title: IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity.
abstract: Dengue virus (DENV) infection in the presence of reactive, non-neutralizing immunoglobulin G (IgG) (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, because only a fraction of infections occurring in the presence of RNNIg advance to DHF/DSS, the presence of RNNIg alone cannot account for disease severity. We discovered that DHF/DSS patients respond to infection by producing IgGs with enhanced affinity for the activating Fc receptor FcγRIIIA due to afucosylated Fc glycans and IgG1 subclass. RNNIg enriched for afucosylated IgG1 triggered platelet reduction in vivo and was a significant risk factor for thrombocytopenia. Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.|Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Taia T
authors.initials: TT
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 10700.
authors.forename: Jaturong
authors.initials: J
authors.lastname: Sewatanon
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Memoli
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.|Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Wrammert
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Bournazos
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.|Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Siddhartha Kumar
authors.initials: SK
authors.lastname: Bhaumik
authors.affiliation: Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.|Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Pinsky
authors.affiliation: Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 10700.
authors.forename: Kulkanya
authors.initials: K
authors.lastname: Chokephaibulkit
authors.affiliation: Department of Research and Development, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand 10700.
authors.forename: Nattawat
authors.initials: N
authors.lastname: Onlamoon
authors.affiliation: Department of Research and Development, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand 10700.
authors.forename: Kovit
authors.initials: K
authors.lastname: Pattanapanyasat
authors.affiliation: Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. ravetch@rockefeller.edu.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D000915:Antibody Affinity; D019067:Antibody-Dependent Enhancement; D001792:Blood Platelets / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D010976:Platelet Count; D017452:Receptors, IgG / Q000276:immunology*; D019595:Severe Dengue / Q000097:blood / Q000276:immunology*; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000821:virology
chemical_list: D000914:Antibodies, Viral; C496124:FCGR3A protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG