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Review
. 2020 Oct;20(10):633-643.
doi: 10.1038/s41577-020-00410-0. Epub 2020 Aug 11.

The role of IgG Fc receptors in antibody-dependent enhancement

Stylianos Bournazos  1 , Aaron Gupta  1 , Jeffrey V Ravetch  2
Affiliations
Review

The role of IgG Fc receptors in antibody-dependent enhancement

Stylianos Bournazos et al. Nat Rev Immunol. 2020 Oct.

Abstract

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 Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-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 FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR 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.

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Conflict of interest statement

J.V.R is a consultant and member of the Scientific Advisory Board of Vir Biotechnology, Inc. S.B. and A.G. declare no competing interests.

Figures

Fig. 1
Fig. 1. Overview of the FcγR family and expression patterns among human effector leukocytes.
Canonical, type I Fcγ receptors (FcγRs) are broadly categorized into activating or inhibitory based on the presence of immunoreceptor tyrosine activating motif (ITAM) or immunoreceptor tyrosine inhibitory motif (ITIM) signalling in their intracellular domains. The majority of effector leukocytes co-express combinations of activating and inhibitory FcγRs and their opposing signalling activities determine the outcome of IgG-mediated inflammation. Although FcγRs are expressed abundantly among the various leukocyte subsets, inflammatory cues and differentiation status modulate the expression of the various FcγRs, thereby altering the responsiveness of effector leukocytes to IgG-mediated signalling. +, constitutive expression; –, no expression; #, inducible expression; *, expression depends on FCGR2C allelic status; NK, natural killer.
Fig. 2
Fig. 2. Downstream signalling events induced upon crosslinking of activating FcγRs by IgG immune complexes.
Multimeric IgG immune complexes engage multiple Fcγ receptors (FcγRs) through low-affinity, high-avidity interactions (step 1). Receptor crosslinking upon IgG immune complex binding triggers phosphorylation (P) of their immunoreceptor tyrosine activating motifs (ITAMs), which in turn leads to the activation of kinases of the SYK and SRC family (step 2), as well as activation of the protein kinase C (PKC) pathway, resulting in a rapid increase in intracellular Ca2+ levels following activation of Ca2+ channels (step 3). Kinase activation also leads to actin remodelling (step 4), which is critical for receptor internalization and phagocytosis of the IgG immune complex. At later stages, cellular activation is associated with activation of specific transcription factors such as p38 and Jun amino-terminal kinases (JNK) (step 5) that drive the expression and release of pro-inflammatory cytokines and chemokines (for example, tumour necrosis factor (TNF), IL-1β and IL-8) (step 6) that shape immune responses and alter the effector function, migration and survival of leukocytes.
Fig. 3
Fig. 3. Diversity of FcγR-mediated antiviral effector functions.
Fc–Fcγ receptor (FcγR) interactions drive pleiotropic effector functions that limit viral replication and provide potent antiviral protection. a | clearance of IgG opsonized virions. b | Cytotoxic elimination and phagocytic clearance of IgG-coated infected cells by natural killer (NK) cells and macrophages. c | Crosslinking of FcγRs on dendritic cells accelerates phagolysosome fusion and maturation, leading to more efficient antigen processing and presentation to CD8+ and CD4+ T cells, which in turn confer antiviral activities. All of these functions are key components of the host antiviral response and are mediated by the specific engagement and signalling of specific activating FcγRs (indicated in the figure) on specific leukocyte subsets.
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