Isotype-specific autoantibody profiles associated with clinical immunological signatures in IgG4-RD

IgG4-related disease (IgG4-RD) involves elevated serum IgG4 and several autoantigens, but the role of different antibody isotypes in pathogenesis remains unclear. This study systematically characterized isotype‑specific autoantibody responses against representative autoantigens and evaluated their clinical and immunological correlations.

We enrolled 61 patients with IgG4‑RD, 31 with systemic lupus erythematosus (SLE), 11 with Sjögren's syndrome (SS), and 30 healthy controls (HC). Serum levels of isotype‑specific autoantibodies were measured using in‑house ELISA. Correlations with clinical and immunological parameters were evaluated using Spearman analysis with Benjamini‑Hochberg false discovery rate (FDR) correction. Tissue validation was performed via immunohistochemistry (IHC) and multiplex immunofluorescence (mIF) on submandibular gland biopsies. Longitudinal changes in autoantibody isotypes were assessed in paired pre‑ and post‑treatment sera from 12 patients.

IgG4‑RD exhibited broad isotype elevations extending beyond IgG4, with positivity rates of 80.33% for anti‑Annexin A11 IgG4, 59.02% for anti‑Galectin‑3 IgG4, and 100% for anti‑Prohibitin IgG4. Phenotype‑restricted patterns were observed: anti‑Galectin‑3 IgG4 was highest in Pancreato‑hepato‑biliary disease (72.73%) but lowest in Retroperitoneal fibrosis/aortitis group (16.67%), whereas anti‑Galectin‑3 IgE was more easily detected in Head‑and‑neck‑limited phenotype (26.09%). Correlation analyses identified 37 robust associations (FDR < 0.05) in IgG4‑RD, predominantly linking antigen‑specific IgG3 and IgG4 antibodies with serum immunoglobulins, CCL18, IL‑10, and IL‑6. Longitudinal paired analysis confirmed significant decrease of multiple detected autoantibodies following immunosuppressive therapy.

Our findings demonstrate that IgG4‑RD encompasses a complex and isotopically diverse autoantibody profile that is associated with immuno-laboratory features and clinical phenotypes of IgG4-RD patients.