Antibody glycosylation in inflammation, disease and vaccination

Abstract

Antibodies are antigen recognizing immunoglobulins with an amazingly diverse repertoire in the antigen specific domain. The diversity of the antibody response is further increased by modifications such as somatic recombination and hypermutation. Furthermore, variation in the isotype and post-translational modifications such as Fc glycosylation further increase diversity of the effector functions. In particular variations in the glycan structures contribute significantly to the functional capacities of the antibodies. This is of particular interest given the dynamic nature of these modifications that is strongly influenced by the inflammatory environment. Intriguingly, the glycan profile of antibodies has been unravelled in great detail in inflammatory (auto)immune diseases but received only limited attention in the area of infectious diseases and vaccination. Here, we reviewed the current knowledge on immunoglobulin glycosylation and specifically focussed on studies in the field of infectious diseases and vaccination against infectious diseases, an area with a lot of interesting opportunities.

Keywords: Antibody; Function; Glycan; Glycosylation; Infectious diseases; Vaccination.

Fig. 1.

The Antibody and its glycan. IgG1 are glycosylated at asparagine-297 in the Fc-domain, to which one of 30 documented structures can be attached, known to have an essential role on antibody structure and effector function The antibody glycan is composed of a biantennary core heptasaccharide composed of a chain of 2 n-acetylglucosamine (GlcNAc) residues (blue squares), followed by a mannose (green circle), followed by a 1,3 and a 1,6 mannose branching and an additional GlcNAc residue on each mannose. Variable addition of an additional fucose (red triangle), an additional bisecting GlcNAc, up to 2 galactoses (yellow circle) or up to 2 sialic acids (purple triangle) then give rise to antibody microheterogeneity.

Fig. 2.

The functional consequences in antibody glycan changes. Changes in galactosylation have been observed across a multitude of human diseases, linked to alterations in antibody inflammatory activity. Specifically, an accumulation of agalactosylated antibodies observed across inflammatory diseases (auto-immunity, infections, malignancy), whereas increased galactosylation is associated with less-inflammatory conditions (pregnancy). Moreover, specific glycan changes have been exploited in the monoclonal therapeutics field demonstrating the critical role of glycans in shaping antibody effector function. For example, removal of fucose reproducibly enhances ADCC activity, whereas changes in bisecting GlcNAc alone have a more modest effect. Additionally, sialylation reproducibly enhance the anti-inflammatory activity of IVIG in vivo.

Fig. 3.

Galactosylation in health and disease. Changes in galactosylation have been widely documented across health and disease. Groundbreaking work pointed to an interesting distribution of glycans across the ages, with increased levels of inflammatory – agalactosylated- antibodies in early life, which re-emerged with age. Moreover, compelling evidence points to an accumulation of agalactosylated antibodies with inflammaging- which may be unlinked from numerical age. Finally, agalactosylated antibodies accumulate across inflammatory diseases of dramatically different etiologies, but decrease in anti-inflammatory states, such as pregnancy.

Fig. 4.

The landscape of antibody-Fc binding receptors. Beyond canonical Fc-receptors, mounting evidence supports a broader role of additional lectin-like proteins in interacting with immune complexes and deploying a broader array of antibody functions including both activating and inhibitory activities.

Fig. 5.

Factors that may affect vaccine efficacy. Vaccination against infectious agents aims in the induction of antibodies that subsequently contribute to elimination of the pathogen. The function of these antibodies is shaped by the glycan repertoire on the Fc portion of the antibody. Different factors may influence the glycosylation profile of antibodies, both host related factor such as age, gender and origin, inflammatory status, as well as vaccine factors determine the end result. Vaccine factors that may influence antibody induction and modification are poorly characterized but may involve antigen, adjuvant, doses, administration routes and the time window since vaccination.

Fig. 6.

Summary. The antibody glycosylation repertoire determines the functional consequences of the antibodies. Different glycosylation structures (inner ring) have functional implications (middle ring). Several of these glycosylation profiles have been associated with autoimmunity, but limited information is available on antigen specific responses during infection or preventive vaccination (outer ring).