Single-cell transcriptomics analysis of bullous pemphigoid unveils immune-stromal crosstalk in type 2 inflammatory disease

Tingting Liu, Zhenzhen Wang, Xiaotong Xue, Zhe Wang, Yuan Zhang, Zihao Mi, Qing Zhao, Lele Sun, Chuan Wang, Peidian Shi, Gongqi Yu, Meng Wang, Yonghu Sun, Fuzhong Xue, Hong Liu () and Furen Zhang ()
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Tingting Liu: Shandong First Medical University
Zhenzhen Wang: Shandong First Medical University
Xiaotong Xue: Shandong First Medical University
Zhe Wang: Shandong First Medical University
Yuan Zhang: Shandong First Medical University
Zihao Mi: Shandong First Medical University
Qing Zhao: Shandong First Medical University
Lele Sun: Shandong First Medical University
Chuan Wang: Shandong First Medical University
Peidian Shi: Shandong First Medical University
Gongqi Yu: Shandong First Medical University
Meng Wang: Shandong First Medical University
Yonghu Sun: Shandong First Medical University
Fuzhong Xue: Shandong University
Hong Liu: Shandong First Medical University
Furen Zhang: Shandong First Medical University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50283-3

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