Immunophenotyping in pemphigus reveals a TH17/TFH17 cell–dominated immune response promoting desmoglein1/3-specific autoantibody production

Background: T(H)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 real-time quantitative PCR. In peripheral blood, the distribution of T H cell and folliclular helper (T-FH) cell subsets was analyzed by flow cytometry. Finally, the capacity of T-H and T-FH 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 patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17(+), T(H)17, T(FH)17, and T(FH)17.1 cells. Notably, levels of T(H)17 and T(FH)17 cells correlated with levels of Dsg-specific CD19(+) CD27(+) memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T(FH)17 cells. Coculture experiments revealed T(FH)17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.Conclusion: Our findings show that T(FH)17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.