TNF-α signaling mediates ST18 –dependent reduced cell-cell adhesion in pemphigus vulgaris – possible implications for therapy

BACKGROUND: Pemphigus vulgaris (PV) is a life-threatening autoimmune mucocutaneous blistering disease. We previously showed that variants within the ST18 gene promoter region are associated with a 6-fold increase in the risk of developing PV. ST18 is overexpressed in the skin of PV patients and promotes autoantibody-mediated abnormal epidermal cell-cell adhesion.

OBJECTIVE: We aimed at delineating the mechanism through which ST18 contributes to PV pathogenesis.

METHODS: We used immunofluorescence microscopy, a luciferase reporter system, qRT-PCR, site-directed mutagenesis and the dispase dissociation assay.

RESULTS: ST18 was shown to promote PV serum- and PV IgG-induced release of TNFα. Using a luciferase reporter system, ST18 was found to increase TNFα promoter activity. Bioinformatics analysis identified a number of binding sites for ST18 across the TNFα promoter. Site-directed deletion of these binding sites abolished ST18-induced activation of the TNFα promoter. Moreover, dual immunofluorescence staining showed increased expression of both ST18 and TNFα in biopsy samples obtained from the skin of PV patients carrying a ST18-associated risk variant for PV as compared to biopsy samples obtained from the skin of PV patients carrying a normal genotype. Finally, using the dispase dissociation assay, we showed that ST18 promotes PV-serum-mediated acantholysis in a TNFα-dependent manner.

CONCLUSIONS: The fact that TNFα mediates the deleterious effect of ST18 increased expression in PV suggests innovative and individualized therapeutic avenues for this condition.