IgG Fc Glycosylation in Human Immunity

Abstract

Glycosylation of IgG Fc domains is a central mechanism in the diversification of antibody function. Modifications to the core Fc glycan impact antibody function by shifting the balance of Type I and Type II Fc gamma receptors (FcγR) that will be engaged by immune complexes. This, in turn, modulates the effector cells and functions that can be recruited during immune activation. Critically, humans have evolved to regulate Fc glycan modifications for immune homeostasis. Dysregulation in Fc glycan modifications can lead to loss of immune tolerance, symptomatic autoimmunity, and susceptibility to infectious diseases. Here, we discuss IgG Fc glycosylation and its role in human health and disease.

Fig. 1. Heterogeneity in the human IgG Fc domain repertoire.

IgG repertoires vary across the population by ratios of activating to inhibitory IgG subclasses ((IgG1+IgG3)/IgG2) and in the abundance of Fc glycoforms that impact Fc domain structure and antibody function. Fucosylated, sialylated Fc glycoforms impart reduced Type I FcγR binding activity and enable binding to the Type II FcγRs. Afucosylated, sialylated or asialylated Fc glycans mediate pro-inflammatory effector functions by virtue of increased affinity for the activating Type I FcγR, FcγRIIIa

Fig. 2. Structure of IgG Fc glycans.

Fc glycoforms are present at Asn 297 within CH2 domains and are complex biantennary glycans. The core Fc glycan (boxed in red) is composed of seven saccharides: 4 N-acetylglucosamine (GlcNAc) and 3 mannose (Man) residues. This core glycan can be modified by a core fucose (Fuc), bisecting GlcNAc, galactose (Gal) at one or both arms and, in the presence of galactose, N-acetyl-neuraminic acid or sialic acid (NeuAc)