2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/644084摘要：B型肝炎病毒(HBV)前表面抗原(Pre-S)蛋白含有B細胞及T細胞的epitopes在宿主對病毒的免疫認知及反應上有重大角色。研究發現這些immune epitopes改變，可能造成宿主對HBV之T細胞及B細胞免疫反應減弱。Pre-S區基因的突變或刪除常見於成人慢性B型肝炎感染、猛爆性肝炎及肝癌患者，最近的研究顯示已接種過疫苗但仍有潛隱性HBV感染者中可發現Pre-S基因變異的HBV。我們在過去1984~2004年間，在台北市相同的地區作了5次兒童B型肝血清流行病學之調查。第一年將所有HBsAg陰性，但anti-HBc / anti-HBs陽性學童以聚合酶連鎖反應法找出所有HBV DNA陽性者並以直接定序法研究其Pre-S區有何種變異存在。藉此大規模的研究可真正了解台灣在全面性免疫預防接種後，究竟有多少潛隱性HBV感染之存在，並重新了解全面疫苗接種之真正效益。本計畫第二年，將研究在兒童的猛暴型B型肝炎，急性自癒型B型肝炎及其可能感染源其Pre-S變異產生的狀況以了解此變種在導致肝細胞嚴重受損之角色。也將研究長期追蹤的慢性B型肝炎病毒感染兒童，其Pre-S突變種自發性產生的狀況以及與anti-HBe血清轉換及肝炎嚴重程度之關聯，以了解在兒童慢性HBV感染自然過程中其在宿主病毒互動中出現的意義。本計畫第三年將研究嬰兒免疫預防接種失敗變成帶原者的母親其HBV之特徵。我們將從第一年開始即前瞻性地收集e抗原陽性帶原產婦產前之血清及其嬰兒在免疫預防接種完成後6個月內之血清。我們將分析母親產前HBV的基因型、病毒量及在Pre-S及S基因上的變異，並比較其在變成帶原嬰兒與接種疫苗成功者之間有何差異，以進一步了解導致嬰兒免疫預防接種失敗的因素究竟何者是最關鍵性的。<br> Abstract: The pre-S proteins of hepatitis B virus (HBV) play an essential role in the interaction of the immune defense to viral immune recognition sites because they contains both T- and B-cell epitopes. Alterations of these immune epitopes can result in a decreased efficacy of the hosts T- and B-cell response. A number of pre-S1/S2 rearrangements, including deletions and initiation codon mutants, have been found in adult patients with chronic hepatitis, fulminant hepatitis and hepatocellular carcinoma. The role of pre-S mutants in viral persistence and in the pathogenesis of liver damage remains to be elucidated. More recently, occult HBV infection in vaccinated children has also been associated with deletion of 3’ terminus of pre-S1 which leads to loss of immune epitopes and function sites.We have previously conducted five previous serosurveys in children before and after universal immunization in Taipei City. In the first year of this study, we will analyze serum samples from these surveyed children who were seronegative for HBsAg but seropositive for either anti-HBs or anti-HBc. HBV DNA level are determined by real-time PCR. Pre-S, S and pre-core/core genes were amplified by nested PCR followed by direct sequencing. Such a study based on a large children population is needed to elucidate the prevalence and clinical significance of occult HBV infection and its related mutants in our vaccinated children within two decades following universal infant immunization.In the second year, we will analyze pre-S nucleotide sequences of HBV DNA isolated from children with fulminant or acute self-limited hepatitis and their mothers to elucidate whether pre-S variants is involved in the pathogenesis of this disease. We will study the nucleotide sequence of pre-S1/S2 region from serial sera of chronic HBV-infected children with and without immunization in infancy to understand sequential changes in the pre-S region of the HBV genome or the incidence of point mutations or deletions before and after anti-HBe seroconversion, and their implications in viral persistence and severity of liver injury.In the third year, we will investigate maternal HBV characteristics underlying the breakthrough HBV infections in infants despite immunoprophylaxis since birth. Collection of ante-partum sera from HBeAg-positive carrier mothers and sera from their offsprings two to six months after the last dose of vaccination will be prospectively conducted since the first year of this study. Quantitation of HBV DNA level, genotyping and nucleotide analysis of pre-S and S region will be performed in maternal sera as well as infant sera. Carrier infants will be analyzed for human leukocyte antigen class I and II antigen. Such study would reveal potential predictors of vertical breakthrough infection and possible pathogenesis of occult HBV infection through maternal-infant transmissionB型肝炎病毒潛隱性感染疫苗接種兒童hepatitis B virusoccult infectionvaccinationchildren