title: Endothelial Cell Sensitization by Death Receptor Fractions of an Anti-Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice.
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.
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Der-Shan
authors.initials: DS
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Ying-Chen
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Te-Sheng
authors.initials: TS
authors.lastname: Lien
authors.affiliation: Institute of Epidemiology, National Taiwan University, Taipei 100, Taiwan;
authors.forename: Chwan-Chuen
authors.initials: CC
authors.lastname: King
authors.affiliation: 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.
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Shih
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Hsuan-Shun
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Teng-Yi
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan;
authors.forename: Chen-Ru
authors.initials: CR
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan;
authors.forename: Chin-Cheng
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Institute of Immunology, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien 970, Taiwan; hhchang@mail.tcu.edu.tw.
authors.forename: Hsin-Hou
authors.initials: HH
authors.lastname: Chang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000925:Anticoagulants; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001777:Blood Coagulation; D002460:Cell Line; D002470:Cell Survival; D002642:Chick Embryo; D009033:Culicidae; D003716:Dengue Virus / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering; D011817:Rabbits; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*; D019595:Severe Dengue / Q000276:immunology / Q000473:pathology*; D018180:Thrombomodulin / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D001323:Autoantibodies; D007074:Immunoglobulin G; C079340:NS1 protein, Dengue virus type 2; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D018180:Thrombomodulin; D017361:Viral Nonstructural Proteins