中文摘要
登革病毒(dengue virus, DV) 的感染會導致血管滲漏與出血的症狀，先前的研究顯示登革病毒非結構性蛋白質1(DV NS1)的抗體會與內皮細胞有結合的現象,並且導致內皮細胞凋亡與活化宿主的免疫反應。在本論文中，我們發現DV NS1的抗體會辨識內皮細胞表面之目標蛋白質(target proteins)，包括氫離子傳送蛋白/ATP合成酶之刍鏈(刍 chain of H+-transporter/ATP synthase, ATPase 刍 chain)、蛋白質双硫鍵轉位酶(protein disulfide isomerase, PDI)、中間絲蛋白(vimentin intermediate filament)與60 kD熱休克蛋白(heat shock protein 60, HSP60)，這些目標蛋白質表現於內皮細胞株HMEC-1的細胞表面，並與anti-DV NS1的抗體結合到內皮細胞的位置相同(co-localization)。而這些目標蛋白質的抗體與內皮細胞結合的現象會被DV NS1所抑制。Anti-DV NS1抗體會與目標蛋白質結合，反之亦然。根據這些實驗結果顯示在DV NS1與目標蛋白質之間可能具有分子相似性(molecular mimicry)的機制存在。利用胺基酸序列比對與辨識決定位(epitope)分析DV NS1與目標蛋白質，發現DV NS1的C端胺基酸第311-330 (P311-330)可能是重要的epitope，並且與目標蛋白質具有序列上的相似性。其中以ATPase、PDI和HSP60與DV NS1的胺基酸P311-330序列相似度較高，與DV NS1結合到anti-ATPase、anti-PDI與anti-HSP60抗體的程度較高於anti-vimentin抗體的結果相符合。在登革出血熱(DHF)病人的血清研究發現，病人血清結合到內皮細胞的程度會被P311-330合成的片段胜肽所抑制。先前的研究證實anti-DV NS1抗體亦會與血小板有交叉反應(cross-reactivity)的情形。在本研究中，我們發現anti-DV NS1抗體可以辨識到血小板細胞膜上的PDI，anti-DV NS1抗體會抑制PDI的活性與血小板的凝集作用，而抗體經過PDI預先吸附處理(pre-absorption)可以清除其所造成的抑制現象。Anti-PDI抗體亦會與P311-330的合成片段胜肽結合，而預先處理P311-330可以減少anti-DV NS1與anti-PDI抗體結合到血小板的程度。與anti-DV NS1抗體作用相似，anti-P311-330抗體會減低PDI的活性與血小板的凝集作用。除此之外，DHF病人的血清交叉反應到血小板的程度可以被PDI與P311-330的預先吸附處理所抑制，而DHF病人血清抑制血小板凝集的作用亦會被PDI與P311-330的預先吸附處理所清除。因此，anti-DV NS1抗體會與血小板細胞表面上的PDI結合進而抑制血小板的凝集作用，這與登革致病機制可能有相關性。此外，DV NS1的P311-330是登革熱致病機轉中自體免疫反應的重要辨識決定位。

Abstract
Dengue virus (DV) infection may cause vascular leakage and hemorrhage. We previously showed a mechanism of molecular mimicry in which antibodies against DV nonstructural protein 1 (NS1) cross-reacted with endothelial cells and induced them to undergo apoptosis and immune activation. In this study, we found that the target proteins recognized by anti-DV NS1 antibodies on HMEC-1 endothelial cells were beta chain of H+-transporter/ATP synthase (ATPase 刍 chain), protein disulfide isomerase (PDI), vimentin intermediate filament, and heat shock protein 60 (HSP60). We confirmed their expression on the HMEC-1 cell surface. Co-localization was shown between the binding sites of anti-DV NS1 antibodies and target proteins on HMEC-1 cells. The antibodies against the target proteins cross-reacted with HMEC-1 cells, but DV NS1 protein pre-absorption inhibited cross-reaction. The cross-reactivity of anti-DV NS1 antibodies with target proteins, and vice versa, indicated a molecular mimicry mechanism. Synthetic peptides of NS1 amino acid residues 311-330 (P311-330), a predicted epitope analyzed using homologous alignments between the C-terminus of DV2 NS1 and target proteins, were bound to anti-ATPase, anti-PDI, and anti-HSP60 antibodies, but much less to anti-vimentin antibodies. The cross-reactivity of dengue hemorrhagic fever (DHF) patient sera with HMEC-1 cells was blocked by P311-330 pre-absorption, which showed that anti-DV NS1-recognized molecules on the endothelial cell surface that may be involved in the pathogenesis of dengue hemorrhage, and that P311-330 is one of the shared epitopes between DV NS1 and its target proteins. Our previous study also showed that antibodies against DV NS1 cross-reacted with platelets. In this study, we demonstrate that protein disulfide isomerase (PDI) on platelet surface is recognized by anti-DV NS1 antibodies. Anti-DV NS1 inhibited PDI activity and platelet aggregation, and both inhibitory effects were prevented when anti-DV NS1 were pre-absorbed with PDI. Anti-PDI antibodies bound to P311-330. The platelet binding activities of anti-PDI and anti-DV NS1 antibodies were reduced by P311-330 pre-absorption. Similar to the findings using anti-DV NS1, antibodies against P311-330 bound to PDI and platelets, followed by inhibition of PDI activity and platelet aggregation. Furthermore, the cross-reactivity of DHF patient sera with platelets was reduced when patient sera were pre-absorbed with PDI or P311-330. DHF patient sera also inhibited platelet aggregation, and this inhibitory effect was blocked by PDI or P311-330 pre-absorption. Therefore, anti-DV NS1 antibodies cross-react with PDI on platelet surface causing inhibition of platelet aggregation, which may have implications in dengue disease pathogenesis. Moreover, the amino acid residues 311-330 of DV NS1 possess an important epitope, which is involved in the autoimmune response of DV pathogenesis.

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