The role of glycosylation in clinical allergy and immunology

Abstract

While glycans are among the most abundant macromolecules on the cell with widespread functions, their role in immunity has historically been challenging to study. This is in part due to difficulties assimilating glycan analysis into routine approaches used to interrogate immune cell function. Despite this, recent developments have illuminated fundamental roles for glycans in host immunity. The growing field of glycoimmunology continues to leverage new tools and approaches to uncover the function of glycans and glycan-binding proteins in immunity. Here we utilize clinical vignettes to examine key roles of glycosylation in allergy, inborn errors of immunity, and autoimmunity. We will discuss the diverse functions of glycans as epitopes, as modulators of antibody function, and as regulators of immune cell function. Finally, we will highlight immune modulatory therapies that harness the critical role of glycans in the immune system.

Keywords: Glycosylation; PGM3; antibody glycosylation; immunomodulation; immunotherapy.

Figure 1:. Glycans can shape immune cell activity.

(A) Glycosylation of proteins occurs through the attachment of glycans to asparagine (N glycosylation) or serine/threonine (O glycosylation) residues. N-glycosylation occurs in the endoplasmic reticulum (ER) and Golgi, whereas O-glycosylation occurs in the Golgi. During N-glycosylation, a precursor is attached to the glycoprotein, which is then trimmed and modified by a series of glycosidases and glycosyltransferases in a sequential manner until it reaches the trans-Golgi. From the trans-Golgi, the glycoprotein is transported through secretory vesicles to its destination. In contrast to N glycosylation, O glycosylation is initiated in the Golgi by the stepwise addition of monosaccharides. (B) Changes in cell surface glycosylation can impact the sensitivity of cell interactions with a glycan-binding protein (GBP). A cell that expresses glycans terminating in α2–6 linked sialic acid can interact with the siglec, CD22. In contrast, removal of sialic acid exposes galactose residues that can serve as ligands for galectins. (C) GBP and glycan regulation of host immunity. Dendritic cells and macrophages express C-type lectins that engage microbes, which can facilitate microbe uptake and/or change the behavior of the cell. Galectins can both directly kill microbes and regulate immune cell activity. Selectins facilitate leukocyte recruitment.

Figure 2:. Glycans as epitopes, glycan regulation of antibody activity, and the impact of glycosylation on immune cell function.

(A) Upper panel: In α-galactose (Gal) allergy, an IgE anti-α-Gal antibody response is triggered by a tick bite. Subsequently, IgE-mediated activation of mast cells triggers an allergic response to α-Gal epitopes found in dietary meat. Middle panel: In Guillain-Barre Syndrome, anti-carbohydrate antibodies form following exposure to Campylobacter jejuni, which expresses surface glycans similar to the ganglioside GM1 found on neurons. This results in cross-reactivity with neuronal GM1, causing neuronal injury. Lower panel: In IgA nephropathy, increases in total IgA result in a corresponding increase in Tn-bearing IgA. The latter are bound by naturally occurring anti-Tn IgM antibodies which form immune complexes that can deposit in glomeruli, causing kidney injury. (B) IgG antibodies possess an asparagine (N) 297 glycan in the Fc domain that can regulate Fc gamma receptor engagement and complement activation. IgE can also be glycosylated on N265, N371, N383, and N394. (C) Changes in glycosylation on the proteins and lipids expressed on the cell surface can impact a variety of fundamental cellular activities. These include receptor residence time, receptor sensitivity to ligand-induced signaling, cellular activation states, and leukocyte trafficking.