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Endothelial Cell Sensitization by Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice.
J Immunol. 2015 Sep 15; 195(6):2743-53.JI

Abstract

The mechanisms leading to the life-threatening dengue hemorrhagic fever (DHF) remain elusive. DHF preferentially occurs during secondary dengue infections, suggesting that aberrant immune responses are involved in its development. We previously demonstrated that the autoantibodies elicited by dengue virus (DENV) nonstructural protein 1 (NS1; anti-NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti-NS1 Igs remain unclear. In this study, the autoreactive Igs in patients with DHF and in NS1-immunized rabbits crossreacted with TNF-related apoptosis-inducing ligand receptor 1 (death receptor [DR]4). Challenges with the DENV in a subcytotoxic dose sensitized endothelial cells to apoptosis. Treatments with the autoantibodies induced proapoptotic activities and suppressed the surface expression of endothelial anticoagulant thrombomodulin. Combined treatments comprising the DENV and DR4 affinity-purified fractions of anti-NS1 IgGs (anti-NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti-NS1-DR4 Ig led to plasma leakage, coagulopathy, and morality in mice with warfarinized anticoagulant suppression. These results suggest that DR4-induced endothelial cell sensitization through NS1-elicited autoantibodies exacerbates anticoagulant suppression, vascular injury, and plasma leakage. Detecting and blocking anti-DR Igs in patients may be novel strategies for managing severe DENV infection.

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Authors+Show Affiliations

Sun DS
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
Chang YC
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
Lien TS
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
King CC
Institute of Epidemiology, National Taiwan University, Taipei 100, Taiwan;
Shih YL
Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan; School of Medical Technology, Taipei Medical University, Taipei 110, Taiwan; and.
Huang HS
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
Wang TY
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
Li CR
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
Lee CC
Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan;
Hsu PN
Institute of Immunology, National Taiwan University, Taipei 100, Taiwan.
Chang HH
Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan; hhchang@mail.tcu.edu.tw.

MeSH

AnimalsAntibodiesAnticoagulantsApoptosisAutoantibodiesBlood CoagulationCell LineCell SurvivalChick EmbryoCulicidaeDengue VirusEndothelial CellsHumansImmunoglobulin GMiceRNA InterferenceRNA, Small InterferingRabbitsReceptors, TNF-Related Apoptosis-Inducing LigandSevere DengueThrombomodulinViral Nonstructural Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26259584

Citation

Sun, Der-Shan, et al. "Endothelial Cell Sensitization By Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice." Journal of Immunology (Baltimore, Md. : 1950), vol. 195, no. 6, 2015, pp. 2743-53.
Sun DS, Chang YC, Lien TS, et al. Endothelial Cell Sensitization by Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice. J Immunol. 2015;195(6):2743-53.
Sun, D. S., Chang, Y. C., Lien, T. S., King, C. C., Shih, Y. L., Huang, H. S., Wang, T. Y., Li, C. R., Lee, C. C., Hsu, P. N., & Chang, H. H. (2015). Endothelial Cell Sensitization by Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice. Journal of Immunology (Baltimore, Md. : 1950), 195(6), 2743-53. https://doi.org/10.4049/jimmunol.1500136
Sun DS, et al. Endothelial Cell Sensitization By Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice. J Immunol. 2015 Sep 15;195(6):2743-53. PubMed PMID: 26259584.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endothelial Cell Sensitization by Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice. AU - Sun,Der-Shan, AU - Chang,Ying-Chen, AU - Lien,Te-Sheng, AU - King,Chwan-Chuen, AU - Shih,Yung-Luen, AU - Huang,Hsuan-Shun, AU - Wang,Teng-Yi, AU - Li,Chen-Ru, AU - Lee,Chin-Cheng, AU - Hsu,Ping-Ning, AU - Chang,Hsin-Hou, Y1 - 2015/08/10/ PY - 2015/01/20/received PY - 2015/07/16/accepted PY - 2015/8/12/entrez PY - 2015/8/12/pubmed PY - 2015/12/30/medline SP - 2743 EP - 53 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J Immunol VL - 195 IS - 6 N2 - The mechanisms leading to the life-threatening dengue hemorrhagic fever (DHF) remain elusive. DHF preferentially occurs during secondary dengue infections, suggesting that aberrant immune responses are involved in its development. We previously demonstrated that the autoantibodies elicited by dengue virus (DENV) nonstructural protein 1 (NS1; anti-NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti-NS1 Igs remain unclear. In this study, the autoreactive Igs in patients with DHF and in NS1-immunized rabbits crossreacted with TNF-related apoptosis-inducing ligand receptor 1 (death receptor [DR]4). Challenges with the DENV in a subcytotoxic dose sensitized endothelial cells to apoptosis. Treatments with the autoantibodies induced proapoptotic activities and suppressed the surface expression of endothelial anticoagulant thrombomodulin. Combined treatments comprising the DENV and DR4 affinity-purified fractions of anti-NS1 IgGs (anti-NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti-NS1-DR4 Ig led to plasma leakage, coagulopathy, and morality in mice with warfarinized anticoagulant suppression. These results suggest that DR4-induced endothelial cell sensitization through NS1-elicited autoantibodies exacerbates anticoagulant suppression, vascular injury, and plasma leakage. Detecting and blocking anti-DR Igs in patients may be novel strategies for managing severe DENV infection. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/26259584/Endothelial_Cell_Sensitization_by_Death_Receptor_Fractions_of_an_Anti_Dengue_Nonstructural_Protein_1_Antibody_Induced_Plasma_Leakage_Coagulopathy_and_Mortality_in_Mice_ DB - PRIME DP - Unbound Medicine ER -