Journal Article

Unraveling the Microenvironment and the Pathogenic Axis of HIF‐1α–Visfatin–Fibrosis in Autoimmune Pancreatitis Using a Single‐Cell Atlas

Li, Shiyu, Ma, Congjia, Yin, Hua, Wang, Zhen, Jiang, Hui, Peng, Lisi, Jin, Zhendong, Ji, Baoan, Li, Zhaoshen, Wan, Dongling, Li, Jiayu, Jiang, Fei, Su, Xiaoju, Li, Wanshun, Sun, Liqi, Liu, Zaoqu, Liu, Yue, Tian, Xiaorong, Wu, Chang, Zhang, Deyu, Liu, Yanfang, Wang, Xinyue, Huang, Haojie, Zhou, Yuyan

2025

Overview

Autoimmune pancreatitis (AIP) is identified as a severe chronic immune‐related disorder in pancreas, including two subtypes. In this study, pancreatic lesions in patients diagnosed as either type 1 AIP or type 2 AIP are examined, and these patients’ peripheral blood at single‐cell level. Furthermore, flow cytometry, immunofluorescence, and functional assays are performed to verify the identified cell subtypes. In type 1 AIP, there is a notable increase in the amount of B cells and plasma cells, and IgG4+ plasma cells are key pathogenic cells of AIP. The differentiation path of naïve‐stage B cells into IgG4+ produced plasma cells is observed, and an increased amount of T helper cells and T follicular helper (Tfh) cells. This study also reveals that HIF‐1α, an activated transcriptional factor, can directly bind to promoter site of NAMPT, promoting higher levels of visfatin production in HIF1A+ classical monocytes. Pancreatic stellate cells can be activated by extracellular visfatin and promote the development of fibrotic response in pancreatic lesions across both AIP subtypes. The current findings shed light on the exploration of dynamic alterations in peripheral blood cells and cell subgroups in pancreatic lesions of AIP, while elucidating a pathogenic cell subset and potential fibrosis mechanism of AIP. Single‐cell RNA sequencing reveals that type 1 AIP exhibits increased amount and subtypes of B and plasma cells, particularly IgG4+ plasma cells, along with an expansion of Tfh and T helper CD4+ cells. Both AIP types share upregulation of HIF1A+ classical monocytes, which promote pancreatic fibrosis through increased visfatin production.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Aged / autoimmune pancreatitis / Autoimmune Pancreatitis - immunology / Autoimmune Pancreatitis - metabolism / Autoimmune Pancreatitis - pathology / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / Biomarkers / Cells / Cytokines - metabolism / Disease / Female / Fibrosis / HIF1‐α / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Male / Middle Aged / Pancreas - pathology / Pancreatic cancer / Pancreatitis / Plasma / Plasma Cells - immunology / Plasma Cells - metabolism / Remission (Medicine) / Single-Cell Analysis - methods / single‐cell atlas / Steroids / visfatin