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• W3201486368 abstract "Dengue virus (DENV) infections are endemic intropical and subtropical regions of the world. While infection withany of four circulating serotypes usually resolves withoutcomplication, secondary infection with an alternate serotype candevelop into more severe disease (i.e., dengue hemorrhagic feverand/or dengue shock syndrome, DHF/DSS). These more severe diseasemanifestations are thought to result from the induction ofcrossreactive, but not crossneutralizing, antibodies elicitedduring primary DENV infection. In this thesis we addressed threespecific aims: (1) To compare the relative roles of activatoryhuman Fcγ receptor classes and their signaling capacity usingsignaling competent or incompetent FcγRIA/γ (CD64/γ) or FcγRIIA(CD32) transfectants mediating dengue immune complex infectivity;(2) To characterize the roles of different E domainspecific IgG(mAb) subclasses and their Fcregion structures in FcγRmediatedneutralization escape and; (3) To design a simplifiedcroneutralization plaque assay that employs human FcγRs which cansimultaneously measure dengue virus neutralizing andimmuneenhancing antibodies in naturally infected subjects. Usingrecombinant constructs designed to individually introduce antibodyFcγ receptors into cells grown in vitro, we found that the nativeform of both receptors mediated enhanced dengue2 immune complexinfectivity; however, the efficiency of immune complex uptake wasfound to be ~810fold greater in the context of FcγRIIA expression.Our results also indicated that ITAM signaling competence wasimportant with regard to FcγRIA/γmediated infectivity, but ITAMsignaling competence was found not to be required in experimentsinvolving FcγRIIAmediated uptake. Thus, we determined the existenceof fundamental biological differences between FcγRIA and FcγRIIAwith respect to relative abilities to enhance dengue immune complexinternalization. We also evaluated whether human IgG subclass(IgG14) may be relevant to dengue virus neutralization. Infectionexperiments were done with mouse mAbs, epitopematched wholeFcregionswitch variant humanizedmouse mAbs and epitopematchedhumanizedchimpanzee mAbs engineered to contain only 39 amino acidchanges in their lower hinge/hinge proximal region of CH2domainthat is important in interaction with FcγRs. The neutralization ofdengue virus was found to be in the order ofIgG3>IgG1~IgG4>IgG2 as measured in FcγRnegative cell lines.We also found that DENVIgG complexes were more efficientlyneutralized in experiments that involved highaffinity FcγRIA/γ, asopposed to low affinity FcγRIIA receptors (H131 and R131allotypes). Thus, antidengue IgG neutralizing potency in humanFcγRexpressing cells was found to be proportional to FcγRIgG ligandaffinity and Fcregion structure, an effect that may operatewithout regard to E domain epitope specificity. We next developed aicroneutralization plaque assay that employed automated 96wellELISPOT readout instrumentation to measure human antidengue virus(DENV) antibodies in CV1 cells stably transfected…" @default.
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• W3201486368 date "2009-01-01" @default.
• W3201486368 modified "2023-09-27" @default.
• W3201486368 title "The Role of human Fcγ receptors in antibody-mediatedDengue virus neutralization: implications for Dengue diseasepathogenesis" @default.
• W3201486368 hasPublicationYear "2009" @default.
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