Allergen‐Specific IgE and IgG4 Signatures in IgG4 ‐Related Disease Revealed by a Large‐Scale PhIP ‐Seq Study

ABSTRACT Objectives Immunoglobulin G4‐related disease (IgG4‐RD) is frequently accompanied by allergic/atopic manifestations, yet its allergen‐specific antibody landscape remains poorly defined. Therefore, we detected allergen‐specific IgE and IgG4 levels in patients with IgG4‐RD to clarify their contribution to IgG4‐RD pathogenesis. Methods In total, 826 plasma samples from 370 patients with IgG4‐RD and 354 healthy controls were used to perform Phage Immunoprecipitation Sequencing. Follow‐up samples from 102 patients (median 3 years) captured temporal dynamics. Machine learning (XGBoost) was used to identify key allergen peptides. ELISA was used for validation in 51 IgG4‐RD patients and 24 healthy controls, including an independent cohort of 20 treatment‐naïve patients. Results Abnormal IgE and IgG4 allergen reactivity was observed in IgG4‐RD patients. Enhanced responses to Apis mellifera and Arachis hypogaea were particularly prominent and correlated with lacrimal gland, parotid gland, paranasal, pulmonary, renal ( A. mellifera ) and pancreatic ( A. hypogaea ) involvement. XGBoost achieved an AUC of 0.91–0.96 and consistently ranked 10 peptides, mainly from bee, peanut, vespid‐venom and fish allergens. ELISA confirmed significantly elevated Ara h 1‐specific IgG4 in IgG4‐RD. Follow‐up sampling showed a global decline in reactivity to most top allergens and an IgE‐to‐IgG4 shift to Staphylococcus aureus peptides, suggesting therapy‐associated modulation and emerging tolerance. Conclusions Comprehensive pan‐allergen profiling suggests distinct IgE and IgG4 signatures in IgG4‐RD and links specific environmental antigens to organ‐selective disease patterns. These findings support a contributory role for aberrant allergen responses in IgG4‐RD pathogenesis and provide a foundation for biomarker development and targeted allergen‐based interventions, especially for future mechanistic investigations.