臺灣博碩士論文加值系統

氣喘是常發生於兒童的慢性呼吸道疾病。 透過基因連鎖的研究指出: 第六染色體區域 (6p21.3) 包含許多與氣喘、過敏反應有關的易感基因, 其中第二 (DR, DQ)、 第三型組織抗原 (腫瘤壞死因子、淋巴毒殺細胞激素) 都扮演重要角色。 腫瘤壞死因子具有免疫調節的功能, 和許多感染性疾病、自體免疫疾病都有密切關聯。 許多實驗證實氣喘病人的支氣管沖出液和呼吸道都發現腫瘤壞死因子明顯增加。 此外, 腫瘤壞死因子啟動區、淋巴毒殺NcoI的多樣性也和氣喘、氣喘的嚴重情形相關聯。 在台灣, 高達85-90%的過敏兒童會針對歐洲、美洲室塵蟎產生特異性的IgE抗體, 但對於塵蟎所引發氣喘的基因背景仍有許多未知的部份。 實驗目的: (1) 是否帶有特殊的HLA基因型會傾向於引發氣喘 (2) 是否腫瘤壞死因子啟動區、淋巴毒素NcoI的多樣性與氣喘相關或影響腫瘤壞死因子產量 (3) 特殊的HLA基因型是否與塵蟎所引發的特異性IgE反應有關。 實驗方法: 研究對象包括244位氣喘病童和144位健康兒童, 利用PCR-SSP方式分析第二類型組織抗原、 腫瘤壞死因子啟動區-238, -308的多樣性; 淋巴毒殺NcoI多樣性是以酵素加以區別, 血清中IgE濃度以比濁法測定, 血清中腫瘤壞死因子和針對塵蟎 (Der p 2, -5, -7) 的特異性IgE抗體是利用ELISA方式來測量。 實驗結果: 個體是否帶有氣喘 (94-110 vs. 93-100 pg/ml, t-test=0.765) 或甚至氣喘的嚴重程度 (One-way ANOVA=0.822) 並不會影響血清中的腫瘤壞死因子濃度, 帶有DRB1*17基因型的個體與氣喘有明顯的關聯性(OR=2.5, CI=1.39-4.50, pc=0.029), 並與DQB1*02(0201/02)存在連鎖的關係(OR=306, p<10-10), 共同影響著氣喘(OR=2.6, p=0.002)。 TNF-308*A變異型在氣喘和對照組的分佈上具有顯著的統計差異 (χ2=9.14, p=0.002)。 但啟動區-238*A變異型 (p=0.108)、 淋巴毒素多樣性LtαNcoI*1 (p=0.08) 則不具有分佈上的差異 (χ2=5.04, p=0.080), 直接排除與氣喘之間的相關性。 實驗結果除了發現 TNF-308*A與 DRB1*17的連鎖關係, 另外發現TNF-308*A與 DRB1*13亦有連鎖的關係。 分析結果顯示, 當個體帶有TNF-308*A變異型與TNF-308*G的個體相比, 並沒有較高的血清腫瘤壞死因子濃度。 但是, 當個體帶有DRB1*17, TNF-308*A基因型與氣喘具有統計的相關性存在(OR=2.7, p=3*10-9), 但不會影響血清中的腫瘤壞死因子濃度。 因此我們認為影響氣喘和血清中的腫瘤壞死因子濃度是利用不同的機轉來進行。 當氣喘病童單獨帶有DRB1*13基因(330-352 vs. 86-103 pg/ml, t-test=0.026)或是DRB1*13和TNF-308*A兩種基因連鎖出現時, 傾向產生大量的血清腫瘤壞死因子濃度(One-Way ANOVA=0.007)。 我們的實驗結論發現: 特殊的TNF-308*A和DRB1*17連鎖關係與氣喘有統計的相關性, 但並不會影響血清中腫瘤壞死因子濃度。另外, 在我們的研究對象中TNF-308*A和DRB1*13基因型有特殊的連鎖關係, 並且會影響血清中腫瘤壞死因子濃度。 因此, 我們推測台灣地區的氣喘病童透過特殊的TNF-308*A和DRB1*13連鎖現象, 調控著血清中腫瘤壞死因子的大量分泌。 帶有DQB1*07(0301/04)基因型的氣喘的個體, 傾向產生大量IgE 。 歐洲室塵蟎和 美洲室塵蟎所引發特異IgE抗體, 與第二類組織抗原並無關聯。

Asthma is a chronic inflammatory airway disease, and also one of the most common disease of children. Previous studies reported linkage of chromosome 6p21.3 region with asthma and atopy. Several candidate genes involved in this region: Human leukocyte antigen (HLA) class II genes (DR, -DQ)、 class III genes (TNFa、 LTa). TNFa is a potent immunomodulator that have been implicated in a number of infectious and autoimmune diseases. The TNFa promoter and lymphotoxin a NcoI polymorphisms have been implicated with asthmatic status in a number of studies. In Taiwan, 85-90 % majority allergic asthmatic patients have IgE antibodies against multiple proteins of D. pteronyssinus and D. farinae. The immunogenetic basis of susceptibility to mite-induced asthma is currently unknown in Taiwan. The study aim is to examine: (1) if HLA genes is involved in genetic susceptibility to development of asthma, (2) the association TNFa promoter、 LTa NcoI polymorphisms with asthma and their effect on TNF a production, (3) if HLA class II allele(s) is associated with house dust mite-induced IgE responsiveness. 244 asthmatic children and 144 nonasthmatic controls determined the HLA-class II alleles、 TNF a promoter -308, -238 by PCR-SSP (sequence specific primer) and determine LTa NcoI polymorphism by restriction analysis. Patients’ total serum IgE was determined by nephelometry and serum TNFa levels、anti-Der p 2, -5, -7 specific antibody were measured by enzyme linked immunoassay (ELISA). The results indicated that TNFa levels are not associated with asthma (94-110 vs. 93-100 pg/ml, t-test=0.765) and asthma severity (One-way ANOVA=0.822). The DRB1*17 is significantly associated with asthma when compared with nonasthmatic controls (OR=2.5, CI=1.39-4.50, pc=0.029), and DQB1*02(0201/02) is linkage with DRB1*17 (OR=306, p<10-10), and associated with asthma (OR=2.6, p=0.002). Asthmatic children are significantly associated with TNF-308*A (p<0.002) but not associated with TNF-238*A (p=0.108) and LTaNcoI*1 (p=0.08). It is noteworthy that TNF-308*A is linkage with DRB1*17 and DRB1*13 in our population. However, upon further analysis, TNF-308*A(+) individuals do not have a significantly higher serum TNF a level than TNF-308*G homozygous in both asthmatics and controls. These results suggested that cause of the elevation of TNFa level and cause of asthma are not related. Asthmatic subjects with DRB1*13 have a significantly higher TNF production than individuals with non-DR13 (330-352 vs. 86-103 pg/ml, t-test=0.026) And asthmatics with TNF-308*A-DR13 haplotype have a significantly higher serum TNFa levels (687-704 pg/ml, One-Way-ANOVA=0.007) than corresponding controls. In conclusion, these observations indicated that both TNF-308*A and DRB1*17 were associated with asthma and although both genes are genetically linked, yet they both significantly contribute to the asthma phenotypes. Atopic status was defined at different levels of total serum IgE (from >300 to >3000 IU/ml), only children with DQB1*07(0301/04) consistently have a higher IgE level than other class II genes. In contrast, there is no association of class II genes with IgE antibodies against recombinant Der p 2, p 5, and p 7 proteins.

目錄
中文摘………………………………………………………………………I
ABSTRACT……………………………………………………………………III
圖目錄………………………………………………………………………V
表目錄………………………………………………………………………VI
表目錄
第一章、 序論…………………………………………………………… 1
第一節:簡介氣喘………………………………………………………… 1
第二節: 氣喘的分類………………………………………………… 1
第三節: 引發氣喘的機轉…………………………………………… 1
第四節: 與氣喘有關的基因………………………………………… 2
第五節: 第六染色體的研究方向…………………………………… 2
第一部份: 氣喘與人類白血球抗原(Human leukocyte antigen,
HLA…………2
第一節: 簡介人類白血球抗原…………………………… …………2
第二節: 氣喘與人類白血球抗原的關係……………………………… 3
第三節: 人類白血球抗原與疾病的相關性…………………………… 3
第二部份: 腫瘤壞死因子起動區多樣性與氣喘的關係…………… 5
第一節: 腫瘤壞死因子的由來及功能……………………………… 5
第二節: 腫瘤壞死因子起動區域的多樣性………………………… 5
第三節: 腫瘤壞死因子與疾病的關係……………………………… 8
第四節: 腫瘤壞死因子的調控……………………………………… 8
第五節: 腫瘤壞死因子與氣喘的研究……………………………… 8
第六節: 腫瘤壞死因子與淋巴毒素阿爾法的關係………………… 9
第七節: 腫瘤壞死因子和人類白血球抗原的關係………………… 10
第三部份: 塵蟎與氣喘……………………………………………………10
第一節: 過敏性體質………………………………………………… 11
第二節: 過敏性體質與人類白血球抗原…………………………… 11
第三節: 塵蟎………………………………………………………… 11
第四節: 過敏原與人類白血球抗原的研究………………………… 12
第五節: 台灣地區的塵蟎…………………………………………… 12
第二章、 材料與方法…………………………………………………… 15
第一節: 病人的來源與評估方式…………………………………… 15
第二節: DNA的抽取………………………………………………… 15
第三節: 血清中IgE濃度的測量…………………………………… 16
第四節: CAP Sepecific Allergy Test 特異性過敏原抗體檢驗
………… 17
第五節: 血清中腫瘤壞死因子濃度的測量………………………… 19
第六節: 血清中針對塵蹣片段 (Der p 2, 5, 7) 的特異IgE抗體測
定…… 21
第七節: 人類白血球組織符合抗原 (HLA) 基因型的測定……… 22
第八節: HLA-DR13亞型的鑑定…………………………………… 23
第九節: 腫瘤壞死因子啟動區-238, -308的測定……………… 27
第十節: 淋巴毒素阿爾法NcoI多樣性的測定…………………… 29
第十一節: 淋巴毒素阿爾法EcoRI多樣性的測定………………… 32
第十二節: 電泳膠回收檢體……………………………………… 35
第十三節: 統計的方法…………………………………………… 36
第三章、結果……………………………………………………… 38
第一部份: 氣喘與人類白血球抗原的關聯性…………………… 38
第二部份: 腫瘤壞死因子起動子的多樣性與氣喘的關…………… 38
第一節: 氣喘與血清中腫瘤壞死因子濃度的關係………………… 38
第二節: 腫瘤壞死因子起動子區域-308的多樣性………………… 38
第三節: TNF-308*A基因型與血清中腫瘤壞死因子濃度………… 44
第四節: HLA-DR13的生物意義……………………………………… 56
第五節: HLA-DR13基因型與TNF-308*A的生物意義……………… 56
第六節: 腫瘤壞死因子起動子區域-238的多樣性………………… 56
第七節: LtαNcoI*1與腫瘤壞死因子的關係……………………… 64
第三部份: 塵蟎 片段與HLA的關聯性……………………………………67
第一節: 過敏性體質與人類白血球抗原的關係…………………… 67
第二節: 人類白血球抗原基因型和IgE的總量………………………67
第三節: 氣喘與IgE的總量的關係………………………………… 76
第四節: 腫瘤壞死因子啟動區、 LTα的變異性的變異性和IgE的總
量…76
第五節: 特異的抗原決定位 (Epitope)………………………… 76
第六節: 塵蟎與人類白血球抗原基因型的關係…………………… 83
第四章、討論…………………………………………………………… 96
第一部份: 氣喘與人類白血球抗原的關聯性………………………… 96
第二部份: 腫瘤壞死因子起動子的多樣性對血清中腫瘤壞死因子濃度的
影響……………………………………………………………… 96
第一節: 氣喘與腫瘤壞死因子的關聯性…………………………… 96
第二節: 細胞激素的多樣性………………………………………… 97
第三節: 腫瘤壞死因子起動子區域-238的多樣性………………… 97
第四節: 腫瘤壞死因子起動子區域-308的多樣性………………… 97
第五節: TNF-308*A多樣性如何調控腫瘤壞死因子……………… 98
第六節: LtαNcoI*1 與腫瘤壞死因子的關係……………………… 99
第七節: HLA基因型與腫瘤壞死因子的關係……………………… 100
第八節: HLA-DR13的生物意義……………………………………… 100
第九節: DRB1*13與TNF-308*1,2的生物意義……………………… 102
第三部份: 塵蟎片段與人類白血球抗原的關聯性………………………102
第一節: 過敏性體質與人類白血球抗原的關係…………………… 102
第二節: 人類白血球抗原基因型和IgE的總量………………………103
第三節: 腫瘤壞死因子、 淋巴毒素多樣性與血清中IgE的濃度… 103
第四節: 特異的抗原決定位(Epitope)………………………………… 103
第五節: 臨床的運用…………………………………………… 104
第六節: 塵蟎與人類白血球抗原基因型的關係……………………… 104
參考文獻………………………………………………………………… 106

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