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.

中文翻译：

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天疱疮的免疫表型分析显示 TH17/TFH17 细胞主导的免疫反应促进桥粒素1/3 特异性自身抗体的产生

背景

T _H 2 细胞被认为是引发自身免疫性水疱病天疱疮的关键因素。然而，其他 T 细胞亚群在天疱疮发病机制中的作用仍不清楚。

客观的

我们旨在表征负责天疱疮发展的 T 细胞的确切表型。

方法

进行全转录组鸟枪法测序以确定天疱疮病变和健康个体皮肤中的差异基因表达。通过实时定量 PCR 进一步评估皮肤细胞因子特征。在外周血中，通过流式细胞术分析T _H细胞和滤泡辅助 (T _FH ) 细胞亚群的分布。最后，在共培养实验中评估了 T _H和 T _FH细胞亚群通过记忆 B 细胞诱导桥粒芯蛋白 (Dsg) 特异性自身抗体的能力。

结果

皮肤样本的转录组分析确定了天疱疮患者的 IL-17A 主导的免疫特征，京都基因和基因组学百科全书通路分析证实了 IL-17A 信号通路的主导地位。IL17A和相关细胞因子的表达增加也通过实时定量 PCR 检测到，比较病变与周围或健康皮肤。有趣的是，流式细胞术的使用表明，活动性天疱疮患者的循环 IL-17 ⁺ _、 T _H 17、T _FH 17 和 T _FH 17.1 细胞水平升高。值得注意的是，T _H 17 和 T _FH 17 细胞的水平与 Dsg 特异性 CD19 ^{+ 的}水平相关CD27 ⁺记忆 B 细胞和急性天疱疮患者显示出更高水平的 Dsg3 自身反应性 T _FH 17 细胞。共培养实验表明 T _FH 17 细胞主要负责诱导 B 细胞产生 Dsg 特异性自身抗体。

结论

我们的研究结果表明，T _FH 17 细胞与天疱疮的发病机制密切相关，并为治疗干预提供了新的靶点。