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研究生:陳彥銘
研究生(外文):Yan-Ming Chen
論文名稱:鑑定與分析點青黴過敏原Penn18之抗原及過敏原決定點:利用兔子多株抗體及人類IgE抗體進行分析
論文名稱(外文):Identification and analysis of the antigenic and allergenic determinants on the allergen Pen n 18: epitope mapping by rabbit polyclonal antibodies and human IgE.
指導教授:周綠蘋周綠蘋引用關係張文章張固剛邱式鴻邱式鴻引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2001
畢業學年度:89
語文別:中文
論文頁數:91
中文關鍵詞:過敏原決定點抗原決定點絲胺酸水解酵素半抗原
外文關鍵詞:allergenic determinantantigenic determinantserine proteasehapten
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全世界大約有20%的人口面臨過敏性疾病的威脅。過敏性疾病包括了過敏性鼻炎、關節炎、氣喘及各種過敏性反應等。當人體內具有辨識過敏原特異性的IgE抗體與過敏原結合後,會進一步與其受器發生交聯反應,並導致一些免疫細胞活化及釋放介質引發過敏性反應。黴菌的孢子是空氣中含量最豐富的有機物質,很久之前便發現它是導致呼吸系統性過敏疾病的重要來源之一。一般來說,Aspergillus和Penicillium這兩個屬的黴菌是室內最常見兩種黴菌。直到目前為止,青黴菌屬大約已經有150種以上的種類被發現,根據研究,最常見的5種青黴菌是P. spinulosum、 P. brevicompactum、 P. oxalicum、 P. notatum 和 P. citrunum.
青黴菌屬中的點青黴是一個已知室內型黴菌,會引起支氣管的氣喘疾病。同時皮膚測試中也使用點青黴的粗萃取物來診斷病人是否對黴菌產生過敏性反應。由於近年來重組DNA科技的日新月異,許多過敏原分子特性的分析都可利用重組蛋白進行研究,並加速相關研究的進行。本研究室的學姐利用二維電泳將點青黴的粗萃取物展開後,利用西方墨點法找到了一個分子量38kDa的過敏原,並將其命名為Pen n 18。接下來便利用基因轉殖的技術以大腸桿菌表現出Pen n 18的重組蛋白,並在其N端序列加上六個Histidine。我們利用一根親和力管柱,純化rPen n 18。純化後的重組蛋白rPen n 18使用病人的血清進行西方墨點試驗,發現其仍然具有與IgE抗體結合的能力,證明了此重組蛋白擁有與自然狀態nPen n 18相同的致敏特性,可以做進一步的研究。
為了找出過敏原Pen n 18的抗原及過敏原決定點,我們使用CNBr化學切割及酵素分解的方式將rPen n 18處理成不同大小的片段,並使用高效能液相層析法將這些片段分離並純化,在將其轉印到PVDF纖維膜上以兔子多株抗體及八位病人的血清進行西方墨點試驗。將其中十九段呈現陽性反應的片段以N端蛋白質定序儀分析其N端序列,並利用MALDI-TOF質譜儀分析所有片段的質量數,結果一共得到至少九段含有抗原決定點的區域,以及九段含有過敏原決定點的區域。我們利用電腦模擬Pen n 18分子的三級結構,觀察這些區域的分佈,發現到幾乎所有的抗原或過敏原決定點都包含一些暴露在Pen n 18分子表面的部分。
在本次實驗之中,我們發現重組過敏原rPen n 18能夠表現出與自然狀態Pen n 18相同的IgE抗體結合能力,這也證明使用容易製備及純化的重組蛋白,能夠提供一個明確且便利的方法用來進一步研究過敏原的結構,並用來發展更精確的診斷方式或治療策略。
Almost 20% of the population suffers from Type Ⅰ allergy. The symptoms of Type Ⅰ allergy (allergic rhinitis, conjunctivitis, asthma, and anaphylaxis) result from the cross-link of effector cell-bound IgE antibodies by innocuous allergens. Fungal spores are the most abundant organic particles in the atmosphere and were long recognized as important cause of respiratory allergy. In general, Aspergillus and Penicillium are commonly found indoor. Until now, more than 150 different species have been discovered in the genus Penicillium. The five most frequently found species of Penicillium indoor and outdoor in Topeka KS were P. spinulosum, P. brevicompactum, P. oxalicum, P. notatum, and P. citrunum.
P. notatum is a well-know indoor aeroallergen considered as one of the causative agents of extrinsic bronchial asthma and is frequently included in skin test panels for allergic diagnosis. Molecular characterization of allergens by recombinant DNA technology progressed rapidly during the last few years. Pen n 18, a novel allergen from P. notatum was identified by two-dimensional immunoblotting, and followed by the molecular cloning and expression of this allergen as a hexahistidine- tagged fusion protein in Escherichia coli. Further purification by Ni-chelate chromatography led to a homologous protein fraction of rPen n 18. Purified rPen n 18 was tested by immunoblotting with sera from patients with allergy and shown strong reaction to IgE, indicating that the allergenic properties are well conserved in the recombinant-derived protein.
In order to identify the antigenic and allergenic determinants of Pen n 18, rPen n 18 was cleaved by cyanogens bromide, and digested with Lysyl-C endopeptidase, Chymotrypsin and Glu-C endopeptidase to generate various peptide fragments which were then separated by HPLC and electroblotting to PVDF membrane. After immuodetection with rabbit plolyclonal antibodies and sera of eight patients, nineteen positive peptide fragments were analyzed for N-terminal protein sequence and all peptides were submitted for mass analysis. Finally we found at least nine regions contain antigenic determinants and seven regions contain allergenic determinants. Finally, By 3D-structure homology modeling of rPen n 18, we found that almost all positive peptide fragments locate at the exposed regions of the molecule.
In summary, we demonstrated that the recombinant allergen of rPen n 18 exhibited a high potency of reactivity with IgE. The facile production and purification of recombinant mold allergens like rPen n 18 provide a straightforward strategy for a detailed study of epitopes structure as well as the development of accurate diagnosis protocols which may lead to effective therapeutic strategies in the future.
中文摘要---------------------------------------------------1
ABSTRACT---------------------------------------------------3
縮寫-------------------------------------------------------5
第一章、序論----------------------------------------------6
第二章、實驗材料-----------------------------------------17
第三章、實驗方法-----------------------------------------19
第四章、實驗結果-----------------------------------------38
第五章、討論---------------------------------------------50
參考文獻--------------------------------------------------61
圖表及說明------------------------------------------------69
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