HBV宫内垂直传播与胎儿HBeAg的关系及胎盘CD35表达的研究
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摘要
第一部分:胎儿HBeAg与乙型肝炎病毒宫内感染关系的研究
研究背景及目的孕妇及新生儿乙肝病毒e抗原(HBeAg)阳性被认为是发生HBV宫内感染的高危因素,但HBeAg是否直接参与HBV宫内感染的发生尚无定论。本研究旨在通过检测HBeAg对胎儿免疫机制的影响来探讨探讨HBeAg在胎儿HBV宫内感染中所起作用。方法将HBsAg阳性孕妇分娩的新生儿50例分为两组:HBeAg阳性组(n=23)和HBeAg阴性组(n=27),分别采用双抗夹心酶联免疫免疫吸附法(DAS-ELISA)和病毒核酸扩增法(实时免疫荧光定量PCR方法)对孕妇静脉血和新生儿脐带血进行HBV血清学标志物和病毒含量的检测,采用DAS-ELISA法检测新生儿脐血中细胞因子白细胞介素—2(IL-2)、干扰素—γ(IFN-γ)、白细胞介素—4(IL-4)和白细胞介素—6(IL-6)水平,比较两组之间细胞因子水平的差异,同时将HBsAg阴性孕妇分娩的新生儿作为正常对照组。结果孕妇HBeAg阳性和阴性者分别为27例和23例,其新生儿脐血HBeAg阳性者分别为22例(81.48%)和1例(4.35%),HBeAg阳性孕妇的新生儿HBeAg阳性率显著高于HBeAg阴性孕妇的新生儿,差异具有显著性(P＜0.05);HBeAg阳性的新生儿(n=23)脐血IL-2、IFN-γ含量显著低于HBeAg阴性组(n=27)(26.08±5.12pg/ml vs 32.16±6.26pg/ml、12.14±1.89pg/ml vs17.20±5.39pg/ml,P＜0.05),而IL-4、IL-6水平则显著高于HBeAg阴性组(17.35±3.18pg/ml vs 11.03±2.64pg/ml、24.01±4.12pg/m vs 17.91±2.81pg/ml);正常对照组脐血IL-2、IFN-γ、IL-4、IL-6水平分别为(33.39±9.69pg/ml、19.27±3.80pg/ml、12.77±4.29pg/ml、18.35±3.24pg/ml),与HBeAg阴性组之间比较无统计学差异(P＞0.05)。结论胎儿体内的HBeAg可由母体传播而来并引起胎儿机体免疫失衡,致使机体不能及时有效地清除病毒,并且可导致胎儿免疫耐受,与HBV宫内感染的发生有密切关系。
第二部分:CD35在胎盘细胞表达的研究
研究背景及目的胎盘感染是引起母婴宫内垂直传播的高危因素,胎盘上的乙型肝炎病毒(HBV)是以HBsAg-抗HBs-补体C3复合物的形式存在的,这种复合物可沉积在滋养层细胞表面与Ig-G受体或者补体C3的受体结合而导致病毒在胎盘上的逐层传递,这对新生儿HBV宫内感染有重要意义;现有研究表明,胎盘组织上固有表达FcγRⅢ受体,可能对HBV宫内传播起到重要作用,但未有研究证实胎盘组织表达补体C3的受体的情况。补体C3的受体为补体受体1型CR1,即CD35,本试验通过检测在胎盘上CD35的表达情况,进一步明确HBV经胎盘途径传播的机制。方法选择HBsAg阳性孕妇6例,HBsAg阴性孕妇3例,剖宫产中取胎盘组织进行石蜡切片,采用用免疫组织化学SABC方法检测胎盘组织中CD35的表达。结果切片免疫组化染色显示CD35在胎盘组织血管中的红细胞及白细胞上表达呈阳性,而在胎盘组织滋养层和间质细胞中均未发现CD35的表达。结论胎盘组织不存在补体C3的受体,因此HBV感染胎盘时,抗原抗体补体复合物不是通过与补体C3的受体的结合而介导胎儿宫内传播的。
Part One:Study on the relationship between HBeAg of fetus and Intrauterine vertical transmission of hepatitis B virus
Abstract:Background and Objective HBeAg of the pregnant women and neonates is a high risk factor of Intrauterine vertical transmission of HBV,but it is unknown that if HBeAg is the direct reason of intrauterine infection of HBV.Our research is to study the mechanism of maternal-infant vertical transmission of hepatitis B virus by testing the influence of the HBeAg on the immunologic state of neonates.Methods 50 neonates born from positive HBsAg mother were divided into positive HBeAg group(n=23)and negative HBeAg group(n=27).By using diantibody sandwich enzyme linked immunosorbant assay(DAS-ELISA)and polymerase chain reaction(PCR),the serum HBV M and HBV DNA were detected in these pregnant women and neonates,IFN-γ,IL-2,IL-4 and IL-6 in these neonates were also detected by using DAS-ELISA,and theses cytokine levels were compared between the two groups,the control group(20 neonates born from negative HBsAg mothers)was set meanwhile.Results Pregnant women were divided into HBeAg group(27 cases)and negative HBeAg group(23 cases),the cases of positive HBeAg neonates of each group were 22(81.48%)and 1(4.35%),The number of positive HBeAg neonates born from positive HBeAg mothers was much more than it is of the positive HBeAg neonates born from negative HBeAg mothers,which had significant difference(P＜0.05);The IL-2,IFN-γlevels of the positive HBeAg group neonates were significant lower than those of the negitive HBeAg group(26.08±5.12pg/ml vs 32.16±6.26pg/ml,12.14±1.89pg/ml vs 17.20±5.39pg/ml),the IL-4,IL-6 levels were signifinant higher 17.35±3.18pg/ml vs 11.03±2.64pg/ml,24.01±4.12pg/ml vs 17.91±2.81pg/ml),and those of the control group were(33.39±9.69pg/ml,19.27±3.80pg/ml, 12.77±4.29pg/ml,18.35±3.24pg/ml),which had no significant difference with the nagative HBeAg group(P＞0.05).Conclusion The HBeAg of positive HBsAg pregnant woman can be transmitted into her neonates and causes immunity unbalance,which makes the organism can not clear the HBV in time and efficiently and brings on the immunotolerance of hepatitis B virus meanwhile,and these mechanisums above-mentioned have the close relationship with HBV maternal-infant vertical transmission.
Part two:study on the distribution in human placenta
Abstract:Background and Objective The placental tissue infection is a high risk factor of the occurrence of HBV intrauterine vertical transmission,the former researches show that the HBV in the placenta exist by means of HBsAg-anti-HBs-C3c complex,the later can attached to the cytoplasm of trophobasts and combined with the related acceptor of Ig-G or C3,which has the important significance of neonates' intrauterine infection;some studies discovered that FcγRⅢexisted in the placenta,which might be very important to the HBV intrauterine transmission,but there is no research to show that if there is acceptor of C3c in the placenta.The acceptor of C3 is CR1(CD35).Our experiment is to study the research of the HBV placenta infection by testing the expression of CD35 on the placenta.Methods 6 negative pregnant women and 3 normal women were studied in our study,placenta of which were detected by immunohistochemistry SABC to show the situation of CD35expression on placenta.Results the result showed that CD35 expressed on the blood cells of placenta blood vessels,but there was no CD35 discovered in placenta trophoblastic cells and interstitial cells.Conclusion CD35 does not exist in placenta and can not cause the HBV intrauterine infection by combining with the HBsAg-anti-HBsAg-C3c complex.
研究背景及目的孕妇及新生儿乙肝病毒e抗原(HBeAg)阳性被认为是发生HBV宫内感染的高危因素,但HBeAg是否直接参与HBV宫内感染的发生尚无定论。本研究旨在通过检测HBeAg对胎儿免疫机制的影响来探讨探讨HBeAg在胎儿HBV宫内感染中所起作用。方法将HBsAg阳性孕妇分娩的新生儿50例分为两组:HBeAg阳性组(n=23)和HBeAg阴性组(n=27),分别采用双抗夹心酶联免疫免疫吸附法(DAS-ELISA)和病毒核酸扩增法(实时免疫荧光定量PCR方法)对孕妇静脉血和新生儿脐带血进行HBV血清学标志物和病毒含量的检测,采用DAS-ELISA法检测新生儿脐血中细胞因子白细胞介素—2(IL-2)、干扰素—γ(IFN-γ)、白细胞介素—4(IL-4)和白细胞介素—6(IL-6)水平,比较两组之间细胞因子水平的差异,同时将HBsAg阴性孕妇分娩的新生儿作为正常对照组。结果孕妇HBeAg阳性和阴性者分别为27例和23例,其新生儿脐血HBeAg阳性者分别为22例(81.48%)和1例(4.35%),HBeAg阳性孕妇的新生儿HBeAg阳性率显著高于HBeAg阴性孕妇的新生儿,差异具有显著性(P＜0.05);HBeAg阳性的新生儿(n=23)脐血IL-2、IFN-γ含量显著低于HBeAg阴性组(n=27)(26.08±5.12pg/ml vs 32.16±6.26pg/ml、12.14±1.89pg/ml vs17.20±5.39pg/ml,P＜0.05),而IL-4、IL-6水平则显著高于HBeAg阴性组(17.35±3.18pg/ml vs 11.03±2.64pg/ml、24.01±4.12pg/m vs 17.91±2.81pg/ml);正常对照组脐血IL-2、IFN-γ、IL-4、IL-6水平分别为(33.39±9.69pg/ml、19.27±3.80pg/ml、12.77±4.29pg/ml、18.35±3.24pg/ml),与HBeAg阴性组之间比较无统计学差异(P＞0.05)。结论胎儿体内的HBeAg可由母体传播而来并引起胎儿机体免疫失衡,致使机体不能及时有效地清除病毒,并且可导致胎儿免疫耐受,与HBV宫内感染的发生有密切关系。
第二部分:CD35在胎盘细胞表达的研究
研究背景及目的胎盘感染是引起母婴宫内垂直传播的高危因素,胎盘上的乙型肝炎病毒(HBV)是以HBsAg-抗HBs-补体C3复合物的形式存在的,这种复合物可沉积在滋养层细胞表面与Ig-G受体或者补体C3的受体结合而导致病毒在胎盘上的逐层传递,这对新生儿HBV宫内感染有重要意义;现有研究表明,胎盘组织上固有表达FcγRⅢ受体,可能对HBV宫内传播起到重要作用,但未有研究证实胎盘组织表达补体C3的受体的情况。补体C3的受体为补体受体1型CR1,即CD35,本试验通过检测在胎盘上CD35的表达情况,进一步明确HBV经胎盘途径传播的机制。方法选择HBsAg阳性孕妇6例,HBsAg阴性孕妇3例,剖宫产中取胎盘组织进行石蜡切片,采用用免疫组织化学SABC方法检测胎盘组织中CD35的表达。结果切片免疫组化染色显示CD35在胎盘组织血管中的红细胞及白细胞上表达呈阳性,而在胎盘组织滋养层和间质细胞中均未发现CD35的表达。结论胎盘组织不存在补体C3的受体,因此HBV感染胎盘时,抗原抗体补体复合物不是通过与补体C3的受体的结合而介导胎儿宫内传播的。
Part One:Study on the relationship between HBeAg of fetus and Intrauterine vertical transmission of hepatitis B virus
Abstract:Background and Objective HBeAg of the pregnant women and neonates is a high risk factor of Intrauterine vertical transmission of HBV,but it is unknown that if HBeAg is the direct reason of intrauterine infection of HBV.Our research is to study the mechanism of maternal-infant vertical transmission of hepatitis B virus by testing the influence of the HBeAg on the immunologic state of neonates.Methods 50 neonates born from positive HBsAg mother were divided into positive HBeAg group(n=23)and negative HBeAg group(n=27).By using diantibody sandwich enzyme linked immunosorbant assay(DAS-ELISA)and polymerase chain reaction(PCR),the serum HBV M and HBV DNA were detected in these pregnant women and neonates,IFN-γ,IL-2,IL-4 and IL-6 in these neonates were also detected by using DAS-ELISA,and theses cytokine levels were compared between the two groups,the control group(20 neonates born from negative HBsAg mothers)was set meanwhile.Results Pregnant women were divided into HBeAg group(27 cases)and negative HBeAg group(23 cases),the cases of positive HBeAg neonates of each group were 22(81.48%)and 1(4.35%),The number of positive HBeAg neonates born from positive HBeAg mothers was much more than it is of the positive HBeAg neonates born from negative HBeAg mothers,which had significant difference(P＜0.05);The IL-2,IFN-γlevels of the positive HBeAg group neonates were significant lower than those of the negitive HBeAg group(26.08±5.12pg/ml vs 32.16±6.26pg/ml,12.14±1.89pg/ml vs 17.20±5.39pg/ml),the IL-4,IL-6 levels were signifinant higher 17.35±3.18pg/ml vs 11.03±2.64pg/ml,24.01±4.12pg/ml vs 17.91±2.81pg/ml),and those of the control group were(33.39±9.69pg/ml,19.27±3.80pg/ml, 12.77±4.29pg/ml,18.35±3.24pg/ml),which had no significant difference with the nagative HBeAg group(P＞0.05).Conclusion The HBeAg of positive HBsAg pregnant woman can be transmitted into her neonates and causes immunity unbalance,which makes the organism can not clear the HBV in time and efficiently and brings on the immunotolerance of hepatitis B virus meanwhile,and these mechanisums above-mentioned have the close relationship with HBV maternal-infant vertical transmission.
Part two:study on the distribution in human placenta
Abstract:Background and Objective The placental tissue infection is a high risk factor of the occurrence of HBV intrauterine vertical transmission,the former researches show that the HBV in the placenta exist by means of HBsAg-anti-HBs-C3c complex,the later can attached to the cytoplasm of trophobasts and combined with the related acceptor of Ig-G or C3,which has the important significance of neonates' intrauterine infection;some studies discovered that FcγRⅢexisted in the placenta,which might be very important to the HBV intrauterine transmission,but there is no research to show that if there is acceptor of C3c in the placenta.The acceptor of C3 is CR1(CD35).Our experiment is to study the research of the HBV placenta infection by testing the expression of CD35 on the placenta.Methods 6 negative pregnant women and 3 normal women were studied in our study,placenta of which were detected by immunohistochemistry SABC to show the situation of CD35expression on placenta.Results the result showed that CD35 expressed on the blood cells of placenta blood vessels,but there was no CD35 discovered in placenta trophoblastic cells and interstitial cells.Conclusion CD35 does not exist in placenta and can not cause the HBV intrauterine infection by combining with the HBsAg-anti-HBsAg-C3c complex.
引文
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[42]Yan YP,Xu DZ,Wang WL,Liu B,Liu ZH,Men K,Zhang JX,Xu JQ.The role of placenta in Hepatitis B vires intrauterine transmission[J].Zhong hua Fuchanke Zazhi(Chin J Obstet Gynecol),1999,34(7):392-395.
[43]Lucifora G,Calabro S,Carroccio G,Brigandi A.Immunocy tochemical HBsA g evidence in placents of asmptomatic carriermothers[J].A m J Obstet Gynecol,1988;159:839-842.
[44]王歆,徐德忠,刘蓬勃,等.免疫荧光双标记技术检测胎盘HBsAg-抗-HBs复合物[J].第四军医大学学报,2001,22(12):1125-1128.
[45]曹宝花,徐德忠,闫永平,等.补体C3c及免疫复合物在HBV宫内传播中作用[J].中国公共卫生,2006,22(1):70-71.
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[49]郦爱贞,肖小敏,陈新,等.FcγRⅢ在乙型肝炎病毒胎盘感染中作用的研究[J].中国遗传与优生杂志,2006,14(5):59-61.
[50]刘蓬勃,徐德忠,王歆,等.Fcγ受体在胎盘细胞的分布[J].第四军医大学学报,2005,22(5):459-461.
[51]程勇前,聂青和,周永兴,等.人胎盘滋养层细胞的分离培养及IgG FcγRⅢ在滋养层细胞的表达[J].2002,15(2):105-111.
[1]魏俊妮.新生儿HBV宫内感染的流行病学研究概况[J].山西医科大学学报,2004,35(5):525-528.
[2]Wang Z,Zhang J,Yang H,et al.Quantitative analysis of HBV DNA level and HBeAg titer in HBsAg positive mothers and their babies:HBsAg passage through the placenta and the rate of decay in babies[J].Med Virol,2003,71(3):360-366.
[3]白菡,赵桂珍.乙型肝炎病毒母婴传播机制及预防的研究进展.国外医学流行病学传染病学分册,2005,32(2):99-102.
[4]常文辉,闫永平,门可,等.HBV宫内传播危险因素的Meta分析[J].第四军医大学报,2003,24(24):2290-2292.
[5]刘蓬勃,徐德忠,王歆,等.Fcγ受体在胎盘细胞的分布[J].第四军医大学学报,2005,22(5):459-461.
[6]王歆,徐德忠,刘蓬勃,等.免疫荧光双标记技术检测胎盘HBsAg-抗-HBs复合物[J].第四军医大学学报,2001,22(12):1125-1128.
[7]曹宝花,徐德忠,闫永平,等.补体C3c及免疫复合物在HBV宫内传播中作用[J].中国公共卫生,2006,22(1):70-71.
[8]原琛利,王素萍,宋秀霞.正常和HBsAg阳性孕妇胎盘中TLR3检测分析[J].中国公共卫生.2007,23(3):287-288.
[9]冯永亮,王素萍,史晓红,等.PBMC中HBV cccDNA与HBV宫内感染关系的研究[J].现代预防医学,2005,32(3):192-194.
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[11]Badur S,Lazizi Y,Ugurfu M,et al.Transplacental passage of hepatitis B virus DNA from hepatitis B e ntigen-negative mothers and delayed immune response in newborns[J].Infect Dis,1994,169(3):704-706.
[12]Bocher Wo,Galum E,Marcus H,et al.Reduced hepatitis B virus surface antigen specific TH1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen specific antibodies in the trinera mouse[J].Reisner Hepatol,2000,31(2):480-487.
[13]Nishimura T,Oh ta A.A critical role for antigen-specific Th1 cells in acute liver injury in mice[J].J Immunol,1999,162(11):6503-6509.
[14]陈凯红,蒋祥虎,蒲云川.慢性乙肝患者外周血Th1/Th2类细胞因子变化的动态观察[J].临床消化病杂志,2006,18(6):345-347.
[15]Kawa K,Tsuda F,Takahashi K,et al.Materno fetal transmission of IgG-bound hepatitis B e antigen[J].Pediatr Res.1982,16(3):247-250.
[16]DR Milich.Is a function of他he secreted hepatitis B e antigen to induce immunologic tolerance in utero?[J].Proc Natl Acad Sci U S A,1990,87(17):6599-6603
[17]许红梅,彭明利,凌宁,等.母婴传播后母子体内乙型肝炎病毒前S/S基因变异研究[J].中华肝脏病杂志,2003,11(7):398-401.
[18]Moffat AS.Improving gene transfer into livestock.Science,1998,282(5394):1619-1620,
[19]王琰,闫永平,门可,等.乙型肝炎高效价免疫球蛋白联合乙型肝炎疫苗免疫母亲和婴幼儿的随访研究[J].中华流行病学杂志,2007,6(28):550-554.
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[22]张凤月,冯杏琳,申华.乙肝免疫球蛋白阻断HBV母婴垂直传播的临床研究[J].中国优生与遗传杂志,2006,14(6):5-6.
[23]郦爱贞,肖小敏,陈新,等.乙肝免疫球蛋白产前阻断HBV母婴传播的研究[J].广东医学,2006,27(6):841-842.
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[2]金仙玉,张心宇,刘善芬,等.外周血单个核细胞在乙型肝炎病毒母婴传播中的作用研究[J].中国妇产科临床,2001,2(3):146-148.
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[36]肖影,群章萍.妊娠各期乙型肝炎病毒携带的产妇胎盘感染的相关研究[J].江西医药,2005,40(10):664-665.
[37]闫永平,徐德忠,王福生.乙型肝炎病毒宫内感染的机制[J].第四军医大学学报,2001,22(6):548-550.
[38]王雪萍,徐德忠,李远贵,等.HBsAg进入体外培养的人绒毛膜滋养层细胞的初步研究[J].第一军医大学学报,2003,23(1):16-20.
[39]李铁钢,王素萍,李淑珍,等.HBsAg阳性孕妇胎盘HBV感染状况及危险因素[J].中国公共卫生,2005,21(2):165-166.
[40]刘颖琳,张建平,张睿,等.乙型肝炎病毒感染胎盘的免疫组织病理学研究[J].中国妇产科杂志,2002,37(5):278-280.
[41]乔云波,于爱莲,邹威中,等.胎盘HBV感染病理形态学研究[J].济宁医学院院报,2005,28(4):28-29.
[42]Yan YP,Xu DZ,Wang WL,Liu B,Liu ZH,Men K,Zhang JX,Xu JQ.The role of placenta in Hepatitis B vires intrauterine transmission[J].Zhong hua Fuchanke Zazhi(Chin J Obstet Gynecol),1999,34(7):392-395.
[43]Lucifora G,Calabro S,Carroccio G,Brigandi A.Immunocy tochemical HBsA g evidence in placents of asmptomatic carriermothers[J].A m J Obstet Gynecol,1988;159:839-842.
[44]王歆,徐德忠,刘蓬勃,等.免疫荧光双标记技术检测胎盘HBsAg-抗-HBs复合物[J].第四军医大学学报,2001,22(12):1125-1128.
[45]曹宝花,徐德忠,闫永平,等.补体C3c及免疫复合物在HBV宫内传播中作用[J].中国公共卫生,2006,22(1):70-71.
[46]Simister N E,Storycm,Chen HL,et al.An IgG transporting Fc receptor expressed in the syncytiotrophoblast of human placenta[J].EurJ Immunol,1996,26:1527-1531.
[47]Brigh t NA,Ock lefo rd CD,A nwar W.Ontogeny and distribution of Fc gamma receptors in the human placenta,transport or immune surveillance[J].J A nat,1994,184(2):297-308.
[48]Nishikiori.N,Koyama M,Kikuchi T,et al.Membrane-spanning Fc gamma receptor Aisoform expressed in human placental trophoblasts[J].A m J Reprod Immunol,1993,29(1):17-25.
[49]郦爱贞,肖小敏,陈新,等.FcγRⅢ在乙型肝炎病毒胎盘感染中作用的研究[J].中国遗传与优生杂志,2006,14(5):59-61.
[50]刘蓬勃,徐德忠,王歆,等.Fcγ受体在胎盘细胞的分布[J].第四军医大学学报,2005,22(5):459-461.
[51]程勇前,聂青和,周永兴,等.人胎盘滋养层细胞的分离培养及IgG FcγRⅢ在滋养层细胞的表达[J].2002,15(2):105-111.
[1]魏俊妮.新生儿HBV宫内感染的流行病学研究概况[J].山西医科大学学报,2004,35(5):525-528.
[2]Wang Z,Zhang J,Yang H,et al.Quantitative analysis of HBV DNA level and HBeAg titer in HBsAg positive mothers and their babies:HBsAg passage through the placenta and the rate of decay in babies[J].Med Virol,2003,71(3):360-366.
[3]白菡,赵桂珍.乙型肝炎病毒母婴传播机制及预防的研究进展.国外医学流行病学传染病学分册,2005,32(2):99-102.
[4]常文辉,闫永平,门可,等.HBV宫内传播危险因素的Meta分析[J].第四军医大学报,2003,24(24):2290-2292.
[5]刘蓬勃,徐德忠,王歆,等.Fcγ受体在胎盘细胞的分布[J].第四军医大学学报,2005,22(5):459-461.
[6]王歆,徐德忠,刘蓬勃,等.免疫荧光双标记技术检测胎盘HBsAg-抗-HBs复合物[J].第四军医大学学报,2001,22(12):1125-1128.
[7]曹宝花,徐德忠,闫永平,等.补体C3c及免疫复合物在HBV宫内传播中作用[J].中国公共卫生,2006,22(1):70-71.
[8]原琛利,王素萍,宋秀霞.正常和HBsAg阳性孕妇胎盘中TLR3检测分析[J].中国公共卫生.2007,23(3):287-288.
[9]冯永亮,王素萍,史晓红,等.PBMC中HBV cccDNA与HBV宫内感染关系的研究[J].现代预防医学,2005,32(3):192-194.
[10]Lo YMD,Lau TK,Chan LYS,et al.Quantitative analysis of the bidirectional fetomaternal transfer of nucleated cells and plasma DNA[J].Clin Chem,2000,46:1301-1309.
[11]Badur S,Lazizi Y,Ugurfu M,et al.Transplacental passage of hepatitis B virus DNA from hepatitis B e ntigen-negative mothers and delayed immune response in newborns[J].Infect Dis,1994,169(3):704-706.
[12]Bocher Wo,Galum E,Marcus H,et al.Reduced hepatitis B virus surface antigen specific TH1 helper cell frequency of chronic HBV carriers is associated with a failure to produce antigen specific antibodies in the trinera mouse[J].Reisner Hepatol,2000,31(2):480-487.
[13]Nishimura T,Oh ta A.A critical role for antigen-specific Th1 cells in acute liver injury in mice[J].J Immunol,1999,162(11):6503-6509.
[14]陈凯红,蒋祥虎,蒲云川.慢性乙肝患者外周血Th1/Th2类细胞因子变化的动态观察[J].临床消化病杂志,2006,18(6):345-347.
[15]Kawa K,Tsuda F,Takahashi K,et al.Materno fetal transmission of IgG-bound hepatitis B e antigen[J].Pediatr Res.1982,16(3):247-250.
[16]DR Milich.Is a function of他he secreted hepatitis B e antigen to induce immunologic tolerance in utero?[J].Proc Natl Acad Sci U S A,1990,87(17):6599-6603
[17]许红梅,彭明利,凌宁,等.母婴传播后母子体内乙型肝炎病毒前S/S基因变异研究[J].中华肝脏病杂志,2003,11(7):398-401.
[18]Moffat AS.Improving gene transfer into livestock.Science,1998,282(5394):1619-1620,
[19]王琰,闫永平,门可,等.乙型肝炎高效价免疫球蛋白联合乙型肝炎疫苗免疫母亲和婴幼儿的随访研究[J].中华流行病学杂志,2007,6(28):550-554.
[20]Centers for disease control and prevention.Recommended childhood immunization schedule-United States.2000.MMWR Morb Mortal Wkly Rep,2000,49(2):35-38.
[21]Huang K,Lin S.Nationwide caccination:a succestory in Taiwan.Vaccine,2000,18(1):35-38.
[22]张凤月,冯杏琳,申华.乙肝免疫球蛋白阻断HBV母婴垂直传播的临床研究[J].中国优生与遗传杂志,2006,14(6):5-6.
[23]郦爱贞,肖小敏,陈新,等.乙肝免疫球蛋白产前阻断HBV母婴传播的研究[J].广东医学,2006,27(6):841-842.
[24]Moodley J,Moodley D,Pillay K,et al.Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type-1 infected pregnant women and their offspring[J].Infect Dis,1998,178(5):1327-1333.
[25]Van Nunen AB,de Man RA,Heijtink RA,et al.Lamivudine in the last 4weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients[J].Hepatol,2000,32(6):1040-1041.
[26]Yang H I,Lu S N,Liaw Y F,et al.Hepatitis B antigen and the risk of hepatocellullular carcinoma[J].N Engl J Med,2002(347):168-174.