029 Transcriptome analysis suggests a role of IL-17-related genes in pemphigus

Pemphigus is an autoimmune blistering skin disease characterized by autoantibodies (auto-ab) directed against the desmosomal proteins desmoglein (Dsg)1 and/or Dsg3. The exact pathogenesis of pemphigus is not fully understood. Some data suggest an association with Th2 immune responses, others with Th1 cells. More recently, IL-17 expression was also reported to be present in pemphigus skin. To better understand the immune signature of pemphigus, we performed transcriptome analysis of pemphigus skin. First, we performed a large scale analysis by whole transcriptome shotgun sequencing (RNA-seq) of six lesional pemphigus skin samples. We compared the data of lesional pemphigus skin to data obtained from healthy control skin samples (n=6). By biostatistics we identified an unexpected IL-17A-dominated immune signature in pemphigus skin with some similarities to psoriatic skin. KEGG pathway analysis revealed that the IL-17A pathway was upregulated in pemphigus with a positive feedback effect on functionally different genes varying from skin modelling genes, antimicrobial peptides as well as pro-inflammatory chemokines and cytokines. To confirm this initial data by conventional quantitative RT-PCR we analyzed lesional skin from 29 patients. In agreement with previous reports, we found some expression of IL-4 and IFN-g. Strikingly, we could confirm the RNA-seq data and detected high expression of IL-17A and associated mediators. In subsequent analysis, we compared the immune signature of lesional skin to perilesional skin and also the features of mucosal lesions compared to non-mucosal sites. Taken together, we found some expression of IL-4 and IFN-g, but dominant expression of certain mediators of the IL-17A pathway, strongly suggesting that pemphigus has a unique IL-17A-dominated immune signature that may be important for autoantibody formation and skin blistering at local tissue sites.