抗原提呈相关转运体基因多态性与HBV感染及HBV特异性CTL的相关性研究
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摘要
目的：
探讨中国北方地区人群抗原提呈相关转运体基因多态性与乙型肝炎病毒感染及HBV特异性CD8~+细胞毒性T淋巴细胞的相关性。
方法：
1．按照2000年9月在西安由中华医学传染病与寄生虫病学分会与肝病学分会联合修订的病毒性肝炎防治方案的诊断标准筛选110例HBV感染者，结合临床情况分为三组，即慢性活动性乙型肝炎组、乙肝肝硬化组、慢性无症状HBV携带组，同时设76例正常对照。
2．采用酶联免疫法测定乙型肝炎病毒系统，基因组DNA快速制备试剂盒提取抗凝血目的DNA，聚合酶链式反应-限制型内切酶多型性技术进行TAP2基因分型。
3．采用人类主要组织相容性复合物(HLA)A2的胞外段与HBcAg表位肽Tc18-27构建的四聚体结合流式细胞仪定量检测HBV感染者外周血中表位肽特异性的CD8~+CTL的数量，并以其占CD8~+细胞总数的百分比表示。
4．采用SPSS12.0统计软件进行统计学分析。HBV感染组、慢性活动性乙型肝炎组、乙肝肝硬化组、慢性无症状HBV携带组和正常对照组之间TAP2等位基因频率比较用x~2检验，采用方差分析比较不同TAP2基因型的HBV感染者之间外周血特异性CTL比率的差异，P＜0.05为有统计学意义。
结果：
1．110例HBV感染病例与正常对照组比较，发现TAP2-651纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.05)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
2．慢性活动性乙型肝炎组与正常对照组比较，发现慢性活动性乙型肝炎组TAP2-651的纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.01)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
3．乙肝肝硬化组与正常对照组比较，发现乙肝肝硬化组TAP2-651的纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.01)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
4．慢性无症状HBV携带组与正常对照组进行比较，发现慢性无症状HBV携带组TAP2-687的纯合多态基因型(TAP2-687Q/Q)频率显著低于正常对照组(P＜0.05)；TAP2-687的野生纯合基因型(TAP2-687S/S)频率显著高于正常对照组(P＜0.05)。
5．根据临床检测肝功指标ALT是否升高(＞40U/L为阳性)，将所有非正常对照样本进行分组，比较组间TAP2基因频率的差异。发现ALT＞40U/L组中：TAP2-651纯合多态基因型(TAP2-651C/C)频率显著低于ALT＜40U/L组(P＜0.01)；TAP2-687野生纯合基因型(TAP2-687S/S)频率显著低于ALT＜40U/L组(P＜0.05)。
6．TAP2-651三种基因型的慢性HBV感染者外周血HBV特异性CTL含量无显著性差异(P＞0.05)。
7．TAP2-687三种基因型的慢性HBV感染者外周血HBV特异性CTL含量无显著性差异(P＞0.05)。
结论：
1．TAP2-651纯合多态基因型(TAP2-651C/C)可能是HBV感染的抗性基因，且携带者感染HBV后不易出现乙肝的慢性化及乙肝后肝硬化。
2．TAP2-651杂合多态基因型(TAP2-651R/C)可能是HBV的易感基因，且携带者感染HBV后易出现乙肝的慢性化及易并发乙肝后肝硬化。
3．TAP2-687野生纯合基因型(TAP2-687S/S)可能对肝脏功能有保护作用，携带者感染HBV后易于出现无症状HBV携带状态。
4．TAP2-651和TAP2-687位点的基因多态性可能与慢性HBV感染者外周血中HBV特异性CTL的含量无关。
Objective:
To investigate the association among in the genetic polymorphisms of TAP2 and Chinese patients with hepatitis B virus infection and HBcAg specific CD8~+ cells.
Methods:
1. According to the definition of The Blue Print of Prevention and Cure of Virosis Hepatitis-2000, 110 patients with chronic active hepatitis B, hepatic cirrhosis or chronic asymptomatic HBV carriers were selected.Choose 76 healthy individuals as control group.
2. TAP2 gene genotypes were determined by means of PCR-RFLP and HBV was detected by means of ELISA.
3. HBVsCTL in whole blood samples of chronic hepatitis B patients were stained with soluble HLA-A2-HBV core 18-27 peptide tetrameric complex were counted by flow cytometry.
4. The results were analysisted by SPSS 12.0. The frequency of the genetic polymorphisms of TAP2 among in chronic active hepatitis B, hepatic cirrhosis, chronic asymptomatic HBV carriers and healthy control were compared by x~2 test; The proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients between different TAP2 genetypes were compared by F test. P < 0.05 were significantly.
Results:
1. In the HBV-infected patients, frequency of TAP2-651C/C was significantly lower than in healthy control group(P<0.05 ) and TAP2-651R/C was significantly higher than in healthy control group(p<0.05) .
2. In chronic active hepatitis B patients, frequency of TAP2-651C/C was significantly lower than in healthy control group (P<0.01) and TAP2-651R/C was significantly higher than in healthy control group (P<0.05).
3. In hepatic cirrhosis patients, frequency of TAP2-651C/C was significantly lower than in healthy control group (P<0.01 ) and TAP2-651R/C was significantly higher than in healthy control group (P<0.05).
4. In chronic asymptomatic HBV carrier, frequency of TAP2-687Q/Q was significantly lower than in healthy control group (P<0.05) and TAP2-687S/S was significantly higher than in healthy control group (P<0.05).
5. In the unmoral ALT group(ALT > 40U/L), frequency of TAP2-651C/C was significantly lower than in normal ALT group (P<0.01 ) ; Frequency of TAP2-687Q/Q was significantly lower than in normal ALT group (P<0.05).
6. There was not significantly different in the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients with three TAP2-651 genetypes (P>0.05) .
7. There was not significantly different in the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients with three TAP2-687 genetypes (P>0.05) .
Conclusion:
1. TAP2-651C/C gene type might be resistant to chronic active hepatitis B and hepatic cirrhosis.
2. TAP2-651R/C gene type might be associated with susceptibility of chronic active hepatitis B and hepatic cirrhosis.
3. TAP2-687S/S gene type might be associated with chronic asymptomatic HBV carrier state.
4. The genetic polymorphisms of TAP2-651 and TAP2-687 might be independent with the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients.
探讨中国北方地区人群抗原提呈相关转运体基因多态性与乙型肝炎病毒感染及HBV特异性CD8~+细胞毒性T淋巴细胞的相关性。
方法：
1．按照2000年9月在西安由中华医学传染病与寄生虫病学分会与肝病学分会联合修订的病毒性肝炎防治方案的诊断标准筛选110例HBV感染者，结合临床情况分为三组，即慢性活动性乙型肝炎组、乙肝肝硬化组、慢性无症状HBV携带组，同时设76例正常对照。
2．采用酶联免疫法测定乙型肝炎病毒系统，基因组DNA快速制备试剂盒提取抗凝血目的DNA，聚合酶链式反应-限制型内切酶多型性技术进行TAP2基因分型。
3．采用人类主要组织相容性复合物(HLA)A2的胞外段与HBcAg表位肽Tc18-27构建的四聚体结合流式细胞仪定量检测HBV感染者外周血中表位肽特异性的CD8~+CTL的数量，并以其占CD8~+细胞总数的百分比表示。
4．采用SPSS12.0统计软件进行统计学分析。HBV感染组、慢性活动性乙型肝炎组、乙肝肝硬化组、慢性无症状HBV携带组和正常对照组之间TAP2等位基因频率比较用x~2检验，采用方差分析比较不同TAP2基因型的HBV感染者之间外周血特异性CTL比率的差异，P＜0.05为有统计学意义。
结果：
1．110例HBV感染病例与正常对照组比较，发现TAP2-651纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.05)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
2．慢性活动性乙型肝炎组与正常对照组比较，发现慢性活动性乙型肝炎组TAP2-651的纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.01)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
3．乙肝肝硬化组与正常对照组比较，发现乙肝肝硬化组TAP2-651的纯合多态基因型(TAP2-651C/C)频率显著低于正常对照组(P＜0.01)；TAP2-651的杂合多态基因型(TAP2-651R/C)频率显著高于正常对照组(P＜0.05)。
4．慢性无症状HBV携带组与正常对照组进行比较，发现慢性无症状HBV携带组TAP2-687的纯合多态基因型(TAP2-687Q/Q)频率显著低于正常对照组(P＜0.05)；TAP2-687的野生纯合基因型(TAP2-687S/S)频率显著高于正常对照组(P＜0.05)。
5．根据临床检测肝功指标ALT是否升高(＞40U/L为阳性)，将所有非正常对照样本进行分组，比较组间TAP2基因频率的差异。发现ALT＞40U/L组中：TAP2-651纯合多态基因型(TAP2-651C/C)频率显著低于ALT＜40U/L组(P＜0.01)；TAP2-687野生纯合基因型(TAP2-687S/S)频率显著低于ALT＜40U/L组(P＜0.05)。
6．TAP2-651三种基因型的慢性HBV感染者外周血HBV特异性CTL含量无显著性差异(P＞0.05)。
7．TAP2-687三种基因型的慢性HBV感染者外周血HBV特异性CTL含量无显著性差异(P＞0.05)。
结论：
1．TAP2-651纯合多态基因型(TAP2-651C/C)可能是HBV感染的抗性基因，且携带者感染HBV后不易出现乙肝的慢性化及乙肝后肝硬化。
2．TAP2-651杂合多态基因型(TAP2-651R/C)可能是HBV的易感基因，且携带者感染HBV后易出现乙肝的慢性化及易并发乙肝后肝硬化。
3．TAP2-687野生纯合基因型(TAP2-687S/S)可能对肝脏功能有保护作用，携带者感染HBV后易于出现无症状HBV携带状态。
4．TAP2-651和TAP2-687位点的基因多态性可能与慢性HBV感染者外周血中HBV特异性CTL的含量无关。
Objective:
To investigate the association among in the genetic polymorphisms of TAP2 and Chinese patients with hepatitis B virus infection and HBcAg specific CD8~+ cells.
Methods:
1. According to the definition of The Blue Print of Prevention and Cure of Virosis Hepatitis-2000, 110 patients with chronic active hepatitis B, hepatic cirrhosis or chronic asymptomatic HBV carriers were selected.Choose 76 healthy individuals as control group.
2. TAP2 gene genotypes were determined by means of PCR-RFLP and HBV was detected by means of ELISA.
3. HBVsCTL in whole blood samples of chronic hepatitis B patients were stained with soluble HLA-A2-HBV core 18-27 peptide tetrameric complex were counted by flow cytometry.
4. The results were analysisted by SPSS 12.0. The frequency of the genetic polymorphisms of TAP2 among in chronic active hepatitis B, hepatic cirrhosis, chronic asymptomatic HBV carriers and healthy control were compared by x~2 test; The proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients between different TAP2 genetypes were compared by F test. P < 0.05 were significantly.
Results:
1. In the HBV-infected patients, frequency of TAP2-651C/C was significantly lower than in healthy control group(P<0.05 ) and TAP2-651R/C was significantly higher than in healthy control group(p<0.05) .
2. In chronic active hepatitis B patients, frequency of TAP2-651C/C was significantly lower than in healthy control group (P<0.01) and TAP2-651R/C was significantly higher than in healthy control group (P<0.05).
3. In hepatic cirrhosis patients, frequency of TAP2-651C/C was significantly lower than in healthy control group (P<0.01 ) and TAP2-651R/C was significantly higher than in healthy control group (P<0.05).
4. In chronic asymptomatic HBV carrier, frequency of TAP2-687Q/Q was significantly lower than in healthy control group (P<0.05) and TAP2-687S/S was significantly higher than in healthy control group (P<0.05).
5. In the unmoral ALT group(ALT > 40U/L), frequency of TAP2-651C/C was significantly lower than in normal ALT group (P<0.01 ) ; Frequency of TAP2-687Q/Q was significantly lower than in normal ALT group (P<0.05).
6. There was not significantly different in the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients with three TAP2-651 genetypes (P>0.05) .
7. There was not significantly different in the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients with three TAP2-687 genetypes (P>0.05) .
Conclusion:
1. TAP2-651C/C gene type might be resistant to chronic active hepatitis B and hepatic cirrhosis.
2. TAP2-651R/C gene type might be associated with susceptibility of chronic active hepatitis B and hepatic cirrhosis.
3. TAP2-687S/S gene type might be associated with chronic asymptomatic HBV carrier state.
4. The genetic polymorphisms of TAP2-651 and TAP2-687 might be independent with the proportions of HBVsCTL in whole blood samples of chronic hepatitis B patients.
引文
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[1] Christopher FH. [J]. Annu Rev Cell Biol, 1992, 8:67-113.
[2] Maya MC, Sophie JD, Henri C, et al.[J]. Immunogeneties, 1997, 45:280-281.
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[1] Christopher FH. [J]. Annu Rev Cell Biol, 1992, 8:67-113.
[2] Maya MC, Sophie JD, Henri C, et al.[J]. Immunogeneties, 1997, 45:280-281.
[3] Quadri SA, Singal DP. [J].Inununol Lett, 1998, 61(1):25-311.
[4] Brigitte LB, Robert Tampe. [J]. Physiological Reviews, 2002,82(1): 187-204.
[5] Vos JC, Reits EA, Wojeik JE, et al. [J]. Curr Biol, 2000, 10(1):127.
[6] Neumann L, Tampe R. [J]. J Mol Biol, 1999, 294(5):1203-1213.
[7] Gorbulev S, Abele R, Tampe R. [J]. Proc Natl Aead Sei USA, 2001, 98(7):3732-3737.
[8] Alberts P, Daumke O, Deverson EV, et al. [J]. Curr Biol, 2001, 11(4):242-251.
[9] Grandea AG, Van Kaer L. [J]. Trends Immunol, 2001, 22(4): 194-199.
[10] Purcell AW. [J]. Mol Immunol, 2000, 37(9):483-492.
[11] Sehiffer R, Baron J, Dagtekin G, et al. [J]. Inflamm Res, 2002, 51(8):403-408.
[12] Zhu K, Wang J, Zhu J, et al. [J].Oncogene, 1999, 18(54): 7740-7747.
[13] Reinhard O, Elena AA, Marga N, et al. [J]. Eur Immunol, 1995, 25: 2170-2176.
[14] Peter ME, Daniela R, Giulia G, et al. [J]. J Exp Med, 1995, 182: 1883-1885.
[15] Daniel S, Brusie V, Caillat ZS, et al. [J]. J Immunol, 1998, 161(2): 617-624.
[16] Saeki H, Kuwata S, Nakapawa H, et al. [J]. Hum Immunol, 1998, 59(8): 503-511.
[17] Neumann L, Tampe R. [J]. J Mol Biol, 1999, 294(5):1203-1213.
[18] Marga N, Hammerling GJ. [J].J Immunol, 1996, 157:5467-5477.
[19] Marga N, Sabine S, Elena AA, et al. [J]. J Immunol, 1996, 156: 2186-2195.
[20] Frank M, Elena AA, Markus P, et al. [J]. J Immunol, 1996, 156: 1756-1763.
[21] Lankat-Buttgereit B, Tample Rebert. [J]. FEBS Lett, 1999, 464(3): 108-112.
[22] Li S, Paulsson KM, Chen SW, et al. [J]. J Biol Chem, 2000, 275(3): 1581-1586.
[23] Tim E. [J]. Immunology Today, 1997, 18:375-379.
[24] Tianmin L. [J]. J Immunol, 1997, 159:5364-5371.
[25] Steven PL, Wendy AT, Neil WB, et al. [J].Eur J Immunol , 1996, 26:1875-1883
[26] Vambutas A, Bonagura VR, Steinberg BM. [J]. Clin Diagn Lab Immunol, 2000, 7(1):79-85.
[27] Sartakova ML, Konenkov VI, Shevehenko AV, et al. [J].Ter Arkh, 1999, 71(11):41-45.
[28] Inui S, Maeda K, Hua DR, et al. [J]. Int Immunol, 2002, 14(2): 189-200.
[29] Penfornis A, Tuomilehto-Wolf E, Faustman DL, et al. [J]. Hum Immunol, 2002, 63(1):61-70.
[30] Kobayashi T, Yokoyama I, Inoko H, et al. [J]. Hum Immunol , 2000, 61(7): 670-674.
[31] Seliger B, Maeurer M J, Ferrone S. [J]. Immunol Today, 2000, 21 (9):455-464.
[32] Yang T, MeNally BA, Ferrone S, et al. [J]. J Biol Chem, 2003, 278(17): 15291-15296.
[33] Ritz U, Drexler I, Sutter D, et al. [J]. J Immunol, 2003, 170(2): 941-946.