Th9细胞通过IL-9调控角质形成细胞的肌动蛋白重构促进寻常型天疱疮的机制研究

寻常型天疱疮（PV）是由抗Dsg3抗体诱发的具有潜在致命危险的自身免疫病，T细胞异常和棘层松解是关键发病环节。IL-9是Th9细胞的效应因子，二者是否参与PV发生未明。本项目前期研究表明PV患者外周Th9细胞和IL-9增加，IL-9水平与病情呈正相关。用IL-9抗体中和PV血清的IL-9可削弱PV血清对HaCat细胞黏附功能和肌动蛋白重构的影响。IL-9可激活HaCat细胞的JAK/STAT3/RhoA途径，抑制JAK活性可阻断IL-9对RhoA的活化。因此提出科学假说：Th9细胞通过IL-9激活JAK/STAT3/RhoA途径调控角质形成细胞肌动蛋白重构和黏附功能，从而促进PV发生。本项目拟采用人角质形成细胞和PV小鼠模型，探讨PV血清、anti-IL-9抗体、IL-9重组蛋白、JAK抑制剂等对其肌动蛋白重构的影响。预期结果将丰富PV的发病机制，为临床治疗PV提供新思路。

Pemphigus vulgaris (PV) is a potentially fatal autoimmune disease induced by anti-Dsg3 antibodies. T cell abnormalities and acantholysis are the key pathogenesis. IL-9 is an effector of Th9 cells. Whether Th9 and IL-9 are involved in the occurrence of PV remains unclear. Our study showed that peripheral Th9 cells and serum IL-9 level increased in PV patients and IL-9 level was positively correlated with the disease severity. Neutralizing the IL-9 of PV serum with IL-9 antibody weakened the influence of PV serum on adhesion function and actin remodeling of HaCat cells. IL-9 could activate the JAK/STAT3/RhoA signaling pathway in HaCat cells. Inhibiting JAK activity blocked IL-9-induced RhoA activation. Therefore, we propose a scientific hypothesis that Th9 cells activate the JAK/STAT3/RhoA pathway via IL-9 to regulate the actin remodeling and adhesion function of keratinocytes, thereby promoting the occurrence of PV. We intend to use human keratinocytes and PV mouse models to explore the effects of PV serum, anti-IL-9 antibody, IL-9 recombinant protein, and JAK inhibitor on actin remodeling. The expected results will enrich the pathogenesis of PV and provide new ideas for PV treatment.