SIGLEC8

Official Full Name

sialic acid binding Ig like lectin 8

Organism

Homo sapiens

GeneID

27181

Background

Sialic acid-binding immunoglobulin (Ig)-like lectins, or SIGLECs (e.g., CD33 (MIM 159590)), are a family of type 1 transmembrane proteins each having a unique expression pattern, mostly in hemopoietic cells. SIGLEC8 is a member of the CD33-like subgroup of SIGLECs, which are localized to 19q13.3-q13.4 and have 2 conserved cytoplasmic tyrosine-based motifs: an immunoreceptor tyrosine-based inhibitory motif, or ITIM (see MIM 604964), and a motif homologous to one identified in signaling lymphocyte activation molecule (SLAM; MIM 603492) that mediates an association with SLAM-associated protein (SAP; MIM 300490) (summarized by Foussias et al., 2000 [PubMed 11095983]).[supplied by OMIM, May 2010]

Synonyms

SAF2; SIGLEC-8; SIGLEC8L;

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Detailed Information

The SIGLEC-8 gene encodes a sialic acid-binding immunoglobulin-like lectin 8, located on human chromosome 19q13.41, a region rich in immune-related genes, including multiple CD33-like SIGLEC family members. SIGLEC-8 is a type I transmembrane protein with an extracellular V-set and C2-set immunoglobulin-like domains; the V-set domain mediates recognition of sialylated glycan ligands. Intracellularly, SIGLEC-8 contains two highly conserved tyrosine motifs: an immunoreceptor tyrosine-based inhibitory motif (ITIM) and a motif associated with signaling lymphocyte activation molecule (SLAM), classifying it as a typical inhibitory receptor. SIGLEC-8 expression is highly cell-specific, predominantly found on human eosinophils, mast cells, and to a lesser extent on basophils, with minimal expression on other immune cells. Its absence in mice poses challenges for preclinical studies, emphasizing its unique role in human immunity.

Biological Significance

SIGLEC-8 functions as an inhibitory receptor, regulating eosinophil and mast cell activation and survival through recognition of sialylated glycans. It preferentially binds α-2,3-linked sialic acids and can recognize α-2,6 linkages, particularly terminal N-acetylneuraminic acid and 6-O-sulfated galactose on glycans (e.g., Gal-6-sulfated sialyl Lewis X). Ligand engagement phosphorylates ITIM motifs, recruiting SH2-domain-containing phosphatases that inhibit activation signaling. Crosslinking SIGLEC-8 on eosinophils induces caspase-dependent apoptosis, whereas on mast cells it suppresses degranulation, histamine and leukotriene release, and cytokine production without directly inducing cell death.

This cell type-specific inhibition positions SIGLEC-8 as a key checkpoint for regulating type 2 immune responses, maintaining homeostasis and preventing hyperactivation of pathogenic effector cells.

Figure 1. Siglec-8 mAb recruits phosphatases like Shp-2 to FcεRI–Siglec-8 complexes, thereby inhibiting mast cell activation. (Korver W., et al., 2022)

Clinical Relevance

SIGLEC-8 is a promising therapeutic target in eosinophil- and mast cell-driven diseases, including eosinophilic gastritis, eosinophilic esophagitis, hypereosinophilic syndrome, severe asthma, chronic inducible urticaria, and systemic mastocytosis. Therapeutic antibodies targeting SIGLEC-8, such as AK0010 (akrotolimab), employ a dual mechanism: suppressing mast cell activation and inducing eosinophil apoptosis through antibody-dependent cellular cytotoxicity. This approach has demonstrated favorable safety and efficacy signals in clinical trials. Research is also exploring ligand mimetics and antibody-drug conjugates to expand therapeutic options. Key challenges include defining endogenous ligand dynamics in human disease and optimizing long-term modulation of the SIGLEC-8 pathway.

References

Kikly KK, Bochner BS, Freeman SD, et al. Identification of SAF-2, a novel siglec expressed on eosinophils, mast cells, and basophils. J Allergy Clin Immunol. 2000;105(6 Pt 1):1093-1100.
Bochner BS. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin Exp Allergy. 2009;39(3):317-324.
Youngblood BA, Brock EC, Leung J, et al. AK0010, a humanized monoclonal antibody to Siglec-8, induces apoptosis of eosinophils and inhibits mast cell activation in vitro and in vivo. J Allergy Clin Immunol. 2019;143(2):AB401.
Korver W, Wong A, Gebremeskel S, et al. The Inhibitory Receptor Siglec-8 Interacts With FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation. Front Immunol. 2022 Jan 28;13:833728.

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