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標題: | 第一型干擾素訊息傳遞途徑在B型肝炎病毒於不同年齡所誘發的免疫反應之調控 Age-Dependent Regulation of anti-HBV Immunity by Type-I Interferon Signaling Pathway |
作者: | Li-Wei Chuang 莊立暐 |
指導教授: | 陳培哲 |
共同指導教授: | 黃妙慈 |
關鍵字: | 第一型干擾素,B型肝炎病毒,先天性免疫,高壓水動能注射,年齡, Type I interferon,HBV,innate immune,Hydrodynamic injection,Age effect, |
出版年 : | 2010 |
學位: | 碩士 |
摘要: | 人類B型肝炎病毒感染後所造成的結果與感染宿主的年齡有關,成人時期感染B型肝炎病毒的臨床症狀主要是急性肝炎,然而在嬰幼兒時期感染B型肝炎病毒,大部分的宿主往往會變成慢性帶原者。第一型干擾素向來被認為是對抗病毒感染的第一道防線並具有促進免疫反應的能力,但是近年來研究發現它其實也具有免疫抑制的功能,並且能促進調節型T淋巴球的分化。這種免疫抑制作用只發生在新生小鼠而非成年小鼠中。因此我們假設B型肝炎病毒感染後第一型干擾素表現在嬰幼兒與成年人中執行著不同的免疫調節功能,所以造成不同的感染結果。
我們之前以高壓水動力注射具複製能力之B型肝炎病毒DNA予4-6週的C57BL/6小鼠,成功建立了第一個慢性B型肝炎病毒帶原的小鼠模式。依據此模式,我們發現此B型肝炎帶原的產生僅限於4-6週大的年輕B6小鼠,而10週以上的小鼠則會有效的清除B型肝炎病毒。我們發現容易慢性感染的年輕小鼠在高壓水動力注射具複製能力之B型肝炎病毒DNA後,其肝臟相較於能清除病毒的成年小鼠表現較多的第一型干擾素α和β。此外干擾素β的免疫調節功能與其濃度有關,在低濃度時會執行免疫活化功能,然而在高濃度時,則造成免疫抑制。我們在活體實驗中也發現在成年小鼠肝臟中提高干擾素β的表現、或是在年輕小鼠肝臟中抑制第一型干擾素訊息傳遞路線皆可以反轉B型肝炎病毒在小鼠肝臟中持續表現的現象。我們更進一步地去探討第一型干擾素執行免疫抑制功能的可能機制,我們發現年輕小鼠的骨髓所培養的樹突細胞較年長小鼠的骨髓樹突細胞表現較多的免疫抑制訊息傳導物質例如TAM (Tyro3, AxL, MerTk)、SOCSs及A20等;除此之外,年輕小鼠的肝臟及肝臟樹突細胞也較年長小鼠的肝臟及肝臟樹突細胞表現較多的免疫抑制訊息傳導物質。 綜合我們的實驗結果顯示在年輕小鼠中第一型干擾素是B型肝炎病毒持續性表現的重要調節因子,目前仍需進一步的實驗來釐清其詳細的作用機轉。 HBV infection in humans is characterized by an age-dependent immunity; it causes acute infection in adult but chronic infection in the young. Type-I interferon (IFN-I) has been known as a key player in eliminating viral infection. However, recent studies have also shown that IFN-I can suppress immune activation despite their anti-viral activity. Moreover, in some rodent studies, the immune suppression function of IFN-I can only be observed in the neonatal mice but not the adult. We hypothesize that IFN-I exert distinct immune regulation between the young and the adult during early HBV infection which leads to an age-dependent infection outcome. We have previously established a murine model of HBV persistence by hydrodynamic injection of replication-competent HBV DNA. In this model, we observed HBV persistence in young mice of 4-6 weeks old but not in adult mice of 10-11 weeks old. In my study using this model, we found higher amount of IFN-I expression in the livers of young mice after HBV injection compared to adult mice. We found that IFN-β exerted a dose-dependent immune regulation function - IFN-β promoted immune activation at low doses whereas it suppressed immune responses at high doses. In vivo, we found that HBV persistence can be reverted by either enhancing hepatic IFN-β expression in adult mice or by blocking IFN-I signaling in the young mice. In addition, to investigate the possible mechanisms of IFN-I immune suppression, we analyzed the expression of IFN-I-associated immune suppressor genes including the TAM receptor tyrosine kinase family, SOCSs, and A20, etc. We found that type I interferon treatment induced the expression of the IFN-I associated suppressor genes by bone marrow-derived DC. In addition, young mice expressed more abundant suppressor genes in the livers and intrahepatic DC after hydrodynamic transfection of HBV than the adult mice. Collectively, our data support the hypothesis that IFN-I is a key regulator in HBV persistence in the young population. Works will be continued to investigate further the functional role and mechanisms of IFN-I signaling in HBV persistence. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47118 |
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