IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

Taia T Wang; Jaturong Sewatanon; Matthew J Memoli; Jens Wrammert; Stylianos Bournazos; Siddhartha Kumar Bhaumik; Benjamin A Pinsky; Kulkanya Chokephaibulkit; Nattawat Onlamoon; Kovit Pattanapanyasat; Jeffery K Taubenberger; Rafi Ahmed; Jeffrey V Ravetch

doi:10.1126/science.aai8128

IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

Science. 2017 Jan 27;355(6323):395-398. doi: 10.1126/science.aai8128.

Authors

Taia T Wang^{1

2}, Jaturong Sewatanon^{3

4

5}, Matthew J Memoli⁶, Jens Wrammert^{4

7}, Stylianos Bournazos¹, Siddhartha Kumar Bhaumik^{4

7}, Benjamin A Pinsky^{2

8}, Kulkanya Chokephaibulkit⁹, Nattawat Onlamoon¹⁰, Kovit Pattanapanyasat¹⁰, Jeffery K Taubenberger⁶, Rafi Ahmed^{3

4}, Jeffrey V Ravetch¹¹

Affiliations

¹ Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
² Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
³ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁴ Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁵ Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 10700.
⁶ 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.
⁷ Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 10700.
¹⁰ Department of Research and Development, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand 10700.
¹¹ Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. ravetch@rockefeller.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Viral / immunology*
Antibody Affinity
Antibody-Dependent Enhancement*
Blood Platelets / immunology
Humans
Immunoglobulin G / immunology*
Platelet Count
Receptors, IgG / immunology*
Severe Dengue / blood
Severe Dengue / immunology*
Severity of Illness Index
Thrombocytopenia / virology

Substances

Antibodies, Viral
FCGR3A protein, human
Immunoglobulin G
Receptors, IgG

Abstract

Publication types

MeSH terms

Substances

Grants and funding