TGF‐β1‐driven epithelial‒mesenchymal transition mediates the fibrotic process in IgG4‐related disease

Background Major challenges exist in understanding the pathogenic mechanisms and developing systemic therapeutic strategies for IgG4‐related disease (IgG4‐RD) due to its rarity, unique clinical manifestations and inconsistent response to specific treatments. To overcome these limitations, comprehensive analysis of gene expression profiles may serve as a crucial stepping stone. Methods A salivary gland transcriptomic dataset encompassing both bulk tissue and single‐cell levels was obtained. Cellular and molecular features were identified by analysing differentially expressed genes and performing functional enrichment analyses. Gene regulatory and cell‒cell communication analyses were also conducted. Results The most enriched processes were the epithelial‒mesenchymal transition (EMT) and extracellular matrix organisation. EMT, which was weighted towards a mesenchymal signature, was closely associated with myofibroblasts, extracellular matrix organisation and the transforming growth factor‐β (TGF‐β) signalling pathway. Fibroblasts were the primary cell subset enriched for in the EMT signature. Additionally, CD19 + B cells, cytotoxic T cells and regulatory T cells were the main sources of TGF‐β1. In the analysis of B cell‒fibroblast communication, EMT of fibroblasts was found to be activated primarily by TGF‐β1 secreted from CD19 + B cells. Reciprocally, fibroblasts supported CD19 + B cells via CXCL14‒CXCR4 and CXCL12‒CXCR4 interactions. Conclusions Our findings suggest a pivotal role for TGF‐β1‐mediated EMT in the pathogenesis of fibrosis associated with IgG4‐RD, with CD19 + B cells identified as a significant source of TGF‐β1. This evidence substantiates the rationale for B‐cell‐depletion therapy as a promising therapeutic strategy for this condition.