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系統識別號 U0026-1908201217474900
論文名稱(中文) 探討登革病毒非結構性蛋白1抗體調控巨噬細胞吞噬血小板在登革疾病的角色
論文名稱(英文) Role of anti-dengue virus nonstructural protein 1 antibodies in platelet phagocytosis by macrophage in dengue disease
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 100
學期 2
出版年 101
研究生(中文) 楊逸紋
研究生(英文) Yi-Wen Yang
學號 s46994099
學位類別 碩士
語文別 英文
論文頁數 62頁
口試委員 指導教授-林以行
口試委員-林秋烽
口試委員-葉才明
口試委員-羅柏安得森
中文關鍵字 登革病毒  非結構性蛋白1  吞噬血小板 
英文關鍵字 dengue virus  nonstructural protein 1  platelet phagocytosis 
學科別分類
中文摘要 登革疾病已經成為全球性重要的議題,由於全球貿易、旅遊盛行和過度的都市化,全世界已有超過100個國家籠罩在登革疾病的風險之下。血漿滲漏和血小板低下是嚴重登革疾病中主要的臨床症狀,目前已經有很多的假說嘗試解釋造成血小板低下的原因,包括血小板生成減少以及破壞增加,先前的研究指出,登革病毒非結構性蛋白1抗體會交叉反應到血小板上,並且和血小板低下有關,除此之外,過去的證據也指出,內皮細胞和巨噬細胞的活化和登革病毒的嚴重性有關。因此我們假設,巨噬細胞黏著在發炎的內皮細胞上,可能透過非結構性蛋白1抗體增強吞噬血小板的現象進而造成血小板低下。在我們的實驗中,發現被非結構性蛋白1抗體調理過的血小板,能夠大量的黏附在經由腫瘤壞死因子-alpha活化的內皮細胞上,而ICAM-1對於這樣的吸附反應扮演重要角色。將吞噬細胞和已經吸附在內皮細胞上之非結構性蛋白1抗體調理過的血小板進行共同培養,發現非結構性蛋白1抗體會增加血小板被吞噬的現象,而這個現象不僅與表現在吞噬細胞上的Fcgamma receptor也與表現在內皮細胞上的ICAM-1有很大的關聯性。我們的研究提供了一個比較全面性的模式,發現發炎的內皮細胞和非結構性蛋白1抗體共同參與在登革疾病造成血小板低下的現象。同時我們也指出非結構性蛋白1抗體透過巨噬細胞吞噬血小板的作用,可能與登革疾病中血小板低下的症狀有關,這樣子的發現可以做為往後研究登革病毒疫苗以及治療上的參考。
英文摘要 Dengue disease has become a major global problem. Due to the global trade, increasing travel between countries and urban crowding, more than 100 countries in the world are at the risk of dengue disease. The important clinical manifestations of severe dengue include plasma leakage and thrombocytopenia. There are many hypotheses concerning the pathogenesis of thrombocytopenia in dengue disease, which include decreased production and increased destruction of platelets. Previous studies showed that antibodies (Abs) against dengue virus (DV) nonstructural protein 1 (NS1) cross-react with platelets and are associated with thrombocytopenia. Furthermore, evidences show activation of endothelial cells and macrophages are related to dengue disease severity. We hypothesize that anti-DV NS1 Abs may play a role in platelet phagocytosis by macrophages seeding on inflamed endothelial cells. First, we found that TNF-alpha induced platelet adhesion to endothelial cells, even with anti-DV NS1 binding on the platelets. We further showed that ICAM-1 plays an important role in platelet adhesion to TNF-alpha-activated endothelial cells. By co-culturing anti-DV NS1 Abs-bound platelets with macrophages on TNF-alpha-activated endothelial cells, results showed that anti-DV NS1 Abs enhanced platelet phagocytosis by macrophages. Moreover, the expression of Fcgamma receptors on macrophages and ICAM-1 on endothelial cells both are critical in anti-DV NS1-mediated platelet phagocytosis. Our study provides a comprehensive model to reveal the role of anti-DV NS1 Abs and inflamed endothelial cells in the pathogenesis of thrombocytopenia in dengue disease. Also, anti-DV NS1 Abs may be associated with thrombocytopenia through enhancing platelet phagocytosis by macrophages. These findings provide information for dengue vaccine development and clinical treatment in dengue patients.
論文目次 中文摘要 I
Abstract II
致謝 IV
Contents V
Figure List VIII
Abbreviation List IX
Introduction 1
Characteristics of dengue virus 1
Epidemiology of dengue virus 3
Clinical manifestation of dengue disease 4
Pathogenesis of severe dengue disease 5
Viral pathogenesis 5
Host factors 6
Antibody-dependent enhancement 6
Complement and cross-reactive T cell response 7
Cytokine storm 7
Autoantibodies 8
Others 8
Hypothesis of thrombocytopenia in dengue disease 9
Interaction among endothelial cells, platelets, and
monocytes 10
Activation of endothelial cells in dengue disease 12
Objective and Specific Aims 13
Materials and Methods 15
A.Materials 15
A-1 Mice 15
A-2 Cell lines 15
A-3 Platelet preparation 15
A-4 Preparation of recombinant proteins and Abs 15
A-5 Drugs and reagents 16
A-6 Antibodies 18
A-7 Consumables 19
A-8 Instruments 20
B.Methods 20
B-1 Cell culture 20
B-2 Antibody titer determination 21
B-3 Surface expression of adhesion molecules 21
B-4 Surface expression of activation markers and FcgammaRs 22
B-5 Adhesion assay 22
B-6 Transfection with siRNA 23
B-7 Cross-binding activity of anti-DV NS1 Abs 23
B-8 Platelet phagocytic assay 23
B-9 Statistics 24
Results 25
1. The role of anti-DV NS1 Abs in platelet adhesion to activated ECs. 25
1.1. To investigate the role of adhesion molecules on platelet adhesion to TNF-alpha-activated ECs. 25
1.2. To detect the role of anti-DV NS1 Abs in platelet adhesion to activated ECs. 25
2. The role of anti-DV NS1 Abs in platelet phagocytosis by macrophages on an inflamed EC layer. 26
2.1. The expression of activation markers and FcgammaR is increased by IFN-gamma stimulation 26
2.2. FcgammaR plays a role in anti-DV NS1 Ab-mediated platelet adhesion to TNF-alpha-activated HMEC-1 cells. 27
2.3. Anti-DV NS1 Abs mediate platelet phagocytosis by macrophages on the TNF-alpha-activated endothelial cells. 27
2.4. ICAM-1 plays a role in platelet phagocytosis on TNF-alpha-activated endothelial cell layer. 28
2.5. FcgammaR mediates anti-DV NS1 Ab-mediated platelet phagocytosis on TNF-alpha-activated endothelial cell layer. 28
Discussion 30
References 37
Figures and figure legends 52
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