Spatial transcriptomics reveals an SPP1-centered immune-fibrotic axis associated with fibrosis-related tissue remodeling in IgG4-related disease.

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by progressive organ damage; however, the spatial organization linking immune dysregulation to fibrotic remodeling remains incompletely understood. In this study, we performed spatial transcriptomic analysis of submandibular gland tissues from patients with IgG4-RD representing two distinct fibrosis-associated tissue states. Gene expression data were normalized and z-scored, and immune- and fibrosis-related module scores were calculated. Fibrotic niches were defined based on COL1A1 expression and fibroblast signatures, and spatial co-localization and correlation analyses were conducted. Fibrosis-high tissue regions exhibited enrichment of SPP1-expressing macrophages that co-localized with COL1A1 and fibroblast-rich areas, consistent with a spatially defined fibrotic niche. These regions were associated with increased expression of PDGFB and TGF-β-related molecules, which correlated with fibrosis-related signatures. Immune network analysis suggested remodeling of the immune microenvironment, with expansion and integration of Tph-associated populations. A preTfh-to-Tph axis became more apparent in fibrosis-high lesions, accompanied by reduced germinal center B-cell signatures and enhanced extrafollicular activation. Exhaustion-associated programs, including PDCD1 and TOX, were associated with T-cell differentiation states and SPP1-related signatures. Together, these findings identify an SPP1-associated immune-fibrotic niche and suggest a spatially coordinated relationship between immune remodeling and fibrosis in IgG4-RD. This hypothesis-generating framework provides insights into fibrosis-associated tissue remodeling and may inform future strategies for disease stratification and therapeutic targeting.