Inflammaging reshapes the immune ecosystem in IgG4-related dacryoadenitis and sialadenitis.

<h4>Objectives</h4>IgG4-related disease (IgG4-RD) predominantly affects middle-aged and elderly individuals; however, the impact of ageing on lesional immune architecture remains poorly understood.<h4>Methods</h4>Bulk transcriptomic analyses were performed using IgG4-RD lesion tissues across a broad age spectrum. Age-associated genes, Hallmark pathways and immune/stromal module scores were evaluated using correlation-based analyses, network analysis and fibrosis pseudo-staging.<h4>Results</h4>Principal component analysis demonstrated age-associated transcriptomic shifts in IgG4-RD lesions. Ageing was associated with increased expression of cytotoxic/exhaustion-related genes, including IFNG, GZMA, GZMH and PRDM1, together with activation of inflammaging(definition)- and senescence(definition)-associated programs. Module analysis demonstrated positive correlations between age and fibroblast, exhaustion, macrophage/M2, fibrosis-associated macrophage (FAM), inflammaging and senescence-associated secretory phenotype (SASP) signatures, whereas germinal-centre B cell programs showed minimal association with age. Hallmark pathway analysis revealed enrichment of interferon-γ response, IL6-JAK-STAT3 signalling, TNFα/NFκB signalling, epithelial-mesenchymal transition and TGF-β signalling in ageing lesions. Network analysis demonstrated segregation between adaptive immune modules and ageing-associated fibro-inflammatory modules. Advanced fibrosis pseudo-stages were enriched in older patients.<h4>Conclusions</h4>Ageing in IgG4-RD was associated with coordinated immune ecosystem remodelling characterized by inflammaging, exhaustion-associated immune programs, stromal activation and relative reduction in the prominence of adaptive germinal-centre immunity. These findings suggest that ageing-associated immune remodelling may contribute to chronic fibro-inflammatory disease evolution in IgG4-related dacryoadenitis and sialadenitis.