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研究生:陳佳宏
研究生(外文):Chia-Hung Chen
論文名稱:抗DNA自體抗體及抗核糖體P蛋白自體抗體之選殖、表現與特性分析
論文名稱(外文):Cloning, expression and characterization of anti-DNA and anti-P antibodies
指導教授:孫光蕙
指導教授(外文):Kuang-Hui s Sun
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:114
中文關鍵詞:全身性紅斑狼瘡抗雙股DNA單株抗體抗酸性核糖體P蛋白單株抗體
外文關鍵詞:systemic lupus erythematosus (SLE)anti-double strand DNA antibodyanti ribosomal P proteins antibody
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全身性紅斑狼瘡病人的血清中存在著許多種不正常的自體免疫抗體,其中抗雙股DNA抗體是診斷全身性紅斑狼瘡的標幟之一,此抗體會與其對應抗原形成免疫複合體,活化補體系統,進而破壞細胞與組織,是造成全身性組織發炎的主因;另外紅斑性狼瘡病人約12%~20%含有抗酸性核糖體P蛋白自體免疫抗體 (anti-P Ab),此抗體與精神異常症狀 (psychosis) 有關。本實驗室已建構抗雙股DNA單株抗體 (9D7) 與抗酸性核糖體P蛋白單株抗體 (9B6),且已在大腸桿菌中大量表現重組9D7 (scFv r9D7),因此本論文目的為重組單鏈9B6之選殖與表現及由9D7模擬結構中去探討抗體與DNA之間交互作用的關係與其特性分析。由ELISA實驗得知9D7會與ds-DNA、ss-DNA、dA12、dT12、dG12、dC12及dG5結合,其中以dG12結合能力最強,dG5及ds-DNA、ss-DNA鍵結能力次之,經由電腦程式的結構模擬分析進一步探討r9D7與dG5之間交互作用的關係;另外本實驗室已從9B6細胞中選殖到重鏈的變異區基因,因此利用SDS-PAGE純化出輕鏈抗體蛋白,再利用LC/MS/MS定出輕鏈N端與C端片斷序列,經由序列比對得知是屬於λ 輕鏈,進而設計專一性引子去選殖出正確的輕鏈變異區基因,並以linker(GGGGS)3將重鏈及輕鏈的變異區連在一起,成功的在大腸桿菌中表現出具有結合P蛋白功能之單鏈重組抗酸性核糖體P蛋白自體免疫抗體 (scFv r9B6),且透過螢光放射光譜分析r9D7經變性再復性結構之變化;圓偏振二旋光譜(CD)分析復性後二級結構的比例,進一步證實r9D7、r9B6有復性成原來之構型。利用電腦模擬及序列比對,分析r9D7、r9B6與已知結構之抗體在序列上之差異,推測出r9D7中Y32、Y33、N35、R98、L99、T100、R101、A102、D104、Y163、Y180、Y181、Y222、K224可能跟DNA有交互作用;r9B6中Y54、R101、R102、Y104、F106、Y168可能跟P蛋白有交互作用,期盼這些結果能對9D7、9B6與其抗原間交互作用有更深入的瞭解,以奠定設計治療全身性紅斑狼瘡 (SLE) 藥物的基礎。
Presence of autoantibodies in the serum is the characteristic of systemic lupus erythematosus (SLE). Among these abnormal antibodies, anti-double strand DNA antibodies (anti-dsDNA) are important markers for the diagnosis of this disease. After penetrating the cell membrane, anti-dsDNA may cause tissue damage or lupus nephritis by binding to their intracellular targets and the activating the complement system. In addition, antibodies specific for ribosomal P proteins (anti-P), detected in 12-20% of the patients, have been reported to be associated with neuropsychiatric manifestations of SLE. Since the monoclonal anti-dsDNA 9D7 and anti-P 9B6 have been constructed in our laboratory, we cloned and expressed scFv of 9D7 and 9B6 antibodies in E. coli and studied the interaction of scFv antibodies with cognate antigens based on its modeling structure. By ELISA, 9D7 was found to bind to dsDNA, ssDNA, dA12, dT12, dG12, dC12, and dG5. The binding of 9D7 was strongest with dG12 and followed by dsDNA, ssDNA, and dG5. The interaction of dG5 with 9D7 was further studied by the modeling structure of 9D7. Since the variable region gene of 9B6 heavy chain has been determined, we cloned the variable region gene of 9B6 light chain in this study. After sequencing the N terminal and C terminal amino acid of the light chain by LC/MS/MS, the light chain was determined to be λ light. The variable region gene of 9B6 light chain was cloned, linked with heavy chain and expressed in E. coli. The structural difference between the denatured and refolded protein was measured by fluorescence emission spectra. By circular dichroism spectra, we confirmed that r9D7 and r9B6 have been refolded. The computer structural modeling and sequence alignment of scFv antibodies complexed to cognate antigens will provide important information for development of therapeutic approaches based on blocking the combining sites of anti-DNA and anti-P antibodies.
中文摘要……………………………………………………… 5
英文摘要……………………………………………………… 7
第一章 緒論………………………………………………….. 9
第二章 材料與方法………………………………………….. 23
第三章 結果………………………………………………….. 48
第四章 討論………………………………………………….. 62
第五章 參考文獻…………………………………………….. 68
第六章 圖表………………………………………………….. 80
第七章 附錄………………………………………………….. 106
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