAg serum levels during the different phases of HBV infection. In spite of the possible limitation of genotype interference, it is interesting to note that HBsAg and HBV-DNA serum levels showed their highest correlation in the early phases of immune clearance, namely in acute hepatitis B and in HBeAg positive CHB (IC) [15], [16]. These findings, together with the parallel kinetics of HBsAg and HBV-DNA in patients responding to Peg-IFN treatment [12], [13], suggest that virion and HBsAg antigen production correlate better when they are concordantly inhibited by a strong immune-response resulting in the efficient control of viral replication, namely HBeAg/anti-HBe or HBsAg/anti-HBs seroconversion. If the immune clearance does not succeed in the complete control of HBV infection, leading to HBsAg clearance and anti-HBs seroconversion, HBV infection evolves into the low replicative phase or HBeAg negative CHB. In both conditions, the discrepancy between HBV-DNA and HBsAg production may increase for several reasons but it is primarily due to the production of defective particles that outnumber the virions during the low replicative phase, as already shown in the older studies, where lower amounts of serum L-HBs (the hallmark of the surface protein of the virion and filaments) were found in non-viremic as compared to viremic HBV carriers [8], [9]. The higher HBsAg/HBV-DNA ratios found by Nguyen and Jaroszewicz in LC are consistent with the previous data, suggesting a relatively lower production of virions versus subviral HBs antigens in this subset of carriers. This might depend on a stronger inhibition of pre-genome transcription from intrahepatic cccDNA as compared to the envelope protein mRNAs, or to the defective secretion of virions as a consequence of the emergence of HBV mutants, which are selected by the long lasting immune pressure on the HBsAg gene that may deregulate HBsAg expression with an asymmetric production of S, M and L proteins [18], [19]. Indeed an inverse relationship was reported between serum HBsAg levels and the intrahepatic cytoplasmic storage of HBsAg (ground glass cells) [14]. In fact, overexpression of L-HBs can cause S protein to accumulate in the Golgi complex and to inhibit the secretion of HBsAg particles, as a proper stoichiometry between L and S proteins is required for the secretion of HBsAg and virions [18], [19]. Finally a role of integrated HBV-DNA in the alteration of HBsAg secretion was also advocated [20].

In conclusion, HBsAg serum levels are the resultant of the complex equilibrium between the virus and the host's immune system as well as the product of the transcription of specific mRNAs rather than viral replication. Thus, we may speculate that serum HBsAg is the indirect expression of transcriptionally active cccDNA rather than total intrahepatic cccDNA. Of course, we cannot exclude a role of integrated HBV-DNA in HBsAg synthesis; however, the evidence that HBsAg serum levels decline significantly with the duration of HBV infection, when the amount of integrated HBV-DNA is supposed to increase, weakens such a hypothesis. The substantial variations of total serum HBsAg in the different phases of HBV infection proposes quantitative HBsAg as a new diagnostic tool for the characterization of the HBV carrier in combination with HBV-DNA. The two HBV markers providing complementary information on the status of HBV infection (Fig. 1) may be very useful in clinical practice to define the specific condition of the single HBV carrier during the highly dynamic phases of chronic HBV infection, just as latitude and longitude allow to define the ship's position in the ocean. This will be of paramount importance to avoid the misclassification of an asymptomatic HBeAg negative CHB patient as an inactive carrier because of a single point serum test with normal transaminases and negative HBV-DNA caused by the typical intermittent disease profile of HBeAg negative CHB.



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lin12345

一个新的角色,表面的老标记
的肝脏的谈话会让

第52期,第4卷,页面475-477问题(4月2010年)


Brunetto Maurizia然而

肝脏的单位,大学附属医院的比萨、意大利


2010年2月1日发布在网上。

指的是文章:

型肝炎表面抗原水平在自然历史的慢性

乙型肝炎:2月17日的角度来看待亚洲,2010年

锡阮、亚历山大·汤普森,斯科特Bowden丰富多彩,凯瑟琳Croagh,莎莉贝尔,保罗v德斯蒙德·米利暗,斯蒂芬- a - Locarnini征收

肝脏病学杂志》上

2010年4月第52期,第33页。508-513发给4,页)

摘要| |全文期刊全文PDF(758 KB)


型肝炎表面抗原(HBsAg)水平在自然历史乙型肝炎病毒(HBV)-infection:欧洲的角度来看,2010年2月15日

杰Jaroszewicz,Beatriz卡尔斯Wursthorn称之为萨拉诺,Deterding,杰罗姆Schlue,Katja雷吉娜Raupach,罗伯特Flisiak,C.-Thomas啤酒,迈克尔,他Manns Wedemeyer页,Cornberg,马库斯

肝脏病学杂志》上

2010年4月第52期,第33页。514-522发给4,页)

摘要| |全文期刊全文PDF(1061 KB)


检测血清中的“澳大利亚抗原”,即B型肝炎表面抗原(HBsAg),是诺贝尔奖的发现,确定乙型肝炎病毒(HBV)关于40years以前的事了,到今日的标志HBsAg仍然是公然的HBV[1]、[2]。在表面的一个宽数组循环颗粒形式:主管virions(42nm粒子),20nm,丹麦直径细丝,20-22nm可变长度的球形颗粒,对应着空有缺陷病毒信封[3]。结果血清表面的不同组合三种蛋白质(小号,中号和大号),不管是糖化与否,都有规定,由一个单一的开放阅读框提供3 carboxy-terminal colinear HBsAg蛋白质的不同长度。小(S)的蛋白质(氨基酸)表达226家在最高水平上竞赛,占了主导地位在这两种virions和subviral粒子和分泌没有app的氨基酸残基在易位因其自组装能力与host-derived内脂肪细胞ER[4]。中间(M)蛋白(含55额外的pre-S2残留域)是受同样的启动子和也有类似的分泌,而大的转录调节蛋白(L)是由一个特殊但是疲软的发起人(pre-S1)[5]。乙型肝炎病毒表面蛋白(大)包含了pre-S2 L-HBs区和108-119额外的残留的pre-S1领域,都是一个重要的组成部分,也代表了virions和丝状10 - 20%的信封上的蛋白质。相比之下,L-HBs仅占2%的球形粒子实现22纳米[6],[7]。生产的复杂性和分泌表面已知自早期的研究表明一个更大的过剩subviral两细丝和球形颗粒出现在高度viremic HBeAg积极载体相比,低viremic携带者,谁anti-HBe积极的衰落的细丝virions相对应的球形粒子温和而仍在过量[8],[9]。因此,subviral HBsAg粒子通过一个变量因素超过virions的102-105和能积累到数百毫克的浓度为每毫升的血清[3]。


介绍了量化的超过20表面前,但是直到最近才有很大的改善新自动化定量测定[10]。几项研究显示出一种新的潜在作用的定量预测,对血清中乙肝病毒具有灭活作用,抗病毒治疗病毒应答,至少在长效干扰素治疗病人[11],[12],[13]。识别non-responders HBsAg显得有用早在12-24weeks后开始的治疗和个体化的治疗疗程的裁缝师[12],[13]。表面之间的相关关系,hbv - dna动力学是复杂的和可变的不同治疗环境;动力学的离解在这两个参数,拉米夫定治疗患者和relapsers长效干扰素,但与此同时持续现场和长效干扰素[12],[13]。初步报告,HBV - dna血清表面在未经治疗的急性和慢性乙型肝炎病例确定这种差异,很少有人了解他们的相对变化沿高度动态的慢性HBV感染[14]。


在这期杂志,提供新的见解,两个手稿在慢性HBV感染血清HBsAg水平在亚洲和欧洲的感染组HBV携带者。作品的新颖性的阮孙俐。[15]和Jaroszewicz孙俐。[16]来源于其学习在相互关系之上在表面和病例的临床及血清病毒学特征分析慢性HBV感染携带者在不同的发展阶段的感染根据最近的一项标准。总的来说,434慢性携带者进行了研究:62 immune-tolerant载体(它),103的患者在immune-clearance HBeAg积极阶段(IC)118 HBeAg负面携带者的非- /低replicative阶段(LC),和151例HBeAg负面肝炎(段的)。结果有两项主要的常见的两项研究1)平均水平显著不同的表面在四阶段的HBV和衰退逐步从它(4.5-4.96log10IU / ml在亚洲和欧洲的航空公司)(2.86-3.09log10IU LC / ml在亚洲和欧洲的航空公司);(2)HBsAg / HBV - dna比值显著增高Asian-1.17 LC(欧洲)为1.05比所有其他的病人(比率范围0.55-0.64)。这些结果需要,表面高度动态的变化而变化的分泌是沿着慢性HBV都进行定量定性。因此,一个有趣的和复杂的问题仍是之间的相关性,hbv - dna血清乙肝病毒具有灭活作用。尽管在欧洲一个全面的相关性(R = 0.75队列研究(p < 0.001),这两个参数相关性弱或者缺席时显示HBV感染的不同的阶段是个别分析或乙肝的基因型。报道了一种负相关基因一个HBeAg阳性(IC、R = -0.24)和负(段),R = -0.07病人中,有一个积极的关系在基因型B,C和D段,在基因型B和C,基因型A和D LC,但所有的相关系数(R从贫穷为0.29 0.57)。相反的,在基因型B和C HBeAg积极的患者(IC)HBsAg和hbv - dna血清显著相关(p = 0.0001),以更好的系数(R = 0.77),以及在12个欧洲急性乙型肝炎病毒(R = 0.79)。这些数据显示HBV基因型之间的相互作用,直接HBsAg血清水平和病毒载量。因此,基因型细胞内的表达模式和细胞外病毒DNA和抗原,表现的Huh7 transfection[17]。在体外实验,基因型的一个显示了强有力的分离HBsAg和hbv - dna生产,最高HBsAg分泌结合生产中最低的hbv - dna培养基[17]。需要更大型的研究HBV基因型地址之间的对应关系动态的过程中表面血清HBV感染的不同的阶段。尽管可能限制基因型干扰,有趣的是,要注意HBsAg和血清hbv - dna,展现了他们的关联度最高,在早期的阶段,也就是免疫清除HBeAg急性乙型肝炎和积极的慢乙肝(IC)[15]、[16]。这些发现,连同平行动力学的患者中,hbv - dna表面响应聚乙二醇干扰素治疗[12],[13],建议(成熟)粒子:生产相关抗原和表面时,更好地抑制他们concordantly依靠一个强大的immune-response造成有效控制病毒复制,即HBeAg / anti-HBe anti-HBs或HBsAg /血清转化率。如果免疫间隙不成功的完全控制,导致的HBV血清转化率和anti-HBs HBsAg间隙,HBV演变为低replicative相或HBeAg负慢乙肝。在两种状态下,HBV - dna和表面之间的差距,因为一些原因生产可能会增加,但它主要是由于生产的数量比virions有缺陷的粒子,在低replicative阶段,正如已经显示在过去的研究中,在低得多,血清L-HBs(的标志(成熟)粒子:表面蛋白的和丝状)被发现在non-viremic相比,viremic HBV携带者[8],[9]。高等HBsAg / hbv - dna比率发现Jaroszewicz由阮和LC是一致的,在以前的数据,这显示出了较低的生产与subviral virions HBs的抗原在这个子集航母。这可能取决于一个更强的抑制pre-genome转录肝内cccDNA相比,蛋白质mRNAs信封,或者有缺陷的分泌的后果virions HBV突变体的出现,这是选中的持久的免疫的压力可能接触表面HBsAg基因表达与非对称生产S、M和L蛋白质[18]、[19]。据报道确实逆关系之间的层次和血清HBsAg贮藏的肝内胞质(磨砂玻璃表面细胞)[14]。事实上,实验的L-HBs能引起S蛋白质积累高尔基联合体和抑制表面的分泌颗粒之间,作为一个适当的还原L和S蛋白分泌的要求和virions表面[18]、[19]。最后一个发挥综合hbv - dna的改变也主张HBsAg分泌物[20]。


总之,HBsAg血清是合成的错综复杂的均衡的病毒和宿主的免疫系统以及产品的具体mRNAs的转录而不是病毒的复制。因此,推测可能是间接表达血清乙肝病毒具有灭活作用的transcriptionally活跃而不是全肝内cccDNA cccDNA。当然,我们不能排除一个发挥综合HBV - dna在HBsAg合成;但是,证据表明HBsAg血清明显下降和英美的HBV的数量,当应该增加综合HBV - dna,弱化这一假设。实质性的变化在总血清HBsAg HBV的不同的阶段提出了定量HBsAg作为一种新的诊断工具,用以表征的HBV载体结合HBV - dna。这两个HBV标志物提供互补信息的状态HBV(图1),可能是非常有用的在临床实践中定义的具体情况单一载体在高度动态HBV感染的慢性HBV感染阶段,正如经度和纬度允许来定义这艘船的位置在大海中。这将是极为重要的,以避免错误分类的无症状的慢性乙肝病人为HBeAg消极无为载体,因为一个单点与正常transaminases血清检测,hbv - dna造成的负面典型剖面HBeAg间歇疾病负面慢乙肝。

lin12345

stw给的资料  找软件翻译的  可能有些语句不是很通顺 大家将就着看看吧

lin12345

StephenW

lin12345 发表于 2011-3-23 14:13
stw给的资料  找软件翻译的  可能有些语句不是很通顺 大家将就着看看吧

这个论文是意大利的好朋友, Stefano (MedHelp, alinia)介绍的.论文作者之一,
Maurizia Rossana Brunetto ,Liver Unit, University Hospital of Pisa, Italy 我相信是他的朋友.另一作者, Stephen A. Locarnini, 来自澳大利亚, 是HBV耐药专家.他最近去过中国, 已与中国
乙肝病毒科学家讨论过.