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研究生:詹志偉
研究生(外文):Chin-Wei Chan
論文名稱:C型肝炎患者自體抗細胞週期抗體研究
論文名稱(外文):A preliminary study on anti-cell cycle related autoantibody for HCV infected patients
指導教授:張銘一
指導教授(外文):Mingi Chang
學位類別:碩士
校院名稱:慈濟大學
系所名稱:微免暨分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
畢業學年度:97
語文別:中文
論文頁數:89
中文關鍵詞:細胞週期C型肝炎自體抗體螢光染色抗核酸自體抗體西方墨點法
外文關鍵詞:cell-cycle related autoantibodymidbycell cyclecleavage furrowANAELISAwestern blotanti-dsDNAanti-ssDNAantii-NS5aanti-core
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先前研究發現慢性C型肝炎患者會產生自體抗體,進而可能導致局部或系統性自體免疫疾病。臨床上以干擾素(interferon, IFN)合併ribavirin治療作為HCV患者主要的治療方法。慢性C型肝炎患者接受此療法成功率僅約五成,且研究指出治療過程可能會引發自體抗體的產生。目前並無全面性探討不同族裔感染HCV後自體抗體的生成與治療過程引發免疫反應的差異。因此本研究蒐集客家與閩南兩個治療成功率不同的族群C型肝炎患者血清,並以HEp-2細胞進行免疫螢光染色觀察客家與閩南兩族群螢光反應的差異和治療前後的變化,並進一步以ELISA和西方墨點法分析。研究顯示HCV患者具有特異性的細胞週期自體抗體,並可觀察到mitotic spindle fiber、centrosome、cleavage furrow、midbody等螢光特徵,且客家、閩南兩族群顯示有不同偏好的螢光反應。利用HCV core蛋白質的ELISA分析和HCV replicon細胞的西方墨點法分析發現治療前有高效價anti-core抗體以及anti-NS5A會有較好的治療結果。以紫外線誘發細胞產生蛋白質方式,發現HCV患者可能具有針對此類蛋白質的自體抗體。這些初步性資料可提供作為未來慢性C型肝炎新的研究方向。
Some previous studies had shown that HCV-infected patients could be induced autoantibodies even engendered local or systemic autoimmune diseases. In clinically, interferon-���n�vINF-��) in combination with ribavirin is a major treatment for chronic hepatitis C, but only approximately 50 percent of HCV- infected patients have better prognosis. This treatment could induce autoantibodies production. At present, there is no comprehensive investigation for autoantibodies production in diference of ethnic group after HCV infection, and different in immune response for treatment. In this study, the collected HCV-infected patients’ sera from two ethnic groups of Hakka and Min-nan were different prognosis. Using HEp-2 cells for immunofluorecence stain showed that response in treatment before and after sera from Hakka and Min-nan. Then characteristic analysis was by ELISA and western blot. The results revealed HCV-infected patients had specific cell-cycle autoantibodies. The patterns were including mitotic spindle fiber, centrosome, cleavage furrow, and midbody. Two groups showed difference outcome. ELISA analysis for HCV core protein and western blot for HCV replicon cell discovered high titer anti-core and anti-NS5A could be better prognosis. UV lignt induced cell to product proteins that HCV-infected patients could detect autoantibodies against these. The preliminary data provided new directions for HCV researches in future.
英文摘要………………………………………………………………. ...I
中文摘要………………………………………………………………....II
緒論
1. C型肝炎病毒簡述……………………………………………….........1
2. C型肝炎流行病學統計……………………………………………….2
3. 自體免疫疾病……………………………………………………...….3
3-1 特異性自體免疫疾病……………………………………………….4
I 愛迪森氏症…………………………………………………………...5
II 自體免疫貧血症……………………………………………………..5
III 古德巴斯德症候群………………………………………………….6
IV 橋本氏甲狀腺炎…………………………………………………….6
V 胰島素依賴型糖尿病………………………………………………..6
VI 格雷氏症…………………………………………………………….7
VII 重症肌無力…………………………………………………………7
VIII 自體免疫性肝炎…………………………………………………...7
3-2 全身性自體免疫疾病………………………………………………..8
I 全身性紅斑性狼瘡……………………………………………………8
II類風溼性關節炎………………………………………………………8
III 多發性硬化症……………………………………………………….8
IV 僵直性脊椎炎……………………………………………………….9
V 修格連氏症候群……………………………………………………..9
4. 自體抗體……………………………………………………………..10
4-1 抗去氧核醣核酸自體抗體…………………………………………11
4-2 Anti-cardiolipin抗體………………………………………………...11
4-3 Anti-SSA/Ro及Anti-SSB/La抗體………………………………...12
4-4 Anti-mitochondrial antibody(AMA), anti-E2, anti-E3……………...13
4-5 Anti-topoisomerase II抗體…………………………………………13
4-6 Rheumatoid factor…………………………………………………..14
5. HCV與自體免疫………………………………………….…………14
5-1 C型肝炎引發自體抗體的機制…………........................................14
5-2 目前已發現HCV引發自體抗體…………………………………16
6. 免疫螢光檢測...……………………………………………………..16
6-1 免疫螢光染色與疾病……………………………………………...16
6-2 細胞週期…………………………….……………………………..17
6-3 抗細胞週期自體抗體……………………………………………...18
6-4 抗細胞週期自體抗體螢光染色特徵……………………………...18
I PCNA………………………………………………………………...18
II Centromere…………………………………………………………..19
III CENP-F/Na…………………………………………………………19
IV Centriole/centrosome……………………………………………….20
V Tubulin………………………………………………………………20
VI NuMA-1/MSA-1…………………………………………………...20
VII NuMA-2…………………………………………………………...21
VIII MSA-2……………………………………………………………21
IX MSA-3……………………………………………………………...21
7. 研究動機...…………………………………………………………..21
材料與方法……………………………………………………………..23
1. 細胞培養與處理(Cell culture and treatment)………………………24
2. 血清樣本(Serum sample)…………………………………………...24
3. SDS-PAGE配製與urea gel配製和蛋白質轉印…………………..25
4. 西方墨點法(Western blot)…………………………………………..25
5. ELISA…………………………………………………………….....26
6. 免疫螢光染色(Immunofluorecense staining)……………………....27
結果……………………………………………………………………..28
1. 螢光染色結果…………………………………………………...…29
2. 抗核酸抗體ELISA測試…………………………………………..31
3. HCV core ELISA測試…………………………………………......33
4. Anti-NS5A反應……………………………………………………34
5. HCV患者臨床生化資料分析……………………………………..34
6. 西方墨點法反應…………………………………………………...35
討論……………………………………………………………………..38
結論……………………………………………………………………..48
表………………………………………………………………………..50
表一、客家族裔螢光染色…………………………………………….50
表二、閩南族裔螢光染色…………………………………………….51
表三、客家族裔細胞週期螢光染色特徵……………………………..52
表四、閩南族裔細胞週期螢光染色特徵…………………………….54
表五、HCV患者螢光統計分析………………………………………56
表六、HCV患者生化與研究資料…………………………………....57
圖………………………………………………………………………..58
圖一: C型肝炎患者500X稀釋血清anti-dsDNA ELISA測試…..….58
圖二: C型肝炎患者500X稀釋血清anti-ssDNA ELISA測試……....59
圖三: C型肝炎患者1000X稀釋血清anti-core ELISA測試………..60
圖四: C型肝炎患者治療前2000X稀釋血清anti-NS5A結果……...61
圖五: 治療前血清anti-NS5A數值化分析…………………………...62
圖六: C型肝炎患者治療後2000X稀釋血清anti-NS5A結果……....63
圖七: HCV患者AFP數值分析…………………………………………......64
圖八:HCV患者GOT數值分析……………………………………………..65
圖九:HCV患者GPT數值分析.……………………………………………..66
圖十: C型肝炎患者治療前與治療後1000X稀釋血清Hela cell西方
墨點分析結果…………….……………………………………..67
圖十一:客家C型肝炎患者1~6治療前後1000X稀釋血清G1, normal
, M結果.....…………………………………………………...68
圖十二: 客家C型肝炎患者7~11治療前後1000X稀釋血清G1, normal
, M結果………………………………………………………69
圖十三: 閩南C型肝炎患者1~7治療前後1000X稀釋血清G1, normal
, M結果………………………………………………………70
圖十四: 閩南C型肝炎患者8~11治療前後1000X稀釋血清G1, normal
, M結果…………………………………………………..…..71
圖十五: HCV患者血清與Huh7細胞和西方墨點法分析結果…...….72
圖十六: HCV患者血清與高劑量紫外線照射Huh7細胞西方墨點
法分析結果……………………………………………………73
附錄
溶液配方………………………………………………………………..74
實驗材料………………………………………………………………..78
參考文獻………………………………………………………………..80
補充圖片……………………………………………………………….光碟
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