{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:36:59Z","timestamp":1789385819663,"version":"build-2803163510"},"reference-count":68,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2013NS1 Igs) induce plasma leakage and mortality in mice with warfarinized anticoagulant suppression. However, the involved pathogenic Ig fractions of anti\u2013NS1 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\u2013NS1 IgGs (anti\u2013NS1-DR4 Ig), but not preimmune control IgGs, in subcytotoxic doses led to apoptosis in endothelial cells. Treatments with the anti\u2013NS1-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\u2013DR Igs in patients may be novel strategies for managing severe DENV infection.<\/jats:p>","DOI":"10.4049\/jimmunol.1500136","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T01:30:40Z","timestamp":1439256640000},"page":"2743-2753","source":"Crossref","is-referenced-by-count":35,"title":["Endothelial Cell Sensitization by Death Receptor Fractions of an Anti\u2013Dengue Nonstructural Protein 1 Antibody Induced Plasma Leakage, Coagulopathy, and Mortality in Mice"],"prefix":"10.1093","volume":"195","author":[{"given":"Der-Shan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University , Hualien 970 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Chen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University , Hualien 970 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Te-Sheng","family":"Lien","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Human Genetics, Tzu-Chi University , Hualien 970 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chwan-Chuen","family":"King","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology, National Taiwan University , Taipei 100 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Luen","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital , Taipei 111 ,","place":["Taiwan"]},{"name":"School of Medical Technology, Taipei Medical University , Taipei 110 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