Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology

Abstract

Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.

Myeloid C-Type Lectin Receptors in Viral Recognition and Antiviral Immunity

“…A complex process of trimming and remodeling of the oligosaccharide by glycosyltransferases and glycosidases, first in the ER and later in the Golgi apparatus, finally leads to the formation of N -glycans of the oligomannose type, the complex type, or the hybrid type [18]. All subtypes share a common pentasaccharide core, where the oligomannose type possesses solely mannose residues attached to the core, while the complex type has antennae initiated by GlcNAc attached to the pentasaccharide core, and the hybrid type comprises both mannose and GlcNAc attachments [17,19]. O- glycosylation takes place once the protein has transited to the Golgi and carbohydrates are linked covalently via glycosidic linkages from serine or threonine residues.…”

Inflammatory glycoproteins in cardiometabolic disorders, autoimmune diseases and cancer

“…Glycans participate in many key biological processes including ligand binding, transport and clearance, cell adhesion, receptor binding and activation and signal transduction [4,[7][8][9]14,15,20]. Inflammation-induced glycan modifications affect protein folding by masking sites for protease cleavage, preventing proteolysis and extending the circulating half-life of serum proteins [4,8,9,20,25].…”

“…Inflammation-induced glycan modifications affect protein folding by masking sites for protease cleavage, preventing proteolysis and extending the circulating half-life of serum proteins [4,8,9,20,25]. Moreover, they alter a protein's tertiary or quarternary structure, redirecting it to different cell membrane receptors and changing its downstream cellular effects [4,8,9,15,20]. These functional alterations may lead to modulation of the immune response or, if modified aberrantly, can lead to autoimmune disease.…”

“…Glycoproteins play key roles in inflammatory and pathological processes [5][6][7][8][9]. Thus, it is not surprising that investigation of the clinical utility of assays that measure inflammatory glycoproteins has received much attention [10][11][12][13].…”

Ultrafast and high-throughput N-glycan analysis for monoclonal antibodies

“…3 Additional terminal sugars, fucose (Fuc), galactose (Gal), and N-acetylneuraminic acid (sialic acid, or NANA) residues may be attached to the core, producing a large diversity of glycan structures. 4,5 The glycan moiety has a profound effect on the biological functions of a glycoprotein, such as protein cell-surface expression, 6 protein quality, 2 immune responses, [7][8][9][10] resistance towards proteases or half-life. 2,4,[11][12][13][14][15] Glycans are essential for the antibody's effector functions because they are required for antibody binding to all Fc gamma receptors, and thus affect efficacy of the antibody if its mode of action involves antibody dependent cell-mediated cytotoxicity (ADCC).…”