Immune regulatory networks coordinated by glycans and glycan-binding proteins in autoimmunity and infection

Abstract

The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults. Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses, whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections, but also influence cancer development and progression. Glycans have emerged as essential components of homeostatic circuits, acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings. Cell surface glycans, present in cells, tissues and the extracellular matrix, have been proposed to serve as “self-associated molecular patterns” that store structurally relevant biological data. The responsibility of deciphering this information relies on different families of glycan-binding proteins (including galectins, siglecs and C-type lectins) which, upon recognition of specific carbohydrate structures, can recalibrate the magnitude, nature and fate of immune responses. This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix. Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation, complex N-glycan branching, core 2 O-glycan elongation, LacNAc extension, as well as terminal sialylation and fucosylation. Moreover, we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways. Finally, we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection.

Towards Biomimetic Recognition of Glycans by Synthetic Receptors

“…The recognition of Neu5Ac is of note one of the most crucial processes in the immune response. [84] Indeed, many protein families expressed on the surface of immune cells have the capability to recognize sialic acid-containing self-antigens. Upon recognition of sialylated glycans different proteins can up-or downregulate the immune response.…”

“…[5,6] Di-, tri-and poly-branched glycans can show high structural complexity and, although generally only the terminal residues are the elective epitopes recognised by proteins, [7,8] the entire polysaccharide is responsible for the correct folding and orientation of these complex structures. [9] Carbohydrate-protein recognition is involved in an enormous number of physiological and pathological processes including cell-growth, [10] neural development, [11] immune system regulation, [8] tumour growth and metastasis, [12] and inflammation. [13] Moreover, carbohydrates are important diagnostic biomarkers in cancer.…”

“…[3,4] Widely expressed on the surface of eukaryotic cells as constituents of the glycocalyx, glycans mediate a variety of events in cell-cell, cellmatrix and cell-molecule interactions, including the adhesion and infection by pathogenic microorganisms such as viruses and bacteria. [5,6] Di-, tri-and poly-branched glycans can show high structural complexity and, although generally only the terminal residues are the elective epitopes recognised by proteins, [7,8] the entire polysaccharide is responsible for the correct folding and orientation of these complex structures. [9] Carbohydrate-protein recognition is involved in an enormous number of physiological and pathological processes including cell-growth, [10] neural development, [11] immune system regulation, [8] tumour growth and metastasis, [12] and inflammation.…”

The Human Blood N-Glycome: Unraveling Disease Glycosylation Patterns

“…Protein glycosylation is one of the most prevalent post-translational modification adding a layer of complexity that goes beyond genetic coding, allowing for subtle alterations in protein activity, stability, and interactions. , N - and O -glycosylation are the most frequent types, distinguished by the specific site on the protein backbone they extend from–asparagine residues at Asn-X-Ser/Thr motifs and serine or threonine residues, respectively . Changes in protein glycosylation have been described for many cell- and tissue (de)­differentiation processes and appear to coincide with normal physiological processes as well as pathologies. , Numerous well-established examples highlight the role of glycosylation in inherited and acquired human diseases. ,, However, for many examples, the causative or contributory role of altered protein glycosylation remains elusive and is therefore an ongoing area of investigation . Such gaps arise due to a lack of mature tools to study and manipulate glycosylation, the utilization of diverse and low-throughput analytical methods on small sample sizes, unsuitable cohorts, flawed or inconsistent data analysis workflows, lack of replication, a restricted set of glycan features analyzed, or a combination thereof .…”

Melanoma tumour‐derived glycans hijack dendritic cell subsets through C‐type lectin receptor binding

“…Another emerging pathway of immune subversion relies on glycans. Glycome harboured a crucial role in basic immunologic processes [24] and glycan/lectin interactions coordinate immune networks in infection, autoimmunity [25,26], inflammatory diseases [27] and cancers [28]. Indeed, tumour cells harbour unusual glycosylation patterns on their cell surface glycoproteins and glycolipids which influence interactions between tumour cells and the surrounding microenvironment [29].…”