登革病毒，一種再度威脅人類的病原體，在全世界的熱帶和亞熱帶感染會造成登革熱的流行。它的傳播是透過埃及斑蚊或白線斑蚊所媒介傳染的，目前世界上有四種登革病毒血清類型(dengue l-4)。它所造成的疾病包括輕症的登革熱(Dengue fever)和嚴重致死的登革出血熱/登革休克症候群(Dengue hemorrhagic fever/ Dengue shock syndrome, DHF/DSS)。DHF/DSS的兩個重要特徵是血小板低下(thrombocytopenia)和血管壁的通透性增加使血漿外流(plasma leakage)。然而造成DHF/DSS的機制仍未明朗。由Dr. Halstead所提出的抗體依靠性增強作用(antibody-dependent enhancement, ADE)假說已主導登革研究與疫苗發展數十年，雖然解釋並連結了體外ADE現象和登革病毒感染造成DHF/DSS患者在流行病學上年齡雙高峰期(bimodal)的現象，然而參與出血過程的因子仍未被明確的確認。病毒感染造成免疫的不當反應，包括T細胞的活化，CD4/CD8的比例在感染後6-10天下降再回升(CD4/CD8 ratio inversion)和有CD69分子的表現在CD4或CD8細胞上。Immature neutrophils、monocytosis和atypical lymphocytosis的出現表示這些細胞在前期的大量破壞與後期的再生。PHA無法有效活化急性期病人PBMC的T細胞增生可能是和血液裡的單核球細胞減少有關。登革出血熱的幼童、嬰兒和成年人的血清分析含有大量的細胞激素表現(IL-6、IFN-g)。IL-6的表現先於IFN-g而IFN-g的表現又先於IL-10。為了研究DHF/DSS的免疫治病機轉，我們發展登革病毒感染A/J小鼠的模式，登革病毒基因可在小鼠感染後第二天的血液和2-3個星期後的腦和肝被偵測到。在這些組織中可分離出具感染力的病毒顆粒。最特別的是被登革病毒感染的小鼠不論是在初級感染或是次級感染都會有低血小板(thrombocytopenia)的現象，且抗血小板抗體(IgG及IgM兩類的抗體)可在小鼠感染早期的第四天被誘發。此外在急性期的DHF小孩血液裏的單核球細胞群(PBMC)被檢驗出有登革病毒抗原的表現。單核球細胞長久以來被認為是登革病毒感染的目標細胞並且在ADE上扮演重要角色。我們設立了以流式細胞儀分析法來定量被登革病毒感染的細胞，並用此方法研究ADE的機制。這方法可匹配傳統量測ADE的病毒斑試驗，但是更為方便、精準和省時。實驗顯示當人類B淋巴瘤細胞(BJAB)和周邊血單核球細胞（PBMC）在有稀釋的登革病患血清存在下被登革病毒感染會有ADE的現象發生。用小鼠製造出的登革單株抗體來研究ADE，結果顯示結構性蛋白的單株抗體(anti-E or anti-prM mAbs)的單株抗體，而非其他非結構性蛋白的單株抗體(anti-NS1 mAb)，會依抗體的濃度增強登革病毒感染帶有Fcg受器的細胞，例如P388D1、DC2.4 and K562。ADE的作用是倚賴完整的免疫球蛋白和目標細胞表面上表現的Fcg接受器。令人驚訝的是anti-prM的抗體較能夠增加病毒感染B融合瘤細胞和不帶有Fcg受器的細胞，例如BHK和A549細胞。Anti-prM抗體所認得的抗原決定位(epitope)是位於prM胺基酸序列的第53-67且靠近prM/M切割位附近稱為M3的胺基酸序列，這胺基酸序列可專一性地阻斷anti-prM抗體所主導的ADE作用。臨床登革病人血清檢體含有anti-M3的抗體並且證明能參與ADE的作用。Anti-prM抗體能增強病毒感染不帶有Fcg受器細胞的機制是anti-prM抗體結合到BHK或A549細胞上的自體抗原將登革病毒拉近至病毒受器，因而增加登革病毒的感染。分子模擬(molecular mimicry)的機制可能參與登革病毒的感染，病人血清中可偵測到抗血小板抗體與抗內皮細胞抗體。測試從登革病毒感染小鼠製造出的單株抗體結合血小板和內皮細胞的能力。大多數抗血小板抗體會和登革病毒NS1抗原有交互作用，有些anti-NS1、anti-E和anti-prM抗體會和內皮細胞有交互作用。在有補體或活化的細胞存在時，可能會有補體活化細胞毒殺(complement-mediated cellular cytotoxicity)和抗體依靠性細胞吞噬作用(antibody-dependent cellular phagocytosis)。能被anti-prM抗體辨認且可能是自體抗原候選蛋白之一的heat shock protein 60 (HSP60)，能在BHK、A549和內皮細胞上被確認。總括來說，登革病毒在二次感染時透過ADE作用會感染大量的細胞，被感染的細胞會釋放大量的病毒抗原刺激免疫系統來產生抗登革病毒抗體和高量的細胞激素，如IL-6、IFN-g，透過分子模擬的機制，所增加的抗登革病毒抗體會結合到表現在血小板、內皮細胞甚至是淋巴球上的自體抗原。在不適當的免疫反應下，活化的淋巴球細胞會釋放大量的細胞激素而活化單核球細胞和噬中性球。活化的吞噬細胞可能會吞噬或使被抗體結合的細胞功能失常，因而造成血小板低下(thrombocytopenia)和血管壁的通透性增加使血漿外流(plasma leakage)。這個自體抗體相關的致病機轉(autoantibody-associated pathogenesis)整合了ADE理論、T細胞活化反應、細胞激素流(cytokine storming)、巨噬細胞活化反應和自體免疫，而成為DHF的免疫致病機轉的基礎和提供未來登革疫苗發展的指引。

Dengue virus, a re-emerging infectious agent, may cause endemic dengue fever in tropical and sub-tropical region worldwide. Its transmission was relied on the domestic mosquito, Ades egypti or Ades albopictus, and there are four dengue serotypes existing in the world. The disease spectrum after dengue virus infection includes self-limited dengue fever (DF) and more complicated forms as dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS). Two important characteristics of severe DHF/DSS are thrombocytopenia and plasma leakage (hemorrhage), but the mechanism underlying DHF/DSS remains elusive. The antibody-dependent enhancement (ADE) hypothesis proposed by Dr. Halstead has governed the dengue research and vaccine development for many years. Although this theory explains the linking of the in vitro ADE effect and the bimodal age-incidence pattern of DHF/DSS, the factors participating in the hemorrhagic process are not identified yet. The aberrant immune status of dengue patients was evident with the transient CD4/CD8 ratio inversion at day 6-10 after fever onset and the expression of early activation marker, CD69 on both CD4 and CD8 cells. The appearance of bandemia, monocytosis and atypical lymphocytosis reflects the early depletion of these blood cells and the later hematopoietic generation of them. The impairment of PHA-stimulated T lymphocyte proliferation at the acute stage was correlated with the deficiency of monocytes in the peripheral blood. Massive cytokine production, such as IL-6 and IFN-g were detectable in the sera of patients from DHF children, DHF infants and DHF adults. The IL-6 expression was earlier than IFN-g, which was followed by IL-10. In order to investigate the immunopathogenesis of DHF/DSS, we developed a murine model for dengue infection in A/J mice. Dengue viral genomes could be detected in the blood (day 2) and the tissues of brain and liver (week 2 or 3) post dengue virus infection. Infectious viral particles were reisolated from those tissues. Interestingly, this murine model will develop transient thrombocytopenia in either primary or secondary infection. The anti-platelet antibodies (both IgM and IgG isotypes) were induced as early as day 4 post-infection. Furthermore, dengue viral antigens could be detected in the peripheral blood mononuclear cells (PBMCs) of DHF children at the acute stage. Monocytes have long been thought as an important target for dengue virus and play a role in the ADE phenomenon. A flow cytometric method was established for the quantification of dengue virus-infected cells and was applied to study the ADE mechanisms. This method was comparable to the conventional plaque assay method, but with more simple, accuracy and timesaving. The ADE phenomenon was demonstrated when B cell line (BJAB) or primary PBMCs were infected by dengue in the presence of diluted dengue immune serum. Anti-dengue monoclonal antibodies (mAbs) generated from dengue 2 virus-infected mice were used to study the ADE effect. Anti-dengue structure mAbs (anti-E or anti-prM mAbs), not anti-non-structure mAb (anti-NS1 mAb), were capable of enhancing dengue virus infection dose-dependently on the Fcg receptor-bearing cells, including P388D1, DC2.4 and K562. This ADE effect depends on the presence of whole anti-dengue immunoglobulins and the expression of the Fcg receptors on target cells. Surprisingly, anti-prM not anti-E mAb preferentially enhance dengue virus infection of B hybridomas and the cells without Fcg receptors, such as BHK and A549. The epitope peptide recognized by anti-prM mAb was mapped as M3, which is located at the a.a.53-67 of the prM protein nearby the prM/M cleavage junction. This M3 peptide could specifically block the anti-prM Ab-mediated ADE effect in a dose dependent manner. The anti-M3 human antibodies were detected in clinical dengue patient sera and could also mediate the ADE infection. The mechanism of anti-prM mAb mediated- ADE effect on non-Fcg R cells was that the anti-prM mAbs bind to BHK or A549 cell surface membrane proteins and bridge the viruses to the putative dengue virus receptors, thus enhancing dengue virus infection. Molecular mimicry mechanism may participate in dengue virus infection, and anti-platelet or anti-endothelial cell autoantibodies have been detected in dengue patients’ sera. Monoclonal antibodies from dengue virus- infected mice could also bind to platelets or endothelial cells. Most anti-platelet mAbs (with different platelet-binding profile) cross-react to dengue viral NS1 antigens, and some anti-NS1, anti-E and anti-prM mAbs cross-react to endothelial cells or lymphocytes. In the presence of complement or activated monocytes, these mAbs may mediate complement-dependent cytotoxicity or antibody-dependent cellular phagocytosis. One autoantigen candidate, heat shock protein 60 (HSP60), for anti-prM mAb was identified on the surface of BHK, A549 and endothelial cells. Collectively, dengue virus can infect more cells in secondary infection by the ADE effect, and infected cells will release more viral antigens to stimulate the immune system to produce more anti-dengue antibodies as well as the high level cytokines, such as IL-6, IFN-g. By the molecular mimicry mechanism, the increased anti-dengue antibodies (anti-E, anti-prM or anti-NS1 antibodies) will cross-react with self-antigens expressed on platelets, endothelial cells or even lymphocytes. In the aberrant immune response, activated lymphocytes will secret lots of cytokines, which may activate monocytes and polymorphonuclear (PMN) cells. Activated phagocytes might engulf or impair the antibody-bound cells and then cause thrombocytopenia and plasma leakage. This autoantibody -associated pathogenic mechanism integrating the ADE theory, activated T cell responses, cytokine storming, macrophage activation responses and autoimmunity will be the basis of DHF immunopathogenesis and provide a guide for future dengue vaccine development.

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