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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林國儀(Kuo-I Lin) | |
| dc.contributor.author | Li-Wen Lo | en |
| dc.contributor.author | 羅麗紋 | zh_TW |
| dc.date.accessioned | 2022-11-23T09:16:32Z | - |
| dc.date.available | 2021-08-18 | |
| dc.date.available | 2022-11-23T09:16:32Z | - |
| dc.date.copyright | 2021-08-18 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-04 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/79915 | - |
| dc.description.abstract | "長期以來在適應性免疫系統中B淋巴細胞扮演著至關重要的角色。由於這些B細胞不僅能產生體液免疫的抗體來調節免疫作用，還可以通過釋放細胞因子來影響免疫應答。然而B細胞除了能產生病原特異性抗體功能外，是否還透過其他的免疫機制來進一步參與病原感染的清除作用目前仍有許多疑問。邊緣區B細胞是一群位於脾臟濾泡區邊界的B細胞子集，可以通過多種機制迅速反應細菌的入侵並且提供第一波抗體的保護。另外，當嗜中性粒細胞探測到血源性細菌感染後會迅速遷移到感染部位進行細菌清除，並且會湧入脾臟邊緣區,有關在感染初期邊緣區嗜中性粒細胞積累的現象目前尚不清楚。本研究的目的就是要去釐清邊緣區B細胞如何對抗血源性細菌感染的作用機制，以及瞭解邊緣區B細胞可否與嗜中性粒細胞產生交互作用，來進一步協同發揮先天性免疫作用和適應性免疫作用的功能，啟動快速對抗細菌入侵的保護模式。我們使用邊緣區B細胞缺陷小鼠模式來分析抵抗細菌感染的作用，結果發現邊緣區B細胞缺陷型小鼠比野生型小鼠更容易受到系統性金黃色葡萄球菌的感染。在經過金黃色葡萄球菌感染後3-4小時，小鼠體內邊緣區B細胞中的白介素（IL）-6和趨化因子CXCLl/CXCL2的表達水平會顯著增加，但又會在感染後24小時降低。另一項結果也發現，經過金黃色葡萄球菌感染後脾臟內嗜中性粒細胞會顯著性增加趨化因子受體CXCR2的表達。利用共軛焦顯微鏡觀察小鼠脾臟經過螢光染色後厚組織切片的影像結果顯示，野生型小鼠中的脾臟嗜中性粒細胞在感染後3小時會形成嗜中性粒細胞簇並與邊緣區B細胞產生緊密接觸。而在邊緣區B細胞缺陷型小鼠和IL-6缺陷型模式小鼠中，這種脾臟嗜中性粒細胞簇的形成維持不久且都相對的少。若在金黃色葡萄球菌感染前1小時通過靜脈注射抗CXCL1和抗CXCL2抗體，先阻斷體內CXCL1/CXCL2的作用後，再將金黃色葡萄球菌以尾靜脈注射方式感染小鼠3小時，可以顯著的抑制脾臟嗜中性粒細胞向邊緣區的募集作用。利用體外細胞培養比較兩組實驗，一組是邊緣區B細胞加入肽聚醣(PGN)刺激後的單獨培養，另一組是邊緣區B細胞與嗜中性粒細胞也加入肽聚醣刺激下的共同培養，後者的實驗結果顯示細胞共同培養進一步增強了邊緣區B細胞的活化和分化的現象。通過螢光壽命成像（FLIM-FRET）所進行的Förster共振能量轉移分析，我們觀察到經過肽聚醣刺激後邊緣區B細胞和嗜中性粒細胞之間有細胞跟細胞直接相互作用的證據。此外，利用中和抗體耗竭小鼠體內的嗜中性粒細胞後，再經過金黃色葡萄球菌以尾靜脈感染２4小時後，測到小鼠體內的金黃色葡萄球菌特異性免疫球蛋白IgM的產量顯著性的減少。綜合上述結果，我們的研究顯示邊緣區B細胞在系統性金黃色葡萄球菌感染的早期階段，會迅速調節嗜中性粒細胞湧入脾臟中，再經由與嗜中性粒細胞的相互作用有助於邊緣區B細胞分化為分泌IgM的細胞，產生快速清除系統性細菌感染的免疫反應。" | zh_TW |
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| dc.description.tableofcontents | "口試委員會審定書 I 誌謝 II 中文摘要 III Abstract V Content Pages VIII Chapter 1 Introduction 1 1.1 B cell development 1 1.2 MZ B cell 3 1.3 Plasma cell 4 1.4 Immunoglobulin M (IgM) 5 1.5 Interleukin IL-6 6 1.6 Chemokine CXCL2 and receptor CXCR2 7 1.7 Neutrophil 8 1.8 Staphylococcus aureus 10 1.9 Aim of this thesis study 11 Chapter 2 Materials and Methods 13 2.1 Mice 13 2.2 Flow cytometry analysis 13 2.3 S. aureus infection and preparation of S. aureus lysates 14 2.4 Measurement of S. aureus-specific IgM by enzyme-linked immunosorbent assay (ELISA) 15 2.5 Neutrophil isolation 16 2.6 Microarray analysis 16 2.7 Real-time PCR analysis 17 2.8 Cytokine measurement 18 2.9 Confocal microscopy analysis of thick tissue sections 19 2.10 Förster resonance energy transfer by fluorescence lifetime imaging (FLIM-FRET) analysis 20 2.11 Statistical analysis 21 Chapter 3 Results 22 3.1 Mice lacking MZ B cells are more susceptible to S. aureus infection 22 3.2 S. aureus-specific IgM antibody production following bacterial infection 23 3.3 Cytokine IL-6 and chemokine CXCL2 were upregulated in MZ B cells after S. aureus infection 24 3.4 Neutrophils express increased levels of multiple chemokine receptors after S. aureus infection 26 3.5 IL-6 and CXCL1/CXCL2 are important for neutrophil swarming to the MZ area in response to systemic S. aureus infection 27 3.6 The neutrophil–MZ B cell interaction promotes IgM production 29 3.7 Neutrophil depletion affects MZ B-cell differentiation after bacterial infection 32 Chapter 4 Discussion 33 Chapter 5 References 43 Chapter 6 Figures 54 Figure 1. Defective MZB cells in RBP-J CKO mice. 54 Figure 2. The survival rate and body weight loss in RBP-J KO and WT mice after S. aureus infections. 55 Figure 3. The S. aureus-specific IgM antibodies released by MZ B cells after infection. 56 Figure 4. Kinetics of plasma cells in RBP-J CKO mice and WT mice during S. aureus infection. 57 Figure 5. The plasma cells in RBP-J CKO mice and WT mice 24 h after S. aureus infection. 58 Figure 6. Changes of cytokine and chemokine expression in MZ B cells and neutrophils in the early stage of S. aureus infection. 59 Figure 7. RT-qPCR analysis of the expression of chemokine-related genes in MZ B cells at 4 and 24 hours after S. aureus infection. 60 Figure 8. MZ B cells released the increased levels of cytokines IL-6, TNF, and IL-10 24 hours after PGN stimulation. 61 Figure 9. Kinetics of IL-6 in spleen of RBP-J CKO mice and WT mice during S. aureus infection. 62 Figure 10. MZ B cells produce IL-6 in response to S. aureus. 63 Figure 11. RT-qPCR analysis showing the expression of Cxcr1/Cxcr2 mRNA in splenic neutrophils after S. aureus infection. 64 Figure 12. Kinetics of the splenic neutrophils in RBP-J CKO mice and WT mice after systemic S. aureus infection. 65 Figure 13. Real time in vivo tracking of neutrophil swarming in spleen. 66 Figure 14. Kinetics of neutrophil swarming and regression in the MZ zone after S. aureus infection. 67 Figure 15. Confocal imaging analysis identifying the Ly6G-labeled area and CD1d-labeled area in MZ at indicated time points after systemic S. aureus infection. 69 Figure 16. Fluorescent labeling areas of Ly6G and CD1d positive area inside the white pulp from confocal microscope acquired images were calculated by MetaMorph software. 70 Figure 17. RT-qPCR analysis showing the expression of Cxcl1/Cxcl2 mRNA levels in MZ B cells of IL-6 KO mice after S. aureus infection. 71 Figure 18. Depletion of anti-Cxcl1/Cxcl2 in mice before S. aureus infection significantly prevents the recruitment of neutrophils to the spleen. 72 Figure 19. Confocal imaging analysis identifying the Ly6G-labeled area and CD1d-labeled area in MZ 3h after systemic S. aureus infection. 73 Figure 20. Confocal images illustrate that both populations of MZ B cells and neutrophils are closely together after infection. 74 Figure 21. Confocal images showing MZ B cells colocalized with neutrophils. 75 Figure 22. Schematic diagram of the co-culture experiment. 76 Figure 23. Flow cytometric analysis showing the up-regulation of CD69 and CD86 on MZ B cells co-cultured with neutrophils 3 hours after PGN stimulation. 77 Figure 24. Flow cytometric analysis showing the up-regulation of CD69 and CD86 on MZ B cells co-cultured with neutrophils 3 hours after heat-killed S. aureus stimulation. 78 Figure 25. FLIM-FRET analysis verifies the direct contact of neutrophils and MZ B cells after PGN stimulation. 79 Figure 26. The IgM production by MZ B cells co-cultured with neutrophils after PGN stimulation. 80 Figure 27. The IgM production by MZ B cells co-cultured with neutrophils after heat-killed S. aureus stimulation. 81 Figure 28. Neutrophil depletion in mice was confirmed by flow cytometry. 82 Figure 29 Depletion of neutrophils affects the survival of mice after S. aureus infection. 83 Figure 30. Effect of neutrophil deficiency on the activation of MZ B cells and IgM production in S. aureus-infected mice. 84 Figure 31. The population of macrophages present in RBP-J CKO mice. 85 Figure 32. MZ B cells recruit neutrophils to help the activation and differentiation of MZ B cells. 86" | |
| dc.language.iso | en | |
| dc.subject | 金黃色葡萄球菌 | zh_TW |
| dc.subject | 螢光共振能量轉移 | zh_TW |
| dc.subject | 白介素-6 | zh_TW |
| dc.subject | CXC-趨化因子受體2 | zh_TW |
| dc.subject | CXC-趨化因子2 | zh_TW |
| dc.subject | 邊緣區B細胞 | zh_TW |
| dc.subject | 嗜中性粒細胞 | zh_TW |
| dc.subject | neutrophil | en |
| dc.subject | CXCL2 | en |
| dc.subject | FLIM-FRET | en |
| dc.subject | IL-6 | en |
| dc.subject | Staphylococcus aureus | en |
| dc.subject | CXCR2 | en |
| dc.subject | Marginal zone B cell | en |
| dc.title | 邊緣區B細胞招募中性粒細胞來協助對抗系統性金黃色葡萄球菌感染之研究 | zh_TW |
| dc.title | Marginal zone B cells assist with neutrophil accumulation to fight against systemic Staphylococcus aureus infection | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 李建國(Hsin-Tsai Liu),顧家綺(Chih-Yang Tseng),徐立中,徐嘉琳 | |
| dc.subject.keyword | 邊緣區B細胞,嗜中性粒細胞,金黃色葡萄球菌,白介素-6,CXC-趨化因子2,CXC-趨化因子受體2,螢光共振能量轉移, | zh_TW |
| dc.subject.keyword | Marginal zone B cell,neutrophil,Staphylococcus aureus,IL-6,CXCL2,CXCR2,FLIM-FRET, | en |
| dc.relation.page | 86 | |
| dc.identifier.doi | 10.6342/NTU202101862 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2021-08-04 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
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