[8][9][10] Siglec-8 was first identified by CD33 homology screening of ESTs from a cDNA library generated from a patient diagnosed with idiopathic hypereosinophilic syndrome and was originally termed SAF-2 (sialoadhesin family 2).

[7] The initially characterized form contains 431 amino acid residues in total, 47 of which comprise an uncharacteristically short cytoplasmic tail compared to most CD33-associated siglecs.

[15][16] Rescreening on a more expanded glycan array reconfirmed this finding, but also identified a second closely related ligand in which the fucose is absent (NeuAcα2–3(6-O-sulfo)Galβ1–4GlcNAc, or 6′-sulfated sialyl N-acetyl-D-lactosamine.

Treatment of human eosinophils with sialidase increases the extent to which a high-avidity glycan ligand (1-MDa polyacrylamide ribbon decorated with 6′-O-sulfo-3′-sialyl-LacNAc) binds to these cells by about 50%.

[23][24][25] Inhibitor studies demonstrate that cell death induced by crosslinking Siglec-8 through the use of an anti-Siglec-8 mAb and a secondary antibody is mediated sequentially through reactive oxygen species (ROS) production, loss of mitochondrial membrane potential, and caspase activation.

[26] In the presence of IL-5, the loss of mitochondrial membrane integrity is accelerated and the secondary crosslinking antibody is no longer necessary to induce cell death.

On IL-5-primed eosinophils, antibody ligation of Siglec-8 was found to lead to CD11b/CD18 integrin upregulation, conformational activation, and subsequent integrin-mediated adhesion.

[29] Disruption of Siglec-8 binding to α2,3-sialylated cis ligands enables Siglec-8 engagement-induced cell death in eosinophils and overcomes the need for cytokine priming (e.g. , with IL-5, GM-CSF, or IL-33) or extensive receptor cross-linking.

[21] The cell death pathway licensed by enzymatic removal of these sialylated cis ligands resembles that described in eosinophils primed with IL-5 in that it involves cell-surface upregulation of CD11b and ROS production and requires the activities of Syk, PI3K, and phospholipase C. Concurrent stimulation of the IL-5 receptor and Siglec-8 leads to a type of cell death resembling regulated necrosis that is promoted by MEK1/ERK signaling.

[31] In experiments using the rat basophilic leukemia cell line RBL-2H3 stably transfected with Siglec-8, the inhibitory effect of Siglec-8 ligation on FcεRIα-mediated degranulation and Ca2+ flux was found to be dependent on the intact ITIM.

[31] In studies involving transgenic mouse Siglec-8-expressing bone marrow-derived mast cells, co-engagement of Siglec-8 and FcεRIα leads to the inhibition of proximal kinase signaling downstream of FcεRI ligation.

[35][36][37] This functional convergence of Siglec-8 and Siglec-F has permitted in vivo studies to be performed in mouse models of eosinophil-mediated disorders that may provide information about the human system.

[36][38] Antibody ligation of Siglec-F has also been shown to inhibit eosinophil-mediated intestinal inflammation and airway remodeling in OVA challenge models.

[36][37] However, Siglec-F–induced eosinophil apoptosis is mediated by a mechanism distinct from that employed by Siglec-8, hindering direct comparisons between the mouse and human systems.

[42] In a randomized clinical trial, lirentelimab, a monoclonal antibody targeting SIGLEC8 has been evaluated as a treatment for eosinophilic gastritis and duodenitis.