Association of Th2-like inflammation with a Tfh/Tph–germinal center immune programs in submandibular gland lesions of IgG4-related disease

OBJECTIVES: IgG4-related disease (IgG4-RD) has long been associated with Th2-predominant immune responses and allergic features. However, the immunological context underlying lesional Th2-like inflammation remains incompletely understood. METHODS: Bulk RNA-seq data from 49 submandibular gland lesions of IgG4-RD were analyzed. Module scores representing Th2, Tfh/Tph, B cell, germinal center B cell (GC_B), plasma cell, macrophage, and stromal/fibrotic programs were calculated. Correlations between Th2 module scores and other immune/stromal modules were assessed using Spearman correlation analysis. Differentially expressed genes between Th2-high and Th2-low lesions were also evaluated. RESULTS: Th2 module scores were strongly associated with Tfh, Tfh/Tph, and Tph helper T cell programs, as well as with B cell, GC_B, and plasma cell signatures. In addition, Th2 module scores positively correlated with M2 macrophage and fibrosis-associated macrophage (FAM) programs. Differential expression analysis demonstrated increased expression of chronic helper T cell-related genes, including PDCD1, TOX, and MAF, together with plasmablast-associated genes such as JCHAIN, MZB1, and PRDM1 in Th2-high lesions. In contrast, serum IgG4 and IgE levels did not significantly differ between Th2-high and Th2-low groups. CONCLUSIONS: Lesional Th2-like inflammation in IgG4-RD was closely associated with chronic Tfh/Tph-germinal center immune programs linked to plasmablast and M2/FAM macrophage responses. No clear association with available systemic allergy-related parameters was observed in this cohort.