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

OBJECTIVES: IgG4-related disease (IgG4-RD) predominantly affects middle-aged and elderly individuals; however, the impact of aging on lesional immune architecture remains poorly understood. METHODS: 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. RESULTS: Principal component analysis demonstrated age-associated transcriptomic shifts in IgG4-RD lesions. Aging was associated with increased expression of cytotoxic/exhaustion-related genes, including IFNG, GZMA, GZMH, and PRDM1, together with activation of inflammaging- and senescence-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 center B-cell programs showed minimal association with age. Hallmark pathway analysis revealed enrichment of interferon-γ response, IL6-JAK-STAT3 signaling, TNFα/NFκB signaling, epithelial-mesenchymal transition, and TGF-β signaling in aging lesions. Network analysis demonstrated segregation between adaptive immune modules and aging-associated fibro-inflammatory modules. Advanced fibrosis pseudo-stages were enriched in older patients. CONCLUSIONS: Aging in IgG4-RD was associated with coordinated immune ecosystem remodeling characterized by inflammaging, exhaustion-associated immune programs, stromal activation, and relative reduction in the prominence of adaptive germinal center immunity. These findings suggest that aging-associated immune remodeling may contribute to chronic fibro-inflammatory disease evolution in IgG4-related dacryoadenitis and sialadenitis.