Functional diversification of IgGs through Fc glycosylation

Abstract

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR-mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc's affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.

Figure 1. The core IgG Fc glycan modifications and type I and type II FcγRs.

Top: The core Fc glycan is attached within the CH2 domain of each IgG heavy chain and can be modified by various glycosyltransferases for addition of fucose (FUT8), galactose (B4GALT1), N-acetylglucosamine (GNTIII), and sialic acid (ST6GAL1) residues. Although sialylation without fucosylation does not impact the enhanced binding of the afucosylated glycoforms to the type I FcγR FcγRIIIa, sialylation of fucosylated glycoforms destabilizes the Fc domain, enabling structural rearrangement that favors type II FcγR binding. Bottom: Type I FcγRs are members of the immunoglobulin super family and transduce activating or inhibitory signaling on the basis of the presence of an intracellular immunoreceptor tyrosine-based activation motif (ITAM) or immunoreceptor tyrosine-based inhibitory motif (ITIM) motif. Type II FcγRs are the C-type lectins DC-SIGN and CD23, which mediate antiinflammatory activity and B cell modulatory activities, respectively. Type II FcγRs are distinguished by their ability to engage sialylated, fucosylated immune complexes.

Figure 2. Sialylated immune complexes trigger high-affinity antibody production through B cell CD23 engagement.

Influenza vaccination triggers production of sialylated anti–HA IgGs by plasmablasts. Immune complexes form and are fixed on specialized antigen-presenting cells called follicular dendritic cells (FDCs) within the germinal center. Coengagement of CD23 with the B cell receptor by sialylated HA immune complexes induces increased expression of the inhibitory FcγRIIb, resulting in selection of higher-affinity B cells.