Heterogeneity in IgG-CD16 signaling in infectious disease outcomes

Abstract

In this review, we discuss how IgG antibodies can modulate inflammatory signaling during viral infections with a focus on CD16a-mediated functions. We describe the structural heterogeneity of IgG antibody ligands, including subclass and glycosylation that impact binding by and downstream activity of CD16a, as well as the heterogeneity of CD16a itself, including allele and expression density. While inflammation is a mechanism required for immune homeostasis and resolution of acute infections, we focus here on two infectious diseases that are driven by pathogenic inflammatory responses during infection. Specifically, we review and discuss the evolving body of literature showing that afucosylated IgG immune complex signaling through CD16a contributes to the overwhelming inflammatory response that is central to the pathogenesis of severe forms of dengue disease and coronavirus disease 2019 (COVID-19).

Keywords: COVID-19; Fc afucosylation; IgG1 antibodies; dengue disease; effector functions.

FIGURE 1

(A) Type I Fcγ receptors (FcγRs) expression pattern on human white blood cell subsets. + indicates constitutive expression; − indicates no expression; +/− indicates no or low expression; * indicates inducible expression; */− indicates low or inducible expression; # indicates expression depending on FCGR2C allelic status. Classical monocytes are defined as CD14 highCD16 ‐ and non‐classical monocytes are defined as CD14 dimCD16 ++. (B) Binding affinities (association constant of binding [K_A]) of four IgG subclasses (IgG1, IgG2, IgG3 and IgG4) to the various type I FcγRs. No color and * indicates that binding was either negligible or not detected to that FcγR. IgG1 AF denotes afucosylated IgG1, whereas IgG1 F is the core fucosylated IgG

FIGURE 2

IgG glycoprotein and N‐linked glycan. IgG domain architecture (PDB 1HZH ¹⁹ ) and cartoon representation of IgG1 Fc glycans

FIGURE 3

Model for antibody‐dependent enhancement (ADE) in dengue infection and the roles of activating type I Fcγ receptors (FcγRs) and afucosylated IgG. Viral attachment and entry occurs mostly by CD32a mediated endocytosis after interactions with anti‐E IgG1:dengue ICs. Additionally, high affinity interactions between afucosylated anti‐E IgG1:dengue ICs and CD16a promotes increased ITAM signaling. ITAM signaling triggers downstream calcium flux and activates the calcineurin signaling network. Specific calcineurin inhibitors prevented FcγR‐dependent dengue virus infection

FIGURE 4

Model for immunopathology of severe COVID‐19 mediated by enhanced CD16a:IgG signaling axis. Enhanced signaling via the ITAM domain of CD16a, which in turn leads to increased proinflammatory cytokine production in lung of severe COVID‐19 patients might be achieved through either formation of ICs with persisting viral antigens and afucosylated anti‐SARS‐CoV‐2 IgG1, which have higher affinity for CD16a on effector cells or by recruitment of effector cells, which have an increased expression of CD16a on their surface and thus an increased inflammatory signaling potential. Thus, proinflammatory elements on both sides of the receptor‐ligand axis might contribute to more severe disease