Polymorphisms in the sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) gene are associated with susceptibility to asthma

Abstract

Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FceRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P¼8.8Â10 À5 ) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P¼0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P¼0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P¼0.016), and replicated among the Brazilian families (P¼0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6¢-sulfo-sLe x , a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.

Siglec-mediated regulation of immune cell function in disease

“…Siglec-8 is specifically expressed on eosinophils in humans, whereas murine eosinophils and alveolar macrophages express an isofunctional paralog, Siglec-F, that shares a novel specificity for sialylated ligands as described below 54–56 . Both Siglecs have ITIMs 3 , and polymorphisms in the gene encoding Siglec-8 are correlated with increased susceptibility to asthma 57 .…”

“…1e). For murine eosinophils, ligation of Siglec-F with antibodies also causes apoptosis, however, the effect is modest and appears to be mediated by a different mechanism 61 , which suggests that information gleaned from disease models involving Siglec-F should be interpreted with caution before translating their relevance to Siglec-8 and human disease 56, 57 .…”

Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation

“…If regulation by inhibitory CD33rSiglecs is perturbed, pathologies may ensue including eosinophilic airway inflammation in mSiglec-F knockout mice [14], elevated pro-inflammatory cytokines in mice lacking mSiglec-G [8], asthma associated with hSiglec-8 polymorphisms [15], or exaggerated T-cell responses linked to an hSiglec-9 gene polymorphism [16]. Mouse microglial cells lacking mSiglec-E showed increased inflammatory responses and neurotoxicity in neuronal co-culture experiments [17], and hSiglec-10 is a selective modulator of the immune response to the DAMP HMGB1 released by necrotic cells [8].…”

Structural basis for sulfation-dependent self-glycan recognition by the human immune-inhibitory receptor Siglec-8

“…There is increasing awareness that dysregulated Siglec-8 function might be critically involved in the pathobiology of allergic and chronic inflammatory disorders, including asthma, where accumulation and delayed apoptosis of activated eosinophils and mast cells in the airways are among the leading causes of persistent inflammation and tissue damage (19,20). Indeed, Siglec-8 gene polymorphisms were identified to correlate with increased asthma risk (21), albeit the detailed molecular pathways linking Siglec-8 to disease have yet to be clarified. On account of its potent eosinophil proapoptotic and mast cell-inhibitory activities, combined with its selective expression on these key inflammatory effector cells, Siglec-8 is considered a promising target for novel antiinflammatory, proresolving treatment strategies for asthma and other disease conditions in which inappropriate and/or prolonged inflammatory responses of these cell types contributes to pathology (20,(22)(23)(24)(25).…”