Immunophenotyping in pemphigus reveals a Th17/Tfh17-dominated immune response promoting desmoglein1/3-specific autoantibody production

ABSTRACT Background T helper (Th) 2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T cell subsets in pemphigus pathogenesis remained unclear. Objective We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus. Methods Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by RT-qPCR. In peripheral blood, the distribution of Th and Tfh cell subsets was analyzed by flow cytometry. Finally, the capacity of Th and Tfh cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments. Results Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in pemphigus patients and KEGG pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by RT-qPCR comparing lesional with perilesional or healthy skin. Interestingly, patients with active pemphigus showed elevated levels of circulating IL-17+ Th17, Tfh17 and Tfh17.1 cells utilizing flow cytometry. Notably, Th17 and Tfh17 cells correlated with levels of Dsg-specific CD19+CD27+ memory B cells and acute pemphigus patients showed higher levels of Dsg3-autoreactive Tfh17 cells. Coculture experiments revealed Tfh17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells. Conclusion Our findings show that Tfh17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention. This study unveils an IL-17-signature in skin and peripheral T cells of patients suffering from the autoantibody-mediated blistering skin disease pemphigus.