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研究生:陳榮富
研究生(外文):Rong-fu Chen
論文名稱:登革二型病毒大流行之登革二型病毒感染之免疫致病機制研究
論文名稱(外文):Immunopathogenesis of dengue-2 infection in a dengue-2 outbreak
指導教授:楊崑德楊崑德引用關係陳錦翠
指導教授(外文):Yang, Kuender D.Cheng, Jiin-Tsuey
學位類別:博士
校院名稱:國立中山大學
系所名稱:生物科學系研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:122
中文關鍵詞:細胞激素登革熱二次感染免疫致病登革出血熱
外文關鍵詞:dengue hemorrhagic feversecondary infectiondengue feverimmunopathogenesiscytokine
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登革熱 (dengue fever, DF) 的發生率在過去 50 年來被估計約有 30 倍的快速增加。登革熱在臨床上的表徵是從一般簡單的發燒與身體酸痛的症狀到可能有致命危險的登革出血熱 (dengue hemorrhagic fever, DHF)。越來越多的研究顯示關於登革熱的疾病嚴重程度需要一個更好的分類標準,來釐清登革感染症的免疫致病機制,用以預防或是處理嚴重的登革出血熱。在本研究論文我們試圖探究是否有不同的免疫機制調控病人出血或血管滲漏的病症。本研究先是以臨床病人為對象,比較臨床表徵與實驗室數據,包括病毒量、 T 輔助細胞激素 (Th1/Th2)與血管滲漏相關因子來探討登革熱與登革出血熱病人之間的差異。接著再從登革熱病人中,定義出一群有出血表徵但沒有符合登革出血熱 (DHF) 定義的病人,並命之為出血傾向登革熱 (DF with bleeding tendency, DF w/B),做進一步的研究分析。結果發現病毒血量在登革熱、出血傾向登革熱與登革出血熱三組病人之間並無差異。但是登革熱病人有代表免疫陽性 (T helper type 1, Th1) 較高的 IFNr表現 (70.0 ± 10.7 vs. 33.1 ± 8.0 vs. 33.0 ± 7.1 pg/ml; DF vs. DF w/B, p = 0.009; DF vs. DHF, p = 0.002),出血傾向登革熱與登革出血熱兩組病人與登革熱病人相比,IL-10 產量都有明顯差異的增加 (14.3 ± 4.1 vs. 26.2 ± 3.3 vs. 26.0 ± 3.5 pg/ml; DF vs. DF w/B, p = 0.023; DF vs. DHF, p = 0.016);而且出血傾向登革熱與登革出血熱兩組病人也都有較高的二次感染頻率 (DF w/B vs. DHF vs. DF: 50.0%、 74.4% 與 14.3%, p < 0.001)。不同的是登革出血熱而非出血傾向登革熱的病人有明顯較高的血管滲漏相關因子:sVCAM-1, PGE2 與 TNFα 表現。出血傾向登革熱與登革出血熱病人相比,有明顯登革熱, 登革出血熱, 免疫致病, 二次感染, 細胞較高的血小板數量 (DF w/B vs. DHF: 66.0 ± 8.3 與 20.7 ± 2.1 x109/L, p < 0.001) ,但代表肝功能的丙胺酸轉胺酵素 (ALT) 較低 (DF w/B vs. DHF: 56.3 ± 7.7 與 144.7 ± 20.5 IU/L)。本研究論文關於登革熱、出血傾向登革熱與登革出血熱三組病人的免疫機制提供了新的視野。登革熱病人與 Th1 反應有關,出血傾向登革熱病人則和改變的 Th2 反應有關;而登革出血熱病人除了與改變的 Th2 反應有關外,也與血管損傷的擴大有關。釐清登革熱、出血傾向登革熱與登革出血熱之免疫機制,將有助於臨床醫師針對某些尚有出血表徵的登革熱病人提供更合適的治療與預防。
Incidence of dengue fever (DF) has been estimated a 30 fold increase in the past 50 years. Clinical manifestations of DF range from a simple febrile illness with physical soreness to life-threatening dengue hemorrhagic fever (DHF). The need for a better classification of the severity in DEN infections has been proposed to clarify the immunopathogenesis for the prevention and management of serious DEN infections. We attempted to investigate whether different mechanisms involved in the varied manifestations of bleeding tendency and vascular leakage in DF. In a hospital-based study, we first compared clinical features as well as laboratory data including virus load, T helper (Th1/Th2) cytokines, and vascular leakage-related mediators between patients with DHF and DF. Moreover, we defined another class of patients associated with bleeding tendency but not fulfilled with DHF criteria, called DF w/B, for a further comparison. The virus load in blood was not significantly different among DF, DHF and DF w/B. DF patients had a higher Th1 cytokine, IFNr, expression (70.0 ± 10.7 vs. 33.1 ± 8.0 vs. 33.0 ± 7.1 pg/ml; DF vs. DF w/B, p = 0.009; DF vs. DHF, p = 0.002), and both DHF and DF w/B patients had a significantly higher IL-10 levels (14.3 ± 4.1 vs. 26.2 ± 3.3 vs. 26.0 ± 3.5 pg/ml; DF vs. DF w/B, p = 0.023; DF vs. DHF, p = 0.016) than DF patients. Both DHF and DF w/B patients also had a higher rate of secondary dengue infection (DF w/B vs. DHF vs. DF: 50.0%, 74.4% and 14.3%, p < 0.001). By contrast, DHF but not DF w/B patients had significantly higher vascular leakage-related mediators: sVCAM-1, PGE2 and TNFα levels than DF patients. Patients with DF w/B had a higher platelet counts (DF w/B vs. DHF: 66.0 ± 8.3 vs. 20.7 ± 2.1 x109/L, p < 0.001) but lower ALT levels than those with DHF (DF w/B vs. DHF: 56.3 ± 7.7 and 144.7 ± 20.5 IU/L). This study provides new insight to different immune mechanisms involved in patients with DF, DF w/B, and DHF. DF involves augmented Th1 reaction, and DF w/B involves altered Th2 reaction, but DHF involves both altered Th2 reaction and augmented vascular insult. Clarification of the immune mechanisms among DF, DFw/B and DHF will facilitate certain specific treatment and prevention of DF patients from varied bleeding tendency and vascular leakage manifestations.
中文摘要 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... II
英文摘要 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... IV
致謝銘 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...VI
表目錄 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...X
圖目錄 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...X
縮寫索引 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...XII
一、緒論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...1
二、研究動機與實驗設計 ... ... ... ... ... ... ... ... ... ... ...15
三、材料與方法 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...19
四、結果 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...32
五、討論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...47
六、結論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...60
七、參考文獻 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...62
八、作者簡歷與論文發表 ... ... ... ... ... ... ... ... ... ... ...105
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