Allergen‐Specific Antibodies Dysregulation and Profiles in IgG4 ‐Related Disease: A Hybrid Case–Control and Cross‐Sectional Study

ABSTRACT Background Although patients with immunoglobulin‐G4‐related disease (IgG4‐RD) frequently have comorbid allergic diseases, the specific allergen‐specific antibody profiles and their association with distinct organ‐involvement phenotypes remain unclear. Methods We conducted a hybrid study with 208 patients with IgG4‐RD and 104 age‐ and sex‐matched general population controls (controls). A case–control approach was used to compare the allergen‐specific antibody profiles between patients and controls. Within the IgG4‐RD cohort, a cross‐sectional analysis was performed by utilizing K‐modes clustering to identify organ‐involvement phenotypes; multivariate logistic regression was used to assess independent associations between antibody patterns and these phenotypes. Results Compared with controls, patients with IgG4‐RD had significantly reduced sIgG4 levels against house‐dust‐mite (HDM) components and elevated sIgE/sIgG4 ratios, which suggested a breakdown in immune tolerance. Within the IgG4‐RD cohort, three distinct organ phenotypes were identified. Multivariate analysis revealed that a pattern of high concurrent sIgE and sIgG4 responses to Der p 5 and Der p 21 was strongly associated with the exocrine gland‐involvement phenotype (OR = 906.70, p = 0.003), whereas an IgE‐dominant pattern against food allergens was inversely associated with this phenotype (OR = 0.16, p = 0.016). Conclusion The shift in the sIgE/sIgG4 balance suggests that impaired allergen‐specific immune tolerance is closely linked to IgG4‐RD clinical heterogeneity. Distinct antibody patterns, specifically a dual IgE/IgG4 response to Der p 5 and Der p 21, were independently associated with exocrine gland involvement. Thus, allergen‐specific profiling constitutes a valuable tool for characterizing disease phenotypes and investigating the underlying pathomechanisms.