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上海肝病在线 Shanghai Liver Diseases' Online

从仅抗HBc抗体/和抗HBe抗体阳性的HBV变异株感染谈----治疗性复合HBV系列疫苗

今天门诊，来了一位老者病友，查HBV-M示抗HBC抗体和抗HBE抗体阳性而肝功能持续异常，B超示肝硬化样改变。有肝掌，老者病友的要求是确排乙肝。因此开HBV DNA（PCR）和进口二对半检测确排HBV变异株感染是首要任务。

傍晚返家，一刚产后二月余的产妇来电咨询，说小三阳怀孕并后三月HBV特异丙球肌注，但生产时检测胎脐血发现脐血大三阳，小孩生后接种乙肝疫苗后，1个半月后查血竟是HBV DNA阳性（只定性而不定量，PCR法与否不知）和抗HBC抗体阳性而HBS AG和HBE AG却阴性，要我分析原因并提出对策。我的意见：1）HBS AG和HBE AG阴性而HBV DNA阳性和抗HBC抗体阳性的原因可能有A）乙肝疫苗接种致HBV的S区和E区均发生基因变异而致HBS AG和HBE AG阴性而HBV DNA阳性和抗HBC抗体阳性，此种可能性极大；B）检测不灵敏/敏感，仍有低滴度的HBS AG和HBE AG而未测出，此种可能较小；C）HBV DNA检测假阳性，但此种可能极少；2）诊断处理方法是重新检测二对半和HBV DNA（PCR法），确排HBV变异可能；3）治疗处理方法是采用治疗性疫苗（据病友说其附近一家医院有此治疗性疫苗卖（10元/支？？？？---乙肝预防性疫苗吧？真的，据我所知，治疗性疫苗目前没有商业性药物供应，应免疫供科研试验的，故此家医院的治疗性疫苗可能有假药之嫌吧）。

国内外进一步研究表明，只有抗HBC抗体高滴度者与HBV感染有关，而低滴度的抗HBC抗体只表明感染过HBV而不表示仍有HBV感染。

但不可否认，随着HBV疫苗与乙肝丙球的应用，使用此法治疗的HBV感染者及其所产的小孩采用上述方法处理其产生HBV变异株的病例数将不断增加，因此新的治疗方法有待研究与开发，而治疗性复合HBV系列疫苗因其激发／产生多克隆、多位点（针对HBV S、前S1、前S2、C/E、X、HBV DNA多聚酶等多处、多位点）、强力和全面（细胞与体液）的免疫功能，故对各种HBV感染有治疗效果。其对ＨＢＶ亦有预防效果，但大材小用了。

国内外关于仅抗HBC抗体阳性的HBV变异株感染的报道很多，部分英文文献参见下列。

Gastroenterology 2002 Mar;122(3):614-24

Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen.

Lau GK, Suri D, Liang R, Rigopoulou EI, Thomas MG, Mullerova I, Nanji A, Yuen ST, Williams R, Naoumov NV.

BACKGROUND & AIMS: Impaired T-cell reactivity is believed to be the dominant cause of chronic hepatitis B virus (HBV) infection. We characterized HBV-specific T-cell responses in chronic hepatitis B surface antigen carriers who received bone marrow from HLA-identical donors with natural immunity to HBV and seroconverted to antibody to hepatitis B surface antigen. METHODS: T-cell reactivity to HBV antigens and peptides was assessed in a proliferation assay, the frequency of HBV core- and surface-specific T cells was quantified directly by ELISPOT assays, and T-cell subsets were analyzed by flow cytometry. RESULTS: CD4+ T-cell reactivity to HBV core was common in bone marrow donors and the corresponding recipients after hepatitis B surface antigen clearance, whereas none reacted to surface, pre-S1, or pre-S2 antigens. Furthermore, CD4+ T cells from donor/recipient pairs recognized similar epitopes on hepatitis B core antigen; using polymerase chain reaction for the Y chromosome, the recipients' CD4+ T lymphocytes were confirmed to be of donor origin. The frequency of core-specific CD4+ and CD8+ T cells was several-fold higher than those specific for surface antigen. CONCLUSIONS: This study provides the first evidence in humans that transfer of hepatitis B core antigen-reactive T cells is associated with resolution of chronic HBV infection. Therapeutic immunization with HBV core gene or protein deserves further investigation in patients with chronic hepatitis B.

精采华丽篇：接受天然HBV免疫的供体进行BMT致HBV感染者的HBS AG清除，其HBV清除作用与HBC AG特异性TH/CD4T细胞从天然HBV免疫的供体过继给HBV感染的受体有密切关系，即天然HBV免疫的供体的HBC AG特异性TH/CD4T细胞在受体内长期存在于受者体内并发挥其抗HBV免疫的免疫调控作用

J Virol 1995 Jun;69(6):3358-68

Activation of a heterogeneous hepatitis B (HB) core and e antigen-specific CD4+ T-cell population during seroconversion to anti-HBe and anti-HBs in hepatitis B virus infection.

Jung MC, Diepolder HM, Spengler U, Wierenga EA, Zachoval R, Hoffmann RM, Eichenlaub D, Frosner G, Will H, Pape GR.

Institute for Immunology, University of Munich, Germany.

Overcoming hepatitis B virus infection essentially depends on the appropriate immune response of the infected host. Among the hepatitis B virus antigens, the core (HBcAg) and e (HBeAg) proteins appear highly immunogenic and induce important lymphocyte effector functions. In order to investigate the importance of HBcAg/HBeAg-specific T lymphocytes in patients with acute and chronic hepatitis B and to identify immunodominant epitopes within the HBcAg/HBeAg, CD4+ T-cell responses to hepatitis B virus-encoded HBcAg and HBcAg/HBeAg-derived peptides were studied in 49 patients with acute and 39 patients with chronic hepatitis B. The results show a frequent antigen-specific CD4+ T-cell activation during acute hepatitis B infection, a rare HBcAg/HBeAg-specific CD4+ T-cell response among HBeAg+ chronic carriers, and no response in patients with anti-HBe+ chronic hepatitis. An increasing CD4+ T-cell response to HBcAg/HBeAg coincides with loss of HBeAg and hepatitis B virus surface antigen (HBsAg). Functional analysis of peptide-specific CD4+ T-cell clones revealed a heterogeneous population with respect to lymphokine production. Epitope mapping within the HBcAg/HBeAg peptide defined amino acids (aa) 1 to 25 and aa 61 to 85, irrespective of the HLA haplotype, as the predominant CD4+ T-cell recognition sites. Other important sequences could be identified in the amino-terminal part of the protein, aa 21 to 45, aa 41 to 65, and aa 81 to 105. The immunodominant epitopes are expressed in both proteins, HBcAg and HBeAg. Our findings lead to the conclusion that activation of CD4+ T lymphocytes by HBcAg/HBeAg is a prerequisite for viral elimination, and further studies have to focus on the question of how to enhance or induce this type of T-cell response in chronic carriers. The immunodominant viral sequences identified may have relevance to synthetic vaccine design and to the use of peptide T-cell sites as immunotherapeutic agents in chronic infection.

精采篇：HBV清除作用与HBC AG/HBe Ag特异性TH/CD4T细胞激活有密切关系，指示今后的HBV治疗性疫苗应重点注意激活机体的针对HBV的C/E区抗原的免疫作用

Zhonghua Yu Fang Yi Xue Za Zhi 1998 Jan;32(1):7-9

[Studies on hepatitis B virus infection in blood donors with positive anti-HBc and negative HBsAg] [Article in Chinese]

Ren F, Li H, Zhao H.

Beijing Red Cross Blood Center.

OBJECTIVE: To study if it is necessary to screen for core antibody against hepatitis B (anti-HBc) to prevent post-transfusion hepatitis B and what is its criteria for screening. METHODS: Relationship between the titer of anti-HBc and HBV DNA in blood from qualified donors by routine testing was conducted. HBV DNA was detected in 297 units of blood with anti-HBc at various titers by immuno-nested polymerase chain reaction (RT-PCR). RESULTS: HBV DNA was detected in one of four units of blood with positive anti-HBc at a dilution of equal to or greater than 1:128, and no HBV DNA was detected in other 75 units of blood with a dilution of anti-HBc less than 1:128. There was significant relationship between HBV DNA and the titer of anti-HBc. No HBV DNA was detected in 218 units of blood with both positive anti-HBc and anti-HBs and in 50 units with negative anti-HBc. Detection rate of HBV DNA in blood with positive anti-HBc was only 0.34% (1/297). CONCLUSION: Blood containing higher titer of single anti-HBc may be infectious. It is suggested that sensitivity of the reagents for detecting HBsAg currently used (1 ng/ml) be improved with the limited budget.

PMID: 10322742

Transplantation 1997 Dec 15;64(11):1582-4

Infectivity of hepatic allografts with antibodies to hepatitis B virus.

Dodson SF, Issa S, Araya V, Gayowski T, Pinna A, Eghtesad B, Iwatsuki S, Montalvo E, Rakela J, Fung JJ. Thomas E.

Starzl Transplantation Institute, Pittsburgh, Pennsylvania 15213, USA.

BACKGROUND: Since suitable recipients for hepatic allografts from donors with antibodies to hepatitis B virus (HBV) have not been determined, a review of our 7-year experience with donors positive for hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), or both was undertaken. METHODS: Recipients of hepatic allografts from donors with antibodies to HBV were identified by a retrospective review of procurement records and screened for HBV infection. RESULTS: From January 1, 1990, to January 1, 1997, 2578 liver transplants were performed and 140 (5.4%) recipients received an allograft from a donor with antibodies to HBV. Twenty-five of 48 recipients of a hepatic allograft from a donor positive only for anti-HBs were screened and none developed HBV infection. Twenty-five of 41 naive recipients of a hepatic allograft from an anti-HBc positive donor were screened and 18/25 (72%) developed HBV infection. Four of these 18 naive recipients with HBV infection received an allograft from a donor positive for both anti-HBc and anti-HBs. Seven of 13 anti-HBs-positive recipients of an allograft from an anti-HBc-positive donor were screened and none developed HBV infection. Fifteen of 16 recipients positive only for anti-HBc who received a hepatic allograft from an anti-HBc-positive donor were screened and 2/15 (13%) developed HBV infection. CONCLUSIONS: Hepatic allografts from donors positive only for anti-HBs do not transmit HBV infection. Hepatic allografts from anti-HBc-positive donors frequently transmit HBV infection to naive recipients regardless of the donor anti-HBs status, and antiviral prophylaxis may be indicated. Anti-HBs-positive recipients appear resistant to HBV infection after orthotopic liver transplantation with an allograft from an anti-HBc-positive donor. Recipients positive only for anti-HBc infrequently develop HBV infection when transplanted with an allograft from an anti-HBc-positive donor; however, HBV prophylaxis may be justified.

PMID: 9415560