Immunophenotyping in pemphigus reveals a T_H17/T_FH17 cell-dominated immune response promoting desmoglein1/3-specific...

T_H2 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.

We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus.

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.

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_H17, T_FH17, and T_FH17.1 cells. Notably, levels of T_H17 and T_FH17 cells correlated with levels of Dsg-specific CD19⁺CD27⁺ memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive T_FH17 cells. Coculture experiments revealed T_FH17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells.

Our findings show that T_FH17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.