The importance of IgG glycosylation-What did we learn after analyzing over 100,000 individuals

Abstract

All four subclasses of immunoglobulin G (IgG) antibodies have glycan structures attached to the protein part of the IgG molecules. Glycans linked to the Fc portion of IgG are found in all IgG antibodies, while about one-fifth of IgG antibodies in plasma also have glycans attached to the Fab portion of IgG. The IgG3 subclass is characterized by more complex glycosylation compared to other IgG subclasses. In this review, we discuss the significant influence that glycans exert on the structural and functional properties of IgG. We provide a comprehensive overview of how the composition of these glycans can affect IgG's effector functions by modulating its interactions with Fcγ receptors and other molecules such as the C1q component of complement, which in turn influence various immune responses triggered by IgG, including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In addition, the importance of glycans for the efficacy of therapeutics like monoclonal antibodies and intravenous immunoglobulin (IVIg) therapy is discussed. Moreover, we offer insights into IgG glycosylation characteristics and roles derived from general population, disease-specific, and interventional studies. These studies indicate that IgG glycans are important biomarkers and functional effectors in health and disease.

Keywords: ADCC; CDC; Fcγ receptors; IVIg; IgG; glycosylation.

FIGURE 1

Glycosylation sites found on IgG1‐4 subclasses and the glycan structures present at these sites. Only the most abundant glycan structures found at each glycosylation site are shown.

FIGURE 2

Three types of N‐glycans: Complex, hybrid, and high‐mannose. All three types of N‐glycans are present on human plasma IgG. Complex glycans are the most predominant, while hybrid and high‐mannose N‐glycans are present at very low abundance.

FIGURE 3

Effects of differential Fc glycosylation on IgG effector functions. The icons used in the creation of this figure were sourced from BioRender.com, and glycan structures were created using GlycoWorkbench. The (?) symbol denotes uncertainty based on current literature.

FIGURE 4

IgG glycans are important biomarkers and functional effectors in health and disease. Changes in IgG glycosylation serve as a measure of alterations in inflammatory status, making IgG glycans useful for monitoring aging trajectories and as indicators of disease status at different stages, including subclinical and early disease, as well as during disease progression. IgG glycans are also recognized as valuable tools for improving the efficacy of IgG‐based therapies, such as therapeutic monoclonal antibodies and IVIg therapy, used in various diseases.