登革熱 (dengue fever, DF) 的發生率在過去 50 年來被估計約有 30 倍的快速增加。登革熱在臨床上的表徵是從一般簡單的發燒與身體酸痛的症狀到可能有致命危險的登革出血熱 (dengue hemorrhagic fever, DHF)。越來越多的研究顯示關於登革熱的疾病嚴重程度需要一個更好的分類標準，來釐清登革感染症的免疫致病機制，用以預防或是處理嚴重的登革出血熱。在本研究論文我們試圖探究是否有不同的免疫機制調控病人出血或血管滲漏的病症。本研究先是以臨床病人為對象，比較臨床表徵與實驗室數據，包括病毒量、 T 輔助細胞激素 (Th1/Th2)與血管滲漏相關因子來探討登革熱與登革出血熱病人之間的差異。接著再從登革熱病人中，定義出一群有出血表徵但沒有符合登革出血熱 (DHF) 定義的病人，並命之為出血傾向登革熱 (DF with bleeding tendency, DF w/B)，做進一步的研究分析。結果發現病毒血量在登革熱、出血傾向登革熱與登革出血熱三組病人之間並無差異。但是登革熱病人有代表免疫陽性 (T helper type 1, Th1) 較高的 IFNr表現 (70.0 ± 10.7 vs. 33.1 ± 8.0 vs. 33.0 ± 7.1 pg/ml; DF vs. DF w/B, p = 0.009; DF vs. DHF, p = 0.002)，出血傾向登革熱與登革出血熱&#63864;組病人與登革熱病人相比，IL-10 產&#63870;&#64038;有明顯差&#63842;的增加 (14.3 ± 4.1 vs. 26.2 ± 3.3 vs. 26.0 ± 3.5 pg/ml; DF vs. DF w/B, p = 0.023; DF vs. DHF, p = 0.016)；而且出血傾向登革熱與登革出血熱&#63864;組病人也&#64038;有較高的二次感染頻&#63841; (DF w/B vs. DHF vs. DF: 50.0%、 74.4% 與 14.3%， p < 0.001)。&#63847;同的是登革出血熱而非出血傾向登革熱的病人有明顯較高的血管滲&#63822;相關因子：sVCAM-1, PGE2 與 TNFα 表現。出血傾向登革熱與登革出血熱病人相比，有明顯登革熱, 登革出血熱, 免疫致病, 二次感染, 細胞較高的血小板&#63849;&#63870; (DF w/B vs. DHF: 66.0 ± 8.3 與 20.7 ± 2.1 x109/L, p < 0.001) ，但代表肝功能的丙胺酸轉胺酵素 (ALT) 較低 (DF w/B vs. DHF: 56.3 ± 7.7 與 144.7 ± 20.5 IU/L)。本研究&#63809;文關於登革熱、出血傾向登革熱與登革出血熱三組病人的免疫機制提供&#63930;新的視野。登革熱病人與 Th1 反應有關，出血傾向登革熱病人則和改變的 Th2 反應有關；而登革出血熱病人除&#63930;與改變的 Th2 反應有關外，也與血管損傷的擴大有關。釐清登革熱、出血傾向登革熱與登革出血熱之免疫機制，將有助於&#63990;床醫師針對某些尚有出血表徵的登革熱病人提供&#63745;合適的治&#63937;與預防。

Incidence of dengue fever (DF) has been estimated a 30 fold increase in the past 50 years. Clinical manifestations of DF range from a simple febrile illness with physical soreness to life-threatening dengue hemorrhagic fever (DHF). The need for a better classification of the severity in DEN infections has been proposed to clarify the immunopathogenesis for the prevention and management of serious DEN infections. We attempted to investigate whether different mechanisms involved in the varied manifestations of bleeding tendency and vascular leakage in DF. In a hospital-based study, we first compared clinical features as well as laboratory data including virus load, T helper (Th1/Th2) cytokines, and vascular leakage-related mediators between patients with DHF and DF. Moreover, we defined another class of patients associated with bleeding tendency but not fulfilled with DHF criteria, called DF w/B, for a further comparison. The virus load in blood was not significantly different among DF, DHF and DF w/B. DF patients had a higher Th1 cytokine, IFNr, expression (70.0 ± 10.7 vs. 33.1 ± 8.0 vs. 33.0 ± 7.1 pg/ml; DF vs. DF w/B, p = 0.009; DF vs. DHF, p = 0.002), and both DHF and DF w/B patients had a significantly higher IL-10 levels (14.3 ± 4.1 vs. 26.2 ± 3.3 vs. 26.0 ± 3.5 pg/ml; DF vs. DF w/B, p = 0.023; DF vs. DHF, p = 0.016) than DF patients. Both DHF and DF w/B patients also had a higher rate of secondary dengue infection (DF w/B vs. DHF vs. DF: 50.0%, 74.4% and 14.3%， p < 0.001). By contrast, DHF but not DF w/B patients had significantly higher vascular leakage-related mediators: sVCAM-1, PGE2 and TNFα levels than DF patients. Patients with DF w/B had a higher platelet counts (DF w/B vs. DHF: 66.0 ± 8.3 vs. 20.7 ± 2.1 x109/L, p < 0.001) but lower ALT levels than those with DHF (DF w/B vs. DHF: 56.3 ± 7.7 and 144.7 ± 20.5 IU/L). This study provides new insight to different immune mechanisms involved in patients with DF, DF w/B, and DHF. DF involves augmented Th1 reaction, and DF w/B involves altered Th2 reaction, but DHF involves both altered Th2 reaction and augmented vascular insult. Clarification of the immune mechanisms among DF, DFw/B and DHF will facilitate certain specific treatment and prevention of DF patients from varied bleeding tendency and vascular leakage manifestations.

中文摘要 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... II
英文摘要 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... IV
致謝銘 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...VI
表目錄 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...X
圖目錄 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...X
縮寫索引 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...XII
一、緒論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...1
二、研究動機與實驗設計 ... ... ... ... ... ... ... ... ... ... ...15
三、材料與方法 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...19
四、結果 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...32
五、討論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...47
六、結論 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...60
七、參考文獻 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...62
八、作者簡歷與論文發表 ... ... ... ... ... ... ... ... ... ... ...105

Altarescu, G., Zimran, A., Michelakakis, H., Elstein, D., 2005. TNF-alpha levels and TNF-alpha gene polymorphism in type I Gaucher disease. Cytokine. 31, 149-152.
Anantapreecha, S., Chanama, S., A-nuegoonpipat, A., Naemkhunthot, S., Sa-Ngasang, A., Sawanpanyalert, P., Kurane, I., 2005. Serological and virological features of dengue fever and dengue haemorrhagic fever in Thailand from 1999 to 2002. Epidemiol. Infect. 133, 503-507.
Avila-Aguero, M.L., Avila-Aguero, C.R., Um, S.L., Soriano-Fallas, A., Canas-Coto, A., Yan, S.B., 2004. Systemic host inflammatory and coagulation response in the Dengue virus primo-infection. Cytokine 27, 173-179.
Bandyopadhyay, S., Lum, L.C., Kroeger, A., 2006. Classifying dengue: a review of the difficulties in using the WHO case classification for dengue haemorrhagic fever. Trop. Med. Int. Health. 11, 1238-1255.
Bethell, D.B., Flobbe, K., Cao, X.T., Day, N.P., Pham, T.P., Buurman, W.A., Cardosa, M.J., White, N.J., Kwiatowski., D., 1998. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J. Infect. Dis. 177, 778-782.
Bhakdi, S., Kazatchkine, M.D., 1990. Pathogenesis of dengue: an alternative hypothesis. Southeast Asian J. Trop. Med. Public Health 21, 652-657.
Bhamarapravati, N., 1989. Hemostatic defects in dengue hemorrhagic fever. Rev. Infect. Dis. 11, S826-829.
Bielefeldt-Ohmann, H., 1997. Pathogenesis of dengue virus diseases: missing pieces in the jigsaw. Trends Microbiol. 5, 409-413.
Blanco-Quiros, A., Casado-Flores, J., Garrote Adrados, J.A., Moro, M.N., Anton, J.A., Sanz, E.A., 2005. Interleukin-13 is involved in the survival of children with sepsis. Acta Paediatr. 94, 1828-1831.
Bozza, F.A., Salluh, J.I., Japiassu, A.M., Soares, M., Assis, E.F., Gomes, R.N., Bozza, M.T., Castro-Faria-Neto, H.C., Bozza, P.T., 2007. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit. Care. 11, R49.
Braga, E.L., Moura, P., Pinto, L.M., Ignacio, S.R., Oliveira, M.J., Cordeiro, M.T., Kubelka, C.F., 2001. Detection of circulant tumor necrosis factor-alpha, soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever. Mem. Inst. Oswaldo. Cruz. 96, 229-232.
Bruno, C.M., Sciacca, C., Cilio, D., Bertino, G., Marchese, E., Politi, G., Chinnice, L., Pellicano, R., 2005. Chronic anaemia and adhesion molecules in patients with liver cirrhosis. A preliminary report. Minerva. Gastroenterol. Dietol. 51, 187-191.
Burke, T., 1968. Dengue haemorrhagic fever: a pathological study. Trans. R. Soc. Trop. Med. Hyg. 62, 682-692.
Butthep, P., Chunhakan, S., Tangnararatchakit, K., Yoksan, S., Pattanapanyasat, K., Chuansumrit, A., 2006. Elevated soluble thrombomodulin in the febrile stage related to patients at risk for dengue shock syndrome. Pediatr. Infect. Dis. J. 25, 894-897.
Chakravarti, A., Kumaria, R., 2006. Circulating levels of tumour necrosis factor-alpha and interferon-gamma in patients with dengue & dengue haemorrhagic fever during an outbreak. Indian J. Med. Res. 123, 25-30.
Chambers, T.J., McCourt, D.W., Rice, C.M., 1989. Yellow fever virus proteins NS2A, NS2B, and NS4B: identification and partial N-terminal amino acid sequence analysis. Virology 169, 100-109.
Chambers, T.J., McCourt, D.W., Rice, C.M., 1990. Production of yellow fever virus protein in infected cells: identification of discrete polyprotein species and analysis of cleavage. Virology 177, 159-174.
Chang, D.M., Shaio, M.F., 1994. Production of interleukin-1 (IL-1) and IL-1 inhibitor by human monocytes exposed to dengue virus. J. Infect. Dis. 170, 811-817.
Chao, D.Y., Lin, T.H., Hwang, K.P., Huang, J.H., Liu, C.C., King, C.C., 2004. 1998 dengue hemorrhagic fever epidemic in Taiwan. Emerg. Infect. Dis. 10, 552-554.
Chareonsirisuthigul, T., Kalayanarooj, S., Ubol, S., 2007. Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells. J. Gen. Virol. 88, 365-375.
Chaturvedi, U.C., Elbishbishi, E.A., Raghupathy, R., Nagar, R., Tandon, R., Younis, O.I., Azizeih, F., 1999a. Sequential production of cytokines by dengue virus infected human peripheral blood leukocyte cultures. J. Med. Virol. 59, 335-340.
Chaturvedi, U.C., Raghupathy, R., Pacsa, A.S. Elbishbishi, E.A., Agarwal, R., Nagar, R., Misra, A., Kapoor, S., Mathur, A., Khan, M.A.Y., Azizieh, F., 1999b. Shift from a Th1-type response toTh2-type in dengue haemorrhagic fever. Curr. Sci. 76, 63-69.
Chaturvedi, U.C., Agarwal, R., Elbishbishi, E.A., Mustafa, A.S., 2000. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol. Med. Microbiol. 28, 183-188.
Chen, R.F., Yeh, W.T., Yang, M.Y., Yang, K.D., 2001. A model of the real-time correlation of viral titers with immune reactions in antibody-dependent enhancement of dengue-2 infections. FEMS Immunol. Med. Microbiol. 30, 1-7.
Chen, R.F., Liu, J.W., Yeh, W.T., Wang, L., Chang, J.C., Yu, H.R., Cheng, J.T., Yang, K.D., 2005. Altered T helper 1 reaction but not increase of virus load in patients with dengue hemorrhagic fever. FEMS Immunol. Med. Microbiol. 44, 43-50.
Chen, R.F., Chang, J.C., Yeh, W.T., Lee, C.H., Liu, J.W., Eng, H.L., Yang, K.D., 2006. Role of vascular cell adhesion molecules and leukocyte apoptosis in the lymphopenia and thrombocytopenia of patients with severe acute respiratory syndrome (SARS). Microbes Infect. 8, 122-127.
Chen, Y.C., Wang, S.Y., King, C.C., 1999. Bacterial lipopolysaccharide inhibits dengue virus infection of primary human monocytes/macrophages by blockade of virus entry via a CD14-dependent mechanism. J. Virol. 73, 2650-2657.
Chien, Y.H., Chang, K.W., Yang, Y.H., Lu, M.Y., Lin, Y.T., Chiang, B.L., 2003. Association between levels of TNF-alpha and TNF-alpha promoter -308 A/A polymorphism in children with Kawasaki disease. J. Formos. Med. Assoc. 102, 147-150.
Chua, M.N., Molanida, C., Guzman, R., Laberuza, F., 1993. Prothrombin time and partial thromboplastin time as a predictor of bleeding in patients with dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Public Health 24, 141-143.
Chung, H.L., Park, H.J., Kim, S.Y., Kim, S.G., 2007. Age-related difference in immune responses to respiratory syncytial virus infection in young children. Pediatr. Allergy Immunol. 18, 94-99.
Diamond, M.S., Edgil, D., Roberts, T.G., Lu, B., Harris, E., 2000. Infection of human cells by dengue virus is modulated by different cell types and viral strains. J. Virol. 74, 7814-7823.
Dinarello, C.A., 1991. The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome. J. Infect. Dis. 163, 1177-1184.
Dokka, S., Shi, X., Leonard, S., Wang, L., Castranova, V., Rojanasakul, Y., 2001. Interleukin-10-mediated inhibition of free radical generation in macrophages. Am. J. Physiol. Lung Cell Mol. Physiol. 280, L1196-L1202.
Elias, J.A., Kang, M.J., Crouthers, K., Homer, R., Lee, C.G., 2006. State of the art. Mechanistic heterogeneity in chronic obstructive pulmonary disease: insights from transgenic mice. Proc. Am. Thorac. Soc. 3, 494-498.
Falgout, B., Chanock, R., Lai, C.J., 1989. Proper processing of dengue virus nonstructural glycoprotein NS1 requires the N-terminal hydrophobic signal sequence and the downstream nonstructural protein NS2A. J. Virol. 63, 1852-1860.
Falgout, B., Pethel, M.Y., Zhang, M., Lai., C.J., 1991. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J. Virol. 65, 2467-2475.
Falgout, B., Miller, R.H., Lai., C.J., 1993. Deletion analysis of dengue virus type 4 nonstructural protein NS2B: identification of a domain required for NS2B-NS3 protease activity. J. Virol. 67, 2034-2042.
Fantini, M.C., Becker, C., Tubbe, I., Nikolaev, A., Lehr, H.A., Galle, P., Neurath, M.F., 2006. Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 55, 671-680.
Fernandez-Mestre, M.T., Gendzekhadze, K., Rivas-Vetencourt, P., Layrisse, Z., 2004. TNF-alpha-308A allele, a possible severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens. 64, 469-472.
Gagnon, S.J., Ennis, F.A., Rothman, A.L., 1999. Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T-lymphocyte clones. J. Virol. 73, 3623-3629.
Gately, S., Li, W.W., 2004. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 31, 2-11.
Gonzalez, S., Rodrigo, L., Martinez-Borra, J., Lopez-Vazquez, A., Fuentes, D., Nino, P., Cadahia, V., Saro, C., Dieguez, M.A., Lopez-Larrea, C., 2003. TNF-alpha -308A promoter polymorphism is associated with enhanced TNF-alpha production and inflammatory activity in Crohn's patients with fistulizing disease. Am. J. Gastroenterol. 98, 1101-1106.
Gorbalenya, A.E., Donchenko, A.P., Koonin, E.V. Blinov, V.M., 1989. N-terminal domains of putative helicases of flavi- and pestiviruses may be serine protaeses. Nucleic Acids Res. 17, 3889-3897.
Gratchev, A., Kzhyshkowska, J., Utikal, J., Goerdt, S., 2005. Interleukin-4 and dexamethasone counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand. J. Immunol. 61, 10-17.
Green, S., Vaughn, D.W., Kalayanarooj, S., Nimmannitya, S., Suntayakorn, S., Nisalak, A., Lew, R., Innis, B.L., Kurane, I., Rothman, A.L., Ennis, F.A., 1999. Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. J Infect Dis. 179, 755-62.
Grutz, G., 2005. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J. Leukoc. Biol. 77, 3-15.
Gubler, D.J., Reed, D., Rosen, L., Hitchcock., J.C.J., 1978. Epidemiologic, clinical and virological observations on dengue in the Kingdom of Tonga. Am. J. Trop. Med. Hyg. 27, 581-589.
Gubler, D.J., Suharyono, W., Lubis, I., Eram, S., Saroso, J.S., 1979. Epidemic dengue hemorrhagic fever in rural Indonesia. I. Virological and epidemiological studies. Am. J. Trop. Med. Hyg. 28, 701-710.
Gubler, D.J. 1998. Dengue and dengue hemorrhagic fever. Clin. Microbiol. Rev. 11, 480-496.
Guzman, M.G., Kouri, G., 2002. Dengue and update. Lancet Infect. Dis. 2, 33-42.
Guzman, M.G., 2005. Deciphering dengue: the Cuban experience. Science 309, 1495-1497.
Hall, W. C., Crowell, T.P., Watts, D.E., Barros, V.L., Kruger, H., Pinheiro, F., Peters, C.J., 1991. Demonstration of yellow fever and dengue antigens in formalin-fixed paraffin-embedded human liver by immunohistochemical analysis. Am. J. Trop. Med. Hyg. 45, 408-417.
Halstead, S.B., 1970. Observations related to pathogenesis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J. Biol. Med. 42, 350-362.
Halstead, S.B., O’Rourke, E.J., 1977. Antibody-enhanced dengue virus infection in primate leukocytes. Nature 265, 739-741.
Halstead, S.B., 1979. In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. J. Infect. Dis. 140, 527-533.
Halstead, S.B., 1982. Dengue: hematologic aspects. Semin. Hematol. 19, 116-131.
Halstead, S.B., Venkateshan, C.N., Gentry, M.K., Larsen, L.K., 1984. Heterogeneity of infection enhancement of dengue 2 strains by monoclonal antibodies. J. Immunol. 132, 1529-1532.
Halstead, S.B., 1988. Pathogenesis of dengue: challenges to molecular biology. Science 239, 476-481.
Harris, E., Videa, E., Perez, L., Sandoval, E., Tellez, Y., Perez, M.L., Cuadra, R., Rocha, J., Idiaquez, W., Alonso, R.E., Delgado, M.A., Campo, L.A., Acevedo, F., Gonzalez, A., Amador, J.J., Balmaseda, A., 2000. Clinical, epidemiologic, and virologic features of dengue in the 1998 epidemic in Nicaragua. Am. J. Trop. Med. Hyg. 63, 5-11.
Hathirat P., Isarangkura, P., Srichaikul, T., Survatte, C., Mitrakul., C., 1993. Abnormal hemostasis in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Public Health 24, 80-85.
Henchal, E. A., Putnak., J.R., 1990. The dengue viruses. Clin. Microbiol. Rev. 3, 376-396.
Hirasawa, K., Kim, A., Han, H.S., Han, J., Jun, H.S., Yoon, J.W., 2003. Effect of p38 mitogen-activated protein kinase on the replication of encephalomyocarditis virus. J. Virol. 77, 5649-5656.
Hober, D., Poli, L., Roblin, B., Gestas, P., Chungue, E., Granic, G., Imbert, P., Pecarere, J.L., Vergez-Pascal, R., Wattre, P., 1993. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am. J. Trop. Med. Hyg. 48, 324-331.
Hober, D., Delannoy, A.S., Benyoucef, S., De Groote, D., Wattre, P., 1996. High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol. Immunol. 40, 569-573.
Hosokawa, Y., Hosokawa, I., Ozaki, K., Nakae, H., Matsuo, T., 2006. Cytokines differentially regulate ICAM-1 and VCAM-1 expression on human gingival fibroblasts. Clin. Exp. Immunol. 144, 494-502.
Innis, B.L., 1995. Dengue and dengue hemorrhagic fever, p 103. In: Porterfield JS (Eds), Kass handbook of infectious diseases: exotic viral diseases. London: Chapman and Hall.
Inobe, J., Slavin, A.J., Komagata, Y., Chen, Y., Liu, L., Weiner, H.L., 1998. IL-4 is a differentiation factor for transforming growth factor-beta secreting Th3 cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. Eur. J. Immunol. 28, 2780-2790.
Jonuleit, H., Schmitt, E., Kakirman, H., Stassen, M., Knop, J., Enk, A.H., 2002. Infectious tolerance: Human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J. Exp. Med. 196, 255–260.
Kalayanarooj, S., Vaughn, D.W., Nimmannitya, S., Green, S., Suntayakorn, S., Kunentrasai, N., Viramitrachai, W., Ratanachueke, S., Kiatpolpoj, S., Innis, B.L., Rothman, A.L., Nisalak, A., Ennis, F.A., 1997. Early clinical and laboratory indictors of acute dengue illness. J. Infect. Dis. 176, 313-321.
Kang, B.Y., Kim, E., Kim, T.S., 2005. Regulatory mechanisms and their therapeutic implications of interleukin-12 production in immune cells. Cell Signal. 17, 665-673.
Kaufman, B.M., Summers, P.L., Dubois, D.R., Cohen, W.H., Gentry, M.K., Timchak, R.L., Burke, D.S., Eckels, K.H., 1989. Monoclonal antibodies for dengue virus prM glycoprotein protect mice against lethal dengue infection. Am J Trop Med Hyg. 41, 576-580.
Ko, Y.C., 1989. Epidemiology of dengue fever in Taiwan. Kaohsiung J. Med. Sci. 5, 1-11.
Koraka, P., Murgue, B., Deparis, X., Van Gorp, E.C., Setiati, T.E., Osterhaus, A.D., Groen, J., 2004. Elevation of soluble VCAM-1 plasma levels in children with acute dengue virus infection of varying severity. J. Med. Virol. 72, 445-450.
Kuberski, T., Rosen, L., Reed, D., Mataika, J., 1997. Clinical and laboratory observations on patients with primary and secondary dengue type 1 infections with hemorrhagic manifestations in Fiji. Am. J. Trop. Med. Hyg. 26, 775-783.
Kulander, L., Pauksens, K., Venge, P., 2001. Soluble adhesion molecules, cytokines and cellular markers in serum in patients with acute infections. Scand. J. Infect. Dis. 33, 290-300.
Kuo, C.H., Tai, D.I., Chang-Chien, C.S., Lan, C.K., Chiou, S.S., Liaw, Y.F., 1992. Liver biochemical tests and dengue fever. Am. J. Trop. Med. Hyg. 47, 265-270.
Kurane, I., Innis, B.L., Nisalak, A., Hoke, C., Nimmannitya, S., Meager, A., Ennis, F.A., 1989a. Human T cell responses to dengue virus antigens. Proliferative responses and interferon gamma production. J. Clin. Invest. 83, 506-513.
Kurane, I., Meager, A., Ennis, F.A., 1989b. Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity. J. Exp. Med. 170, 763-775.
Kurane, I., Innis, B.L., Nimmannitya, S., Nisalak, A., Meager, A., Janus, J., Ennis, F.A., 1991. Activation of T lymphocytes in dengue virus infections. High levels of souble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J. Clin. Invest. 88, 1472-1480.
Kurane, I., Rothman, A.L., Livingston, P.G., Green, S., Gagnon, S.J., Janus, J., Innis, B.L., Nimmannitya, S., Nisalak, A., Ennis, F.A., 1994. Immunopathologic mechanisms of dengue hemorrhagic fever and shock syndrome. Arch. Virol. Suppl. 9, 59-64.
Kurane, I., Ennis, F.A., 1997. Immunopathogenesis of dengue infections, p. 273-290. In: D. J. Gubler and G. Kuno (Eds.), Dengue and dengue hemorrhagic fever. CAB International, London, United Kingdom.
Kurane, I., Takasaki, T., 2001. Dengue fever and dengue hemorrhagic fever: challenges of controlling an enemy still at large. Rev. Med. Virol. 11, 301-311.
Lee, C.H, Chen, R.F., Liu, J.W., Yeh, W.T., Chang, J.C., Liu, P.M., Eng, H.L., Lin, M.C., Yang, K.D., 2004. Altered p38 mitogen-activated protein kinase expression in different leukocytes with increment of immunosuppressive mediators in patients with severe acute respiratory syndrome (SARS) J. Immunol. 172, 7841-7847.
Lee, I.K., Liu, J.W., Yang, K.D., 2005. Clinical characteristics and risk factors for concurrent bacteremia in adults with dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 72, 221-226.
Leitmeyer, K. C., Vaughn, D.W., Watts, D.M., Salas, R., Villalobos de Chacon, I., Ramos, C., Rico-Hesse, R., 1999. Dengue virus structural differences that correlate with pathogenesis. J. Virol. 73, 4738-4747.
Levings, M.K., Bacchetta, R., Schulz, U., Roncarolo, M.G., 2002. The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int. Arch. Allergy Immunol. 129, 263-276.
Liao, C.L., Lin, Y.L., Wu, B.C., Tsao, C.H., Wang, M.C., Liu, C.I., Huang, Y.L., Chen, J.H., Wang, J.P., Chen, L.K., 2001. Salicylates inhibit flavivirus replication independently of blocking nuclear factor kappa B activation. J. Virol. 75, 7828-7839.
Libraty, D.H., Endy, T.P., Houng, H.S. Green, S., Kalayanarooj, S., Suntayakorn, S., Chansiriwongs, W., Vaughn, D.W., Nisalak, A., Ennis, F.A., Rothman, A.L., 2002. Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J. Infect. Dis. 185, 1213-1221.
Littaua, R., Kurane, I., Ennis, F.A., 1990. Human IgG receptor II mediates antibody-dependent enhancement of dengue virus infection. J. Immunol. 144, 3183-3186.
Liu, J.W., Khor, B.S., Lee, C.H., Chen, R.F., Yang, K.D., 2003. Dengue hemorrhagic fever in Taiwan. Dengue Bull. 27, 19-23.
Liu, W.T., Chen, C.L., Lee, S.S., Chan, C.C., Lo, F.L., Ko, Y.C., 1991. Isolation of dengue virus with a human promonocyte cell line. Am. J. Trop. Med. Hyg. 44, 494-499.
Mady, B.J., Erbe, D.V., Kurane, I., Fanger, M.W., Ennis, F.A., 1991. Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fcreceptors. J. Immunol. 147, 31393144.
Malasit, P. 1987. Complement and dengue hemorrhagic fever/shock syndrome. Southeast Asian J. Trop. Med. Pub. Health. 18, 316-320.
Mangada, M.M., Igarashi, A., 1998. Molecular and in vitro analysis of eight dengue type 2 viruses isolated from patients exhibiting different disease severities. Virology 244, 458-466.
Mangada, M.M., Endy, T.P., Nisalak, A., Chunsuttiwat, S., Vaughn, D.W., Libraty, D.H., Green, S., Ennis, F.A., Rothman, A.L., 2002. Dengue-specific T cell responses in peripheral blood mononuclear cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J. Infect. Dis. 185, 1697-1703.
Mangada, M.M., Rothman, A.L., 2005. Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes. J. Immunol. 175, 2676-2683.
Monath, T.P. 1994. Dengue: the risk to developed and developing countries. Proc. Natl. Acad. Sci. USA 91, 2395-2400.
Mongkolsapaya, J., Dejnirattisai, W., Xu, X.N., Vasanawathana, S., Tangthawornchaikul, N., Chairunsri, A., Sawasdivorn, S., Duangchinda, T., Dong, T., Rowland-Jones, S., Yenchitsomanus, P.T., McMichael, A., Malasit, P., Screaton, G., 2003. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 9, 921-927.
Morens, D.M., 1994. Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin. Infect. Dis. 19, 500-512.
Murgue, B., Cassar, O., Deparis, X., 2001a. Plasma concentrations of sVCAM-1 and severity of dengue infections. J. Med. Virol. 65, 97-104.
Murgue, B., Roche, C., Chungue, E., Deparis, X., 2001b. Prospective study of the duration and magnitude of viraemia in children hospitalized during the 1996-1997 dengue-2 outbreak in French Polynesia. J. Med. Virol. 63, 29-34.
Mustafa, A.S., Elbishbishi, E.A., Agarwal, R., Chaturvedi, U.C. 2001. Elevated levels of interleukin-13 and IL-18 in patients with dengue hemorrhagic fever. FEMS Immunol. Med. Microbiol. 30, 229-233.
Nanayakkara. P.W., Teerlink, T., Stehouwer, C.D., Allajar, D., Spijkerman, A., Schalkwijk, C., ter Wee, P.M., van Guldener, C., 2005. Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure. Kidney Int. 68, 2230-2236.
Nash, M.C., Shah, V., Dillon, M.J., 1995. Soluble cell adhesion molecules and von Willebrand factor in children with Kawasaki disease. Clin. Exp. Immunol. 101, 13-17.
Norris, P.J., Pappalardo, B.L., Custer, B., Spotts, G., Hecht, F.M., Busch, M.P., 2006. Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection. AIDS Res. Hum. Retroviruses. 22, 757-762.
Pang T., Cardosa, M.J., Guzman, M.G.., 2007. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol. 85, 43-45.
Panteva, M., Korkaya, H., Jameel, S., 2003. Hepatitis viruses and the MAPK pathway: is this a survival strategy? Virus Res. 92, 131-140.
Peter, K., Weirich, U., Nordt, T.K., Ruef, J., Bode, C., 1999. Soluble vascular cell adhesion molecule-1 (VCAM-1) as potential marker of atherosclerosis. Thromb. Haemost. 82 Suppl 1, 38-43.
Perez, A.B., Garcia, G., Sierra, B., Alvarez, M., Vazquez, S., Cabrera, M.V., Rodriguez, R., Rosario, D., Martinez, E., Denny, T., Guzman, M.G., 2004. IL-10 levels in Dengue patients: some findings from the exceptional epidemiological conditions in Cuba. J. Med. Virol. 73, 230-234.
Phuong, C.X., Nhan, N.T., Kneen, R., Thuy, P.T., van Thien, C., Nga, N.T., Thuy, T.T., Solomon, T., Stepniewska, K., Wills, B.; Dong Nai Study Group, 2004. Clinical diagnosis and assessment of severity of confirmed dengue infections in Vietnamese children: is the world health organization classification system helpful? Am. J. Trop. Med. Hyg. 70, 172-179.
Preugschat, F., Strauss., J.H., 1991. Processing of nonstructural proteins NS4A and NS4B of dengue 2 virus in vitro and in vivo. Virology 185, 689-697.
Preugschat, F., Yao, C.W., Strauss, J.H., 1990. In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3. J. Virol. 64, 4364-4374.
Randolph, V.B., Winkler, G., Stollar, V., 1990. Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology. 174, 450-458.
Rennick, D., Davidson, N., Berg, D., 1995. Interleukin-10 gene knock-out mice: a model of chronic inflammation. Clin. Immunol. Immunopathol. 76, S174-S178.
Rice, C.M., Aebersold, R., Teplow, D.B., Pata, J., Bell, J.R., Vorndam, A.V., Trent, D.W., Brandriss, M.W., Schlesinger, J.J., Strauss, J.H., 1986. Partial N-terminal amino acid sequences of three nonstructural proteins of two flaviviruses. Virology. 151, 1-9.
Rice, C.M., 1996. Flaviviridae: the viruses and their replication, p. 931-959. In: Fields, B.N., Knipe, D.M., Howley, P.M. (Eds), Field's Virology. Third edition. Lippincott-Raven, Philadelphia.
Rico-Hesse, R., 2003. Microevolution and virulence of dengue viruses. Adv. Virus Res. 59, 315-341.
Rico-Hesse, R., Harrison, L.M., Salas, R.A., Tovar, D., Nisalak, A., Ramos, C., Boshell, J., de Mesa, M.T.R., Nogueira, R.M.R., Travassos da Rosa, A., 1997. Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 230, 244-251.
Rigau-Perez, J.G., Clark, G.G., Gubler, D.J., Reiter, P., Sanders, E.J., Vorndam, A.V., 1998. Dengue and dengue haemorrhagic fever. Lancet 352, 971-977.
Rigau-Perez, J.G., 2006. Severe dengue: the need for new case definitions. Lancet Infect. Dis. 6, 297-302.
Rosen, L., 1977. The emperor’s new clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 26, 337-343.
Rothman, A.L., 1997. Viral pathogenesis of dengue infections, p. 245-272. In: D. J. Gubler and G. Kuno (Eds.), Dengue and dengue hemorrhagic fever. CAB International, London, United Kingdom.
Rothman, A.L., Ennis, F.A., 1999. Immunopathogenesis of dengue hemorrhagic fever. Virology 257, 1-6.
Rothman, A.L., 2004. Dengue: defining protective versus pathologic immunity. J. Clin. Invest. 113, 946-951.
Roux, P.P., Blenis, J., 2004. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320–344.
Russell, P.K., Brandt, W.E., Darlymple, J.M., 1980. Chemical and antigenic structure of flaviviruses, p. 503-529. In R. W. Schlesinger (Eds.), The togaviruses. Academic Press, Inc., New York.
Simmons, C.P., Dong, T., Chau, N.V., Dung, N.T., Chau, T.N., Thaole, T.T., Dung, N.T., Hien, T.T., Rowland-Jones, S., Farrar, J., 2005. Early T-cell responses to dengue virus epitopes in Vietnamese adults with secondary dengue virus infections. J. Virol. 79, 5665-5675.
Shapiro, L., Heidenreich, K.A., Meintzer, M.K., Dinarello, C.A., 1998. Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro. Proc. Natl. Acad. Sci. USA. 95, 7422-7426.
Srichaikul, T., Nimmannitya, S., 2000. Haematology in dengue and dengue haemorrhagic fever. Baillieres. Best. Pract. Res. Clin. Haematol. 13, 261-276.
Stevens, L., Htut, T.M., White, D., Li, X., Hanidu, A., Stearns, C., Labadia, M.E., Li, J., Brown, M., Yang, J., 2006. Involvement of GATA3 in protein kinase C theta-induced Th2 cytokine expression. Eur. J. Immunol. 36, 3305-3314.
Sumbayev, V.V., Yasinska, I.M., 2006. Role of MAP kinase-dependent apoptotic pathway in innate immune responses and viral infection. Scand. J. Immunol. 63, 391-400.
Vaughn, D.W., Green, S., Kalayanarooj, S. Innis, B.L., Nimmannitya, S., Suntayakorn, S., Endy, T.P., Raengsakulrach, B., Rothman, A.L., Ennis, F.A., Nisalak, A., 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J. Infect. Dis. 181, 2-9.
Wahid, S.F., Sanusi, S., Zawawi, M.M., Ali, R,A,, 2000. A Comparison of the pattern of liver involvement in dengue hemorrhagic fever with classic dengue fever. Am. J. Trop. Med. Hyg. 31, 259-263.
Wang, L.Y., Chang, W.Y., Lu, S.N., Chen, T.P., 1990. Sequential changes of serum transaminase and abnormal sonography in patients with suspected dengue fever. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 6, 483-489.
Wang, W.K., Chao, D.Y., Kao, C.L. Wu, H.C., Liu, Y.C., Li, C.M., Lin, S.C., Ho, S.T., Huang, J.H., King, C.C., 2003. High levels of plasma dengue viral load during defervescence in patients with dengue hemorrhagic fever: implications for pathogenesis. Virology 305, 330-338.
Weaver, S.C., 2005. Host range, amplification and arboviral disease emergence. Arch Virol Suppl, 33-44.
Wengler, G., Czaya, G., Farber, P.M., Hegemann, J.H., 1991. In vitro synthesis of West Nile virus proteins indicates that the amino-terminal segment of the NS3 protein contains the active centre of the protease which cleaves the viral polyprotein after multiple basic amino acids. J. Gen. Virol. 72, 851-858.
World Health Organization, 1999. Strengthening implementation of the global strategy for Dengue fever and Dengue haemorrhagic fever, prevention and control. Report in the informal consultation, WHO HQ, Geneva. 18-20.
World Health Organization. 1975. Technical guides and diagnosis, treatment, surveillance, prevention and control of dengue hemorrhagic fever. World Health Organization, Geneva.
Wu, Y.C., 1986. Epidemic dengue 2 on Liouchyou Shiang, Pingtung County in 1981. Chinese J. Microbiol. Immunol. 19, 203-211.
Yang, K.D., Wang, C.L., Shaio, M.F., 1995. Production of cytokines and platelet activating factor in secondary virus infections. J. Infect. Dis. 172, 604-605.
Yang, K.D., Yeh, W.T., Yang, M.Y., Chen, R.F., Shaio, M.F., 2001. Antibody dependent enhancement of heterotypic dengue infections involved in suppression of IFNgamma production. J. Med. Virol. 63, 150-157.
Yeh, W.T., Chen, R.F., Wang, L., Liu, J.W., Shaio, M.F., Yang, K.D., 2006. Implication of previous subclinical dengue infection but not virus load in dengue hemorrhagic fever. FEMS Immunol. Med. Microbiol. 48, 84-90.
Yue, F.Y., Dummer, R., Geertsen, R., Hofbauer, G., Laine, E., Manolio, S., Burg, G., 1997. Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int. J. Cancer 71, 630-637.
Zhang, L., Mohan P.M., Padmanabhan., R., 1992. Processing and localization of dengue virus type 2 polyprotein precursor NS3-NS4A-NS4B-NS5. J. Virol. 66, 7549-7554.
Zhang, L.J., Wang, X.Z., 2006. Interleukin-10 and chronic liver disease. World J. Gastroenterol. 12, 1681-1685.
Zheng, Y., Li, J., Johnson, D.L., Ou, J.H., 2003. Regulation of hepatitis B virus replication by the ras-mitogen-activated protein kinase signaling pathway. J. Virol. 77, 7707-7712.