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研究生:仇琍茵
論文名稱:免疫遺傳因子對B型肝炎病毒自然感染及疫苗注射後表面抗體反應之家族病例對照先驅研究
論文名稱(外文):Immunogenetic Basis of HBV Vaccine Responsiveness and HBV Natural Infection : a Pilot Study of Family Case-Control Study
指導教授:何美鄉何美鄉引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:流行病學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:1999
畢業學年度:87
語文別:英文
論文頁數:89
中文關鍵詞:B型肝炎病毒家族病例對照研究連鎖不平衡分析免疫逃避突變人類白血球組織相容性抗原
外文關鍵詞:HBVfamily case-control studyTransmission disequilibrium testVaccine-induced immune escape mutantHuman Leukocyte Antiden
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  背景:台灣地區實施B型肝炎疫苗接種以來,仍舊有一定比例的疫苗反應不良者存在,且在接種疫苗的族群中有1-3%仍會成為B型肝炎表面抗原帶原者。在先前之研究中已知疫苗反應因種族而異。另外許多其他的研究也顯示一些免疫遺傳因子與B型肝炎慢性帶原有關。為了探討遺傳因子對於B型肝炎疫苗失效的影響,本研究利用兩種研究設計分別進行研究,依其研究對象的選取可分為家族病例對照研究及族群相關性研究。
  研究對象:本研究從台灣地區北、中、南、東四縣市共收集了106位接種過疫苗之兒童,包括帶原者、感染過之非帶原者、疫苗低及高反應者等四類指標個案(proband)及其家屬261人進行家族病例對照研究,初步分析遺傳因素與B型肝炎自然感染間的關係。另外,並從南投信義鄉選取357位接種過B型肝炎疫苗的3-6歲兒童,探討遺傳因素對B型肝炎疫苗反應的影響。
  研究方法:研究個案皆以結構式問卷收集其基本的人口學資料,並由地方衛生單位檔案確認其疫苗接種狀況。B型肝炎血清學狀況是以酵素免疫分析法(enzyme linked immunosorbant assay),偵測其血漿中B型肝炎表面抗原(HBsAg)、抗B型肝炎表面抗原抗體(anti-HBs)效價、及抗B型肝炎病毒核心IgG抗體(anti-HBc),而B型肝炎病毒基因序列則是以聚合脢連鎖反應及核酸序列分析定型。HLA -A, -B, -DRB1及TNF-□ promoter的基因多型性是利用特異核酸序列探針雜交(sequence-specific oligonucleotide probe hybridization method)的方式定型。
  結果:本研究再次在另一族群中發現布農族原住民兒童對於B型肝炎疫苗抗體反應效價較鄰近的漢族兒童為低(Mantel-Haenszel test for trend, P=0.02)。而以此布農族兒童做其HLA及B型肝炎表面抗原抗體效價分析顯示,HLA-A2與增加抗體反應有關係(Pc=0.001)。同時HLA-A2也在家族病例對照研究中,發現與產生較高的抗體有關係,並且經由連鎖不平衡分析(Transmission disequilibrium test)也顯示了相同的結果。另外,分析家族病例對照研究中的帶原個案時則發現,帶有HLA-A2基因的兒童其較容易帶有免疫逃避突變種的B型肝炎病毒。除此之外,HLA-DRB1*14則是被發現與帶原有關,且在疫苗反應良好的指標個案中並無此種基因型存在。
  結論:本研究顯示遺傳因素對於B型肝炎慢性帶原及疫苗反應確實有其貢獻。若以HLA做為遺傳因子,則可發現HLA-A2與免疫系統中B細胞的免疫反影應有關係,因此在進行疫苗計劃後,此種與抗體反應有關的現象會日益明顯,且其對於增加免疫逃脫病毒株的出現非常需要做更進一步的探討,以期對未來的疫苗接種計劃有所改善。另外,在先前的研究中曾經有報HLA-DRB1*14與疫苗反應不良有關,而在本研究中則首次發現其與慢性帶原有關,此種在台灣原住民中佔有很高比例的基因型,應值得對其機轉再繼續作深入的研究。


  Background: While the hepatitis B virus (HBV) mass vaccination program has achieved an initial success, a small fraction of vaccine failure still occurs. In order to investigate whether the genetic determinants for vaccine failure (i.e. vaccine unresponsivenes and HBV persistent infection) exist, we conducted a family casecontrol study and a population based serosurvey to explore the importance of genetic basis.
  Subjects: In the family case-control study, 261 family members of the 106 proband children (belong to carriers, noncarriers, and lower responders or higher responders to HBV vaccination), including multiple ethnic groups of Han and several indigenous minorities in Taiwan, were recrujited. In the population based study, 357 fully vaccinated Pulong children, aged 3-6 years old, were recruited from the serosurvey of Nanto Indigenous Village.
  Methods: All HBV serological markers were examined by enzyme linked immunosorbant assay (ELISA) and some by radioimmunoassay (RIA). HBV DNA from plasma was detected by polymerase chain reaction (PCR). HLA class I (-A,-B), HLA class II (-DRB1), and polymorphism of TNF-□ promoter (-238,-308) were genotyped by sequence-specific oligonucleotide probe hybridization method (PCR-SSOP) and some verified by DNA sequence analysis.
  Results: In the population based study, anti-HBs titers among HBsAg seronegative Pulong children were lower than that of Han childern (Mantel- Haenszel test for trend, P=0.02). The frequency of HLA-A02 allele was noted to be positively correlated with a higher anti-HBs antibody level in the Pulong minority children, yet no specific A02 alleles were prevail. In the family casecontrol study, the potential shared genetic susceptibility of family members was studied by genotyping HLA for each proband child and their family members. The frequency of HLA-A02 allele was found to be higher among vaccinated children with a higher level of anti-HBs (Chi-sqaure test, P=0.00024; Corrected Pc=0.0012) and further substantiated in the TDT analysis. In addition, the frequency of HLA-DRB1*14 was significantly higher in carrier children (50%) but underrepresented in the high anti-HBs responder group (0%). This result was also supported by the examination with the transmission disequilibrium test (TDT) among child/parents pairs (McNemar's test, P=0.01; P=0.04). When analyzed the HBV genotype in the carrier probands, a significantly association between HLA-A02 allele and HBV 'a' determinant variants was found (Fisher exact method, P=0.012).
  Conclusion: We concluded that genetic predisposition to vaccine response and chronic HBV infection exits. HLA-A2 is associated with antibody response to HBV vaccination and is associated with the occurrence of immune escape HBV variants. Via what mechanism that HLA-A2 might link to B cell response remains to be elucidated. Furthermore, this is the first study to identify the correlation between HLA-DRB1*14 and chronic HBV infection in addition to HBV vaccine unresponsiveness. Understanding the genetic basis for HBV vaccine response and HBV chronic infection could provide potential means to improve HBV infection control in targeted infection.

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