title: Dengue virus-induced autoantibodies bind to plasminogen and enhance its activation.
abstract: Dengue virus infection can lead to life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) in patients. Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks associated with DHF/DSS patients. However, the mechanisms that cause pathology in DHF/DSS patients are still unclear. Because conversion of plasminogen (Plg) to plasmin (Plm) is the first step in the activation of fibrinolysis, Abs against Plg found in DHF/DSS patients may be important. Therefore, to investigate the specificity, function, and possible origin of these Abs, we generated several Plg cross-reactive mAbs from DENV-immunized mice. An IgG mAb, 6H11, which recognizes an epitope associated with a dengue envelope protein, demonstrated a high level of cross-reactivity with Plg. The 6H11 Ab was further characterized with regard to its effect on Plg activation. Using Plm-specific chromogenic substrate S-2251, we found that mAb 6H11 demonstrated serine protease activity and could convert Plg directly to Plm. The serine protease activity of mAb 6H11 was further confirmed using serine protease chromogenic substrate S-2288. In addition, we found several Plg cross-reactive mAbs that could enhance urokinase-induced Plg activation. Lastly, mAb 6H11 could induce Plm activity and increase the level of D-dimer (a fibrin degradation product) in both human and mouse platelet-poor plasma. Taken together, these data suggest DENV-induced Plg cross-reactive Abs may enhance Plg conversion to Plm, which would be expected to contribute to hyperfibrinolysis in DHF/DSS patients.
authors.affiliation: Institute of Basic Medical Sciences, Medical College, National Cheng Kung University, Tainan, Taiwan 701.
authors.forename: Yung-Chun
authors.initials: YC
authors.lastname: Chuang
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000378:metabolism; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D001323:Autoantibodies / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D001666:Binding Sites, Antibody / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D003715:Dengue / Q000276:immunology / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000276:immunology; D006801:Humans; D007223:Infant; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D019595:Severe Dengue / Q000276:immunology / Q000821:virology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D001323:Autoantibodies; D010958:Plasminogen; D005341:Fibrinolysin