The role of IgG Fc receptors in antibody-dependent enhancement

Antibody-dependent enhancement (ADE) has been described as a mechanism that contributes to the pathogenesis of dengue virus infection. Limited evidence also suggests that it can also occur in other viral infections. Here, the authors explore the history of the ADE phenomenon, discuss the diversity of Fc effector functions and consider its potential relevance in the context of SARS-CoV-2 infection. Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fc gamma receptor (Fc gamma R)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative Fc gamma R-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon Fc gamma R engagement and review the available experimental evidence supporting the role of Fc gamma Rs in antiviral protection and pathogenesis through ADE. We explore Fc gamma R engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.