Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China.
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Nat Commun. 2024 Jul 15;15(1):5949. doi: 10.1038/s41467-024-50283-3.
Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.
大疱性类天疱疮（BP）是一种 2 型炎症和免疫驱动的皮肤疾病，但对免疫景观，特别是 BP 中的免疫-基质相互作用的全面理解仍难以捉摸。在此，我们使用单细胞 RNA 测序（scRNA-seq）和体外功能分析，确定了 Th2 细胞、树突状细胞（DCs）和成纤维细胞为关键细胞群体。IL13-IL13RA1 配体-受体对被鉴定为 BP 中免疫-基质相互作用的最重要介质。值得注意的是，表达 IL13RA1 的成纤维细胞和 DC 对分泌 IL13 的 Th2 细胞作出反应，从而放大 Th2 细胞介导的级联反应，这是通过成纤维细胞中 PLA2G2A 和髓样细胞中 CCL17 的特异性上调来实现的，形成了免疫-基质相互作用的正反馈回路。此外，PLA2G2A 和 CCL17 导致 BP 患者中致病性抗 BP180-NC16A 自身抗体滴度增加。我们的工作提供了对 BP 发病机制的全面了解，并展示了调节免疫-基质相互作用的机制，为未来的治疗研究提供了潜在途径。
