Predictors of Chronic Obstructive Pulmonary Disease Exacerbations

Takeo Ishii; Kozui Kida

Disclosures

Curr Opin Pulm Med. 2014;20(2):138-145. 

In This Article

A New Prediction Factor for an Exacerbation-prone Phenotype: SIGLEC-14, an Antibacterial, Proinflammatory Lectin

Siglecs are a family of sialic acid-binding immunoglobulin-type lectins expressed mainly on innate immune cells.[28] Siglec-14, a family member with an activating signaling property, and Siglec-5, an inhibitory counterpart with an extensive sequence identity to Siglec-14, are both expressed on myeloid cells. Siglec-14 likely contributes to host protection by eliciting inflammatory responses, which might inadvertently lead to COPD exacerbation (Fig. 2a).[29,30] In humans, the ancestral (wildtype) SIGLEC gene cluster has both SIGLEC14 and SIGLEC5 genes in tandem, whereas a derived (SIGLEC14-null) allele harbors a single SIGLEC14/5 fusion gene, whose product is identical to Siglec-5 at the amino acid level, but without the SIGLEC14 allele[30] (Fig. 2b); this genetic variation is detected as a copy-number variant (CNV). A loss of Siglec-14 could result in attenuated immune responses against pathogenic bacteria that express sialic acids, such as non-typeable Haemophilus influenzae (NTHi), a major cause of COPD exacerbations[31] that expresses lipooligosaccharides, which contain sialic acids.[32] We found that NTHi interacts with Siglec-14 in order to enhance proinflammatory cytokine production, and that a loss of Siglec-14, because of SIGLEC14-null allele homozygosity, is associated with a reduced COPD exacerbation risk.[29] Siglec-14 and its downstream signaling pathway facilitate the 'infection–inflammation–exacerbation' axis of COPD disease progression, although it could have a role in host protection against bacteria, such as the above-mentioned mannose-binding lectin.

Figure 2.

CNVs in SIGLEC14 and a frequent-exacerbation phenotype in COPD. (a) Possible mechanism behind the association between the SIGLEC14 genotype and a frequent-exacerbation phenotype in COPD. Siglec-14, a family member with an activating signaling property, and Siglec-5, an inhibitory counterpart with extensive sequence identity to Siglec-14, are both expressed on myeloid cells. Siglec-14 likely contributes to host protection by eliciting inflammatory responses, which might inadvertently lead to COPD exacerbation. (b) Schematic diagram of SIGLEC5 and SIGLEC14 genes as CNVs. In humans, the ancestral (wildtype) SIGLEC gene cluster has both SIGLEC14 and SIGLEC5 genes in tandem, whereas a derived (SIGLEC14-null) allele harbors a single SIGLEC14/5 fusion gene, whose product is identical with respect to Siglec-5 at the amino acid level, without the SIGLEC14 allele. CNVs, copy-number variants; COPD, chronic obstructive pulmonary disease; NTHi, non-typeable Haemophilus influenzae. (a) Reproduced with permission from [29]; (b) modified with permission from [30].

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