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

Abstract

Background: 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.

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_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.

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

Keywords: IL-17; Pemphigus vulgaris; T-cell–B-cell interaction; autoantibodies; autoimmunity; bullous disease; desmoglein; follicular T cells; helper T cells; pemphigus foliaceus.