HLA-DQB1-mediated B cell-epithelial crosstalk drives EBV-associated inflammation in Hunner-type interstitial cystitis.

Hunner-type interstitial cystitis (HIC) is a chronic condition marked by persistent pain and inflammation. To elucidate its immunogenetic drivers, we integrated bulk RNA sequencing and single-cell RNA sequencing datasets with targeted major histocompatibility complex (MHC) sequencing. Transcriptomic analysis revealed selective expansion of B cells and epithelial cells, with strong enrichment of Epstein-Barr virus (EBV) response signatures. CellChat and NicheNet modeling uncovered bidirectional communication wherein B cells secrete IL-1β, FGF2, LIF, and TNFSF9, activating prostaglandin synthesis, matrix metalloproteinases, and stress genes in epithelial cells. In turn, epithelial BMP4, TGF-β2, and SHH modulate B cell survival. SCENIC regulatory network analysis identified IRF8 as the top B cell regulator; its regulon controls HLA-DQB1, CD40, and CIITA, linking EBV latency to heightened antigen presentation. Among differentially expressed genes, HLA-DQB1 was the most strongly induced in EBV+ HIC (∼1,000-fold), emerged as the most frequently mutated gene in targeted MHC sequencing, and ranked as a high-confidence IRF8 target. Notably, the evolutionarily constrained variant rs1049133 (A>G) lies within a low-entropy HLA-DQB1 domain, underscoring functional importance. Our integrated analysis supports a model where IRF8-driven, EBV-infected B cells perpetuate HIC via variant HLA-DQB1-mediated antigen presentation and epithelial cytokine loops, highlighting a tractable axis for precision therapy.