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IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

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Science  27 Jan 2017:
Vol. 355, Issue 6323, pp. 395-398
DOI: 10.1126/science.aai8128

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A rare ability to enhance dengue virus disease

In some cases, secondary infections of dengue virus can be extremely serious and result in plasma leakage, thrombocytopenia, and hemorrhagic disease. This phenomenon has been attributed to antibody-dependent enhancement. Wang et al. show that a specific subclass of antibody, IgG1, which lacks fucosyl residues on the Fc segment of the heavy chain of the immunoglobulin, is elevated in patients with severe secondary dengue disease. These non-neutralizing antibodies bind activating Fc receptors and appear to cross-react with platelet antigens to cause platelet depletion, contributing to thrombocytopenia.

Science, this issue p. 395

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.

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