臺灣博碩士論文加值系統

異位性疾病（Atopy），包括過敏性氣喘（atopic asthma），在最近二十年間許多地區的盛行率普遍都有升高的趨勢，特別是氣喘，更是全世界小孩中最常見的慢性疾病之一。在探討氣喘的形成機制時，通常會從遺傳基因與環境因子兩方面來著手，環境因子的影響除了一些常見的過敏原之外，空氣中的污染物、病毒及細菌都有可能間接或直接造成氣喘，而其造成氣喘的原因也許是經由加強Th2主導的過敏反應過程，或是影響氣管上皮-間質營養層（EMTU）的分化來達到目的。
在眾多影響過敏性疾病（包括氣喘）發展的原因中，過敏原的接觸是主要原因之一，而幼兒（甚至是胎兒）在不同年齡層的免疫系統發展與環境的關係，是影響過敏兒形成與否的重要關鍵，為了知道T-bet與GATA-3在過敏反應形成中所扮演的角色，我們利用臍帶血與8歲以下小孩，其周邊血中的淋巴球來當作研究對象，觀察T-bet與GATA-3在不同年齡層Th1及Th2免疫系統發展中的變化。我們的實驗結果中發現，早在胎兒時期，T-bet的表現就已經出現差異性，但在GATA-3並未發現，而在經過植物性凝集素（PHA）刺激後所表現的IFN-γ亦是如此，而且此變化都與臍帶血全量（total）IgE的量呈現負相關（p<0.01或p<0.05），再加上全量IgE與塵螨抗原的增生作用呈現正相關的趨勢，因此所有證據都顯示，胎兒Th1的成熟表現在出生前就已受到影響。除了基因的觀點外，母體周圍環境塵螨過敏原的接觸，應該也是一項很重要的因素。
除從胎兒的角度來觀察致敏形成機制外，我們亦在8歲以下的小孩中，發現T-bet在0∼3歲、3∼6歲與6∼8歲三個年齡層間的表現量，不管有沒有氣喘，都與塵螨專一性IgE的量呈負相關性（p<0.01或p<0.05），但在GATA-3方面並沒有見到這樣的結果（p>0.05）。T-bet的表現量在0∼3歲間即有著明顯差異，這表示早期接觸塵螨過敏原有機會影響往後Th1的發展。在塵螨專一性IgE小於0.35（kU/L）以及大於100（kU/L）這兩族群中，我們發現氣喘與非氣喘的兒童隨著年齡，T-bet的表現並不盡相同。在患有氣喘的小孩中T-bet的表現並未與年紀呈現正相關性（p>0.05），但在沒有氣喘的小孩其T-bet的表現卻會隨年紀增加而持續升高（p<0.05或p<0.01），而在6∼8歲間氣喘與否T-bet表現呈現出明顯差異（p<0.05），而其IFN-γ mRNA與IFN-γ蛋白質的表現亦是如此（p<0.05或p<0.01）。除了早期過敏原的接觸，T-bet的表現似乎在6∼8歲間氣喘的形成與否也相當具有影響力，其結果也暗示著除了塵螨過敏原外，尚有其他因子在早期或這個時期影響到T-bet的表現而造成氣喘。

Allergy disease (Atopy), including the allergic asthma , there was an universal increase in prevalence worldwide over two decades. Asthma especially, was one of the most common chronic disorders in childhood. While inquiring into the development of asthma, researcher would usually investigate both the inheritable genes and environmental factors. Concerning the environmental factors, in addition to some common allergens, there were still the pollutants in the air, virus and bacteria, all of these could directly or indirectly make the asthma developed through enhanced the predominance of Th2-mediated allergy, or affected the differentiation of the epithelial mesenchymal trophic unit (EMTU) to achieve this purpose.
In numerous factors affecting atopy development (including asthma) the contact of the allergen was one of the main factors, but in infant (even fetus), the interactive relation between immune system maturation with age and environmental variations were another major factor influencing allergic child development. In order to investigate the role of T-bet (Th1) and GATA-3 (Th2) in allergy development with age, we utilized reverse-transcription polymerase chain reaction (RT-PCR) to detect T-bet and GATA-3 mRNA expression in 0-8 years old children and fetus. In our results, as early as fetal period, the T-bet performance had appeared the difference, but did not find in the GATA-3, and IFN-γperformance stimulated by phytohemagglutinin (PHA) had similar tendency to T-bet. The manifestation of T-bet or IFN-γshowed significant decrease with cord blood total IgE increasing (p<0.01 or p<0.05), but the cord blood proliferation induced by the mite allergen showed significant increase (p<0.01), anyhow all the results revealed that Th1 maturation had be influenced in fetus, in addition to inheritance, to contact maternal environmental allergen might be one major factor.
Except for intra uterine (fetus), in the 0-8 years old children we also found that whatever asthma or not, T-bet expression decreased significantly with mite-allergen sensitization in the age of 0-3, 3-6 and 6-8 (p<0.01 or p<0.05). However, we did not find any difference in GATA-3 (p>0.05). As early as the age of 0-3, T-bet performance had noticeable divergence with allergen-sensitization state, it meant that allergen possessed marked influence on Th1 maturation in these age.
In the mite-specific IgE < 0.35 KU/L or > 100 KU/L children, T-bet expression revealed difference with age increasing in the asthmatic and non-asthmatic groups. In the non-asthmatic children, T-bet expression of both increased with age (p<0.05 or p<0.01), especially in the age of 6-8 (p<0.05), but not in the asthmatic ones. Whatever, we also found that in IFN-γmRNA and protein. It indicated that in addition to allergen, there were another factors affecting T-bet expression (Th1 maturation) until the age of 6-8.

中文摘要……………………………………1
英文摘要……………………………………3
第一章 緒論……………………………… 5
第一節 氣喘的盛行…………………………5
第二節 氣喘概論……………………………5
第三節 氣喘免疫病理學……………………7
過敏性發炎的免疫分子機制……………………8
上皮-間質營養層（EMTU）……………………11
Th2 inflammation and EMTU…………………12
第四節 氣喘與環境的關係……………………13
第五節 家塵蟎抗原與致敏化…………………17
第六節 Th1/Th2免疫系統分化機制………… 18
T-bet與GATA-3所引導的Th免疫系統分化…………………… 19
第七節 T-bet與GATA-3在老鼠氣喘模型中的研究………………23
第八節 胎兒與幼兒早期免疫系統的致敏化…………………… 25
第九節 研究動機與目的………………………………………… 27
第二章 材料與方法…………………………………………………30
第一節 實驗材料………………………………………………… 30
第二節 實驗方法………………………………………………… 34
第三章 實驗結果……………………………………………………40
第一節 母體內（intra uterine）早期致敏化機制的探討……40
一、 胎兒致敏化程度與母親過敏性體質的關係…………………40
二、 臍帶血單核細胞對塵蟎過敏原（Der p2）刺激的增生反應
………………………………………………………………………41
三、 臍帶血單核細胞中T-bet與GATA-3的表現分析…………… 42
四、 植物性凝集素（PHA）刺激下臍帶血單核細胞IFN-γ表現量試
驗………………………………………………………………42
第二節 出生後（post natal）0∼8歲小孩致敏化機制與年齡關係的探
討…………………………………………………………………43
一、 小孩周邊血單核細胞對塵蟎過敏原（Der p2）的增生反應
………………………………………………………………………43
二、 小孩周邊血單核細胞中T-bet與GATA-3的表現分析……… 45
三、 Th1免疫系統成熟與過敏兒（過敏性氣喘）發展的關係… 45
第四章 討論…………………………………………………………… 49
參考文獻…………………………………………………………………60
圖表………………………………………………………………………75
附錄appendix………………………………………………………… 109

呂克桓、王文卿（2001）。小兒氣喘。
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