Eichinger, A. | bioRxiv Science

bioRxiv2025

Dynamic remodeling of the pancreas immune landscape in obesity.

Obesity is a known risk factor for diseases of the pancreas, including diabetes, pancreatic cancer and pancreatitis, but mechanisms remain unclear. To elucidate how obesity impacts pancreatic immune homeostasis, we performed spatial, transcriptomic and functional profiling of human pancreatic immune cells from obese and non-obese organ donors. Obesity was associated with higher density of tissue resident memory T-cells (TRM) in the exocrine pancreas which display high cytotoxic functions and aggregated around macrophages. Single cell sequencing of pancreatic macrophages revealed two main subsets - FOLR2+ CD11c- fetal-derived macrophages with pro-repair and immunoregulatory function and a FOLR2- CD11c+ monocyte-derived macrophages with greater T-cell interactions and pro-inflammatory function. In obesity, the pancreatic macrophage landscape shifts to lower predominance of FOLR2+ CD11c- macrophages and higher FOLR2- CD11c+ macrophages which interact selectively with the TRM and inflamed exocrine epithelium. Together, these results identify macrophage-T cell circuits and immune epithelial interactions that fuel chronic pancreatic inflammation in obesity - a potential unifying mechanism for obesity-related pancreatic diseases.

immunology↗

bioRxiv2024

Spatial and Single Cell Mapping of Castleman Disease Reveals Key Stromal Cell Types and Cytokine Pathways

Castleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGF{beta}, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment. Key pointsO_LICastleman Disease is characterized by activation and proliferation of CXCL13+ FDCs, PDGFRA+ reticular cells, and ACTA2-positive PRCs. C_LIO_LIVEGF and IL-6 from lymph node stromal cells are associated with B-cell activation and differentiation, endothelial proliferation, and inflammation in CD C_LI

pathology↗