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  • Review Article
  • Published:

Siglec-mediated regulation of immune cell function in disease

Key Points

  • Siglecs are a family sialic acid-binding immunoglobulin-like co-receptors that are expressed on most cells of the innate and adaptive immune systems.

  • As Siglecs recognize sialic acid-containing glycans that are expressed on all mammalian cells, they can help immune cells to discriminate between self and non-self.

  • Sialylated pathogens can both subvert and promote immune responses through Siglec-dependent interactions.

  • Siglecs have important roles in the regulation of activatory and inhibitory receptors on immune cells, which can influence host–pathogen interactions, inflammation, neurodegeneration, autoimmune diseases and cancer.

  • Most Siglecs exhibit highly restricted expression on immune cell subsets and they are recognized as attractive therapeutic targets for cell type-specific therapies.

Abstract

All mammalian cells display a diverse array of glycan structures that differ from those that are found on microbial pathogens. Siglecs are a family of sialic acid-binding immunoglobulin-like receptors that participate in the discrimination between self and non-self, and that regulate the function of cells in the innate and adaptive immune systems through the recognition of their glycan ligands. In this Review, we describe the recent advances in our understanding of the roles of Siglecs in the regulation of immune cell function in infectious diseases, inflammation, neurodegeneration, autoimmune diseases and cancer.

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Figure 1: Mechanisms by which sialoside ligands of the Siglecs mediate immunomodulatory effects.
Figure 2: Siglecs in host–pathogen interactions.
Figure 3: Ligand-mediated recruitment of B cell Siglecs to the immunological synapse.
Figure 4: Therapeutic potential of targeting Siglecs in disease.

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Acknowledgements

Work in the authors' laboratories is supported by grants from the US National Institutes of Health (J.C.P.) and the Wellcome Trust (P.R.C.).

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Correspondence to James C. Paulson.

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Several pharmaceutical companies have expressed interest in investigating commercial application of technologies that will be mentioned in the review (J.C.P. and M.S.M.). P.R.C. declares no competing interests.

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FURTHER INFORMATION

Functional Glycomics Gateway

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Glossary

Sialic acid

A family of nine-carbon keto sugars that includes N-acetylneuraminic acid (NeuAc), the predominant sialic acid in humans. Other common sialic acids are 9-O-acetyl-NeuAc, which is also found in humans, and N-glycolyl-neuraminic acid (NeuGc), which is found in most mammalian species but not in humans.

Immunoreceptor tyrosine-based inhibitory motifs

(ITIMs). Short peptide motifs containing tyrosine residues that are found in the cytoplasmic regions of many inhibitory receptors. These motifs are phosphorylated after receptor activation, often by SRC family protein-tyrosine kinases, which produces a binding site for cytoplasmic phosphatases and other signalling molecules, resulting in the dephosphorylation of activation complexes and inhibition of signalling cascades.

SHP1 and SHP2

SH2 domain-containing phosphatases that bind phosphorylated immunoreceptor tyrosine-based inhibitory motifs. The recruitment of SHP1 and SHP2 by Siglecs represents a general mechanism for modulation of immune cell signalling.

Immunoreceptor tyrosine-based activation motif

(ITAM). A short peptide motif containing tyrosine residues that is found in the cytoplasmic tails of several signalling molecules and in adaptors such as DAP12. The tyrosine is phosphorylated after receptor activation and triggers a cascade of intracellular events that typically results in cellular activation.

Osteopetrosis

A disease characterized by the thickening of bones, which occurs as a result of an imbalance between bone generation and resorption by osteoblasts and osteoclasts, respectively.

Cis interactions

Binding of Siglec ligands — such as sialic acid-containing glycans that are commonly found on glycoproteins and glycolipids — that occur on the same Siglec-expressing cell.

Trans interactions

Binding of Siglec ligands — such as sialic acid-containing glycans that are commonly found on glycoproteins and glycolipids — that occur on opposing cells that are contacted by the Siglec-expressing cell.

B cell receptor

(BCR). On naive B cells, the BCR complex is composed of membrane form of IgM along with Igα (also known as CD79A) and Igβ (also known as CD79B), which initiate BCR signalling through proximal signal components.

Retinoic acid-inducible gene I

(RIG-I). A pattern recognition receptor that has an intricate role in immunity against RNA viruses. RIG-I directly recognizes double-stranded RNA and triggers an antiviral response.

gp120

A highly glycosylated protein on the surface of the HIV envelope, which recognizes CD4 on T cells as a portal of entry.

Alzheimer's disease

The most common form of dementia occurring as a result of plaque deposition and neurofibrillar tangles in the brain.

Amyloid-β

A peptide that is proteolytically processed from amyloid precursor protein and that can aggregate to form oligomers and give rise to the amyloid plaques found in the brains of patients with Alzheimer's disease.

Sialoside

A glycan-containing sialic acid linked via its anomeric carbon to the next sugar. In a biological context, sialosides may be complex glycans linked to proteins or lipids.

Haemophilia A

A condition caused by a genetic deficiency in the gene encoding the blood clotting factor FVIII. Patients with this disease are treated using intravenous FVIII replacement therapy.

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Macauley, M., Crocker, P. & Paulson, J. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14, 653–666 (2014). https://doi.org/10.1038/nri3737

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