Journal
SCIENCE
Volume 355, Issue 6323, Pages 395-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aai8128
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Funding
- National Center for Advancing Translational Sciences, NIH [UL1TR001866]
- Clinical and Translational Science Award program
- NIH [IRO1AI099385]
- American Foundation for AIDS Research Mathilde Krim Fellowship in Basic Biomedical Research [109519-60-RKVA]
- National Institute of Allergy and Infectious Diseases of the NIH [U19AI111825, U19AI109946, U19AI057266, U01AI115651]
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID)
- NIAID Extramural Clinical Research Acceleration Program
- Rockefeller University
- Stanford University School of Medicine
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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 Fc gamma RIIIA 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.
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