Single-cell multi-omics analysis revealed the expansion of age-associated B cells in the pancreas of type 1 autoimmune pancreatitis patients

Background: Type 1 autoimmune pancreatitis (AIP) is pancreatic manifestation of IgG4-related disease (IgG4-RD), characterized by pancreatic lymphoplasmacytic infiltration. Despite this well-known pathological feature, the immune microenvironment and the complex cellular interactions within the pancreas in AIP remain poorly understood. This study aimed to characterize the local immune features of the pancreas in AIP patients.

Methods: We employed single-cell RNA Sequencing (scRNA-seq), immune receptor repertoire Sequencing (scTCR/BCR-seq), and spatial transcriptome Sequencing on biopsy samples from lesion tissues of AIP patients. Flow cytometry, multicolour immunofluorescence, and functional assays were performed to validate the findings from bioinformatics analysis.

Results: Our results revealed an increased presence of IgD^- age-associated B cells (ABCs) in the pancreas of AIP patients. These ABCs were predicted to differentiate into plasma cells that secrete IgG. Additionally, CXCL9⁺ macrophages were found to recruit IgD^- ABCs via the CXCL9-CXCR3 axis. Elevated levels of T follicular helper cells (Tfhs) were also observed, which interacted with IgD^- ABCs through IL-21 secretion. Both ABCs and Tfhs were localized at the periphery of pancreatic tertiary lymphoid structures (TLSs). Importantly, these immune abnormalities were specific to AIP and were not present in the pancreases of patients with chronic pancreatitis.

Conclusions: These findings highlight significant alterations in the pancreatic immune microenvironment in AIP and propose a potential pathogenic model involving ABCs, Tfhs, and macrophages. This model provides valuable insights that could inform the development of targeted therapeutic strategies for AIP.

Age-associated B cells; CXCL9; IgG4-related disease; Single-cell RNA sequencing; T follicular helper cells; Type 1 autoimmune pancreatitis.