Sialic acid-binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses

Abstract

The mammalian immune system evolved to tightly regulate the elimination of pathogenic microbes and neoplastic transformed cells while tolerating our own healthy cells. Here, we summarize experimental evidence for the role of Siglecs-in particular CD33-related Siglecs-as self-receptors and their sialoglycan ligands in regulating this balance between recognition of self and non-self. Sialoglycans are found in the glycocalyx and extracellular fluids and matrices of all mammalian cells and can be considered as self-associated molecular patterns (SAMPs). We also provide an overview of the known interactions of Siglec receptors and sialoglycan-SAMPs. Manipulation of the Siglec-SAMP axis offers new therapeutic opportunities for the treatment of inflammatory conditions, autoimmune diseases and also cancer immunotherapy.

Keywords: Autoimmunity; Pattern recognition; Self-receptor; Tolerance.

Fig. 1

Schematic drawing of human and murine Siglec receptors. Conserved Siglecs can be found in different mammals and have orthologues between mice and humans. CD33-related Siglecs underwent rapid evolutionary changes and no orthologues can be found between mice and humans, but rather functional paralogues (e.g. Siglec-E and Siglec-9). Reprinted with permission from [136]

Fig. 2

Interactions of Siglec receptors with sialoglycans mediate immune escape of pathogens and tumor cells. a Under physiological conditions, sialoglycan-Siglec interactions are inhibiting immune activation and mediate peripheral tolerance. b Pathogens can exploit the sialoglycan-Siglec pathway and bind via sialoglycan-mimicking or protein ligands to inhibitory Siglec receptors and evade immune control. Activating Siglec receptors evolved to counteract this exploitation. Pathogens engaging inhibitory Siglec receptors can escape immune control resulting in more severe infections. c Tumor cells can exploit the sialoglycan-Siglec axis in a similar way as pathogens. The hypersialylated glycocalyx of tumor cells can engage Siglec receptors on different immune cells and mediate immune escape, cancer progression and metastasis