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系統識別號 U0026-1608201313490300
論文名稱(中文) 正常及缺乏活性氧分子的吞噬性白血球在分枝桿菌感染下對肉芽腫及三級淋巴組織形成之角色
論文名稱(英文) The role of phagocytic leukocytes with normal or defective reactive oxygen species production in granuloma and tertiary lymphoid tissue formation in mycobacterial infection
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 101
學期 2
出版年 102
研究生(中文) 劉榮海
研究生(英文) Jiung-Hai Liu
學號 s96001016
學位類別 碩士
語文別 英文
論文頁數 81頁
口試委員 指導教授-謝奇璋
口試委員-林秋烽
口試委員-蔡曜聲
中文關鍵字 結核病  分枝桿菌  菸鹼胺腺嘌呤二核磷酸氧化酶  活性氧分子  肉芽腫  三級淋巴結構 
英文關鍵字 Tuberculosis  NADPH oxidase 2  reactive oxygen species  M. bovis bacillus Calmette-Guérin  lung inflammation  granuloma  tertiary lymphoid tissue 
學科別分類
中文摘要 結核病是目前世界上已知最廣泛的傳染性疾病之一,全球每年約有百萬人以上因結核病而死亡。結核病的病原菌結核桿菌為一種細胞內細菌,在被巨噬細胞吞噬後,藉由抑制吞噬體和溶酶體結合以躲避毒殺,進而在細胞內存活並繁殖。當免疫系統無法有效清除結核桿菌時,會在感染部位形成肉芽腫 (granuloma)或是三級淋巴結構(tertiary lymphoid tissue, TLT)以控制感染。研究已證實缺乏p47phox (Ncf1-/-)的基因缺陷型老鼠的吞噬型白血球無法依靠菸鹼胺腺嘌呤二核磷酸氧化酶(NADPH oxidase)產生活性氧分子(ROS),因此較易被分枝桿菌感染。然而,白血球產生的活性氧分子在對抗分枝桿菌感染的機制中尚未清楚。因此本研究運用缺乏活性氧分子的基因缺陷型老鼠在感染減毒性牛分枝桿菌 (BCG)的情況下,探討活性氧分子對免疫反應的調控。實驗終將野生型老鼠及NADPH oxidase基因缺陷型老鼠經氣管感染BCG之後,觀察其肺部發炎反應。實驗發現NADPH oxidase基因缺陷型老鼠在感染後有較嚴重的發炎反應,包括細胞浸潤增加及促發炎激素如TNF-α及IL-17A的上升,同時肺部內肉芽腫的形成亦有相對增加。而檢測肺部灌流液及組織免疫螢光染色後,進一步發現在NADPH oxidase基因缺陷型老鼠增益性的發炎反應是由嗜中性球所誘發。然而當以螢光抗酸菌染色檢測肺部菌量時,發現雖然發炎反應在NADPH oxidase基因缺陷型老鼠有上升,但卻無法有效控制分枝桿菌的感染。再進一步的免疫螢光染色分析及趨化素檢測則發現,NADPH oxidase基因缺陷型老鼠在感染後會減少三級淋巴結構生成相關的趨化素如CCL19及CCL21的產生,因此相較於野生型老鼠之下,NADPH oxidase基因缺陷型老鼠無法有效形成三級淋巴結構,進而控制分枝桿菌的感染。經由這些結果顯示,吞噬型白血球上的NADPH oxidase所產生的活性氧分子不只在自然免疫的過程中幫助吞噬型白血球消滅感染的分枝桿菌,同時亦會影響適應性免疫的三級淋巴結構形成來控制分枝桿菌的感染。因此,活性氧分子的存在對宿主對抗結核桿菌感染的整體免疫反應都是不可或缺的。
英文摘要 Tuberculosis (TB) is a worldwide infectious disease which kills more than 1.5 million people every year. The pathogen of TB, Mycobacterium tuberculosis (M. tb), is an aerosol infectious pathogen which can infect macrophages and initiate local inflammation in the host lung, which recruits innate immune cells (including other macrophages, monocytes and polymorphonuclear cells (PMNs)) and lymphocytes to form granulomas. In addition, mycobacterial infection can also induce tertiary lymphoid tissue (TLT) formation, which is effective to activate adaptive immune response to control pathogen invasion. Within the immune response against M. tb infection, NADPH oxidase-produced reactive oxygen species (ROS) plays an important role. Previous studies have shown that mice with mutant p47phox (Ncf1-/-), which leads to lack of functional NADPH oxidase 2 (NOX2) and hence defective ROS production by leukocytes, are susceptible to mycobacterial infection. However, the specific roles of how leukocytes’ ROS resist mycobacteria invasion are still unclear. In this study, we intratracheally infected both wild type mice and Ncf1-/- mice with M. bovis bacillus Calmette-Guérin (BCG), and found that cell infiltration, proinflammatory cytokines production, granuloma number and bacterial load in the lungs of Ncf1-/- mice were increased when compared with WT mice. In addition, the numbers of neutrophils in Ncf1-/- mice were extremely higher than WT mice, and lead to forming the granuloma in Ncf1-/- mice. Moreover, Ncf1-/- mice had impaired ability to form well-organized tertiary lymphoid tissue after BCG infection due to reduced TLT-related chemokines production. In conclusion, our results showed that leukocyte-produced ROS can effectively eradicate mycobacterial infection and modulate both granuloma and TLT formation.
論文目次 Table of Contents
Abstract in Chinese 1
Abstract 3
Acknowledgement 4
Abbreviation 6
1. Introduction 13
1.1 Reactive oxygen species (ROS) 14
1.2 Tuberculosis 16
1.3 Early immune response against mycobacterial infection 17
1.3.1 Mycobacterial recognition 17
1.3.2 Cytokines/chemokines production during the infection 18
1.3.3 Control of mycobacterial infection 18
1.4 Granuloma 19
1.4.1 The structures of granulomas 19
1.4.2 The functions of granulomas 20
1.4.3 Neutrophils in granulomas 20
1.4.4 Dendritic cells in granulomas 21
1.4.5 T cells in granulomas 21
1.4.6 B cells in granulomas 21
1.5 Tertiary lymphoid tissue (TLT) 22
1.5.1 Features of TLT 22
1.5.2 Cytokines and chemokines in TLT formation 22
1.5.3 TLT in mycobacterial infection 23
1.6 Hypothesis 23
2. Materials and Methods 24
2.1 Mice 25
2.2 Mycobacterium bovis bacillus Calmette-Guérin (BCG) 25
2.3 Intratracheal infection of mice 25
2.4 Tuberculin skin test 26
2.5 Analysis of lung tissue histology 26
2.6 Cytokines and chemokines detection by ELISA 27
2.7 Fluorescent acid fast stain and determination of bacterial load 27
2.8 Analysis of bronchoalveolar lavage fluid (BALF) 28
2.9 Statistical analysis 28
3. Results 30
3.1 Intratracheally infection with mycobacterial induced positive DTH response 31
3.1.1 Both WT mice and Ncf1-/- mice had increased footpad swelling in DTH response 31
3.1.2 Ncf1-/- mice had increased neutrophil infiltration in the footpad in DTH response 31
3.2 Cell infiltration increased in lungs of Ncf1-/- mice after mycobacteria infection 32
3.2.1 Ncf1-/- mice had increased cell infiltration in acute infection 32
3.2.2 Ncf1-/- mice had increased cell infiltration in sub-acute infection 32
3.2.3 Mycobacterium marinum induced similar cell infiltration with attenuated BCG 32
3.2.4 Granuloma formation was accelerated in Ncf1-/- mice 32
3.3 Mycobactericidal ability was decreased in Ncf1-/- mice 33
3.4 Cytokines and chemokines production were different in WT mice and Ncf1-/- mice after mycobacteria infection 34
3.4.1 TNF-α production was increased in Ncf1-/- mice 34
3.4.2 Proinflammatory cytokines production was increased in Ncf1-/- mice 34
3.4.3 IL-17A production was increased in Ncf1-/- mice 35
3.4.4 Ncf1-/- mice expressed higher level of CXCL13, while produced reduced amount CCL19 and CCL21 during mycobacterial infection 35
3.5 Neutrophil was dominant BALF of ROS deficiency mice after mycobacterial infection 35
3.6 Ncf1-/- mice formed neutrophil-dominant granulomas after mycobacteria infection 36
3.6.1 Macrophage distribution was scattered in Ncf1-/- mice 36
3.6.2 Neutrophils were centered in granuloma formation in Ncf1-/- mice 36
3.7 Ncf1-/- mice had higher amount of macrophage, neutrophil and B lymphocyte, but decreased the cell number of T lymphocyte and HEV after BCG infection 37
3.7.1 Both macrophage and neutrophil increased in Ncf1-/- mice 37
3.7.2 Ncf1-/- mice had differ amount of TLT-related cells 37
3.8 Ncf1-/- mice formed poorly-organized tertiary lymphoid tissues after mycobacteria infection 38
3.8.1 WT mice formed typical TLT during mycobacterial infection 38
3.8.2 Ncf1-/- mice had impaired TLT forming ability 38
4. Discussion 39
4.1 BCG induced similar infiltration response with RD-1-contained virulent M. marinum 40
4.2 Difference in immune defense against mycobacteria in WT mice and Ncf1-/- mice 41
4.3 Immune response against mycobacterial infection 42
4.3.1 Proinflammatory cytokine production in BCG infection 42
4.3.2 Neutrophil accumulate in BCG infection 42
4.4 The role of granuloma in defense against mycobacteria 43
4.5 TLT in mycobacterial infection 45
4.6 Future direction 45
5. References 48
6. Figures and legends 59
Figure 1. 60
Figure 1. Mice intratracheally infected with mycobacteria induced positive DTH response 62
Figure 2. 63
Figure 2. ROS deficiency increased the cell infiltration and granuloma formation after mycobacteria infection 64
Figure 3. 65
Figure 3. Mycobactericidal ability was decreased in Ncf1-/- mice 67
Figure 4. 68
Figure 4. Proinflammation cytokines and chmokines production in BCG-infected mice 70
Figure 5. 71
Figure 5. Neutrophil was dominant in the BALF of ROS deficiency mice after mycobacteria infection 72
Figure 6. 73
Figure 6. Ncf1-/- mice formed neutrophil-dominant granulomas after mycobacteria infection 75
Figure 7. 76
Figure 7. Ncf1-/- mice had higher amount of macrophage, neutrophil and B lymphocyte, but decreased the cell number of T lymphocyte and HEV after BCG infection 77
Figure 8. 78
Figure 8. Ncf1-/- mice formed poorly-organized tertiary lymphoid tissues after mycobacteria infection 81
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