Abstract
Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease caused by disruption of intercellular adhesion due to auto-antibodies directed against epithelial components. Treatment is limited to immunosuppressive agents, which are associated with serious adverse effects. The propensity to develop the disease is in part genetically determined. We therefore reasoned that the delineation of PV genetic basis may point to novel therapeutic strategies. Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the ST18 gene confer a significant risk for the disease. Here, using targeted deep sequencing, we identified a PV-associated variant residing within the ST18 promoter region (p<0.0002; odds ratio = 2.03). This variant was found to drive increased gene transcription in a p53/p63-dependent manner, which may explain the fact that ST18 is up-regulated in the skin of PV patients. We then discovered that when overexpressed, ST18 stimulates PV serum-induced secretion of key inflammatory molecules and contributes to PV serum-induced disruption of keratinocyte cell-cell adhesion, two processes previously implicated in the pathogenesis of PV. Thus, the present findings indicate that ST18 may play a direct role in PV and consequently represents a potential target for the treatment of this disease.
Highlights
Pemphigus refers to a group of autoimmune blistering disorders which affect mucocutaneous tissues [1,2]
Using a genome-wide association approach, we recently found that genetic variants in the vicinity of the suppression of tumorigenicity 18 (ST18) gene confer a significant risk for the disease
Using a genome wide association approach, we recently identified pemphigus vulgaris-associated genetic variations in the vicinity of the ST18 gene
Summary
Pemphigus refers to a group of autoimmune blistering disorders which affect mucocutaneous tissues [1,2]. The propensity to develop the disease is believed to be to a large extent genetically determined as attested by familial occurrence of PV, the presence of circulating PV IgG Abs in healthy first-degree relatives of PV patients and ethnic clustering [3,5,6,7]. This in turn offers the possibility to identify elements of importance to PV etiology through a genetic approach. We examined the possibility that ST18 plays a direct role in PV pathogenesis
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