IgG antibodies to dengue enhanced for FcγRIIIA binding determine disease severity

Abstract

Dengue virus (DENV) infection in the presence of reactive, non-neutralizing IgG (RNNIg) is the greatest risk factor for dengue hemorrhagic fever (DHF) or shock syndrome (DSS). Progression to DHF/DSS is attributed to antibody-dependent enhancement (ADE); however, since 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 IIIA 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 (OR 11.00, p=0.0139). Thus, therapeutics and vaccines restricting production of afucosylated, IgG1 RNNIg during infection may prevent ADE of DENV disease.

Characterization of Zika virus binding and enhancement potential of a large panel of flavivirus murine monoclonal antibodies

“…ADE disease severity observed in vivo may also be due to increased cytokine release and vascular permeability (Balsitis et al, 2010; Beatty et al, 2015). Recent studies suggest that ADE is associated with IgGs that have high affinity for activating Fc receptors (Wang et al, 2017). …”

A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates

“…FcγR and FcRn binding affinity of the Z004 Fc domain variants was determined by surface plasmon resonance (SPR) (Li et al, 2017; Wang et al, 2017b). Briefly, all experiments were performed on a Biacore T200 SPR system (GE Healthcare) at 25°C in HBS-EP + buffer (GE Healthcare; pH 7.4 for FcγRs, pH 6.0 for FcRn).…”

Diversification of IgG effector functions

“…Indeed, recent analyses of the Fc glycan composition revealed distinct fluctuations at the levels of specific glycoforms upon vaccination, during pregnancy, in chronic inflammatory and neoplastic diseases, in response to systemic metabolic changes and during infection (34,(60)(61)(62)(63)(64)(65). Examples include inflammatory diseases, such as rheumatoid arthritis and Wegener's granulomatosis, which are characterized by reduced galactosylation and sialylation, as well as infectious diseases, such as Dengue infection, in which increased levels of afucosylated glycoforms are associated with clinical disease severity and thrombocytopenia (60,61,(63)(64)(65).…”