Large-Scale Autoantibody Reactome Analysis Reveals Shared and Specific Signatures Across Different Immune-Mediated Inflammatory Diseases.

Abstract

Objective: The shared and disease-specific mechanisms across the immune-mediated inflammatory diseases (IMIDs) spectrum remains incompletely characterized, despite the recognized role of autoantibodies as important indicators of immune tolerance breakdown and immune dysregulation.

Methods: Autoantibody reactome profiling of IgG and IgA autoantibodies was performed across eight IMIDs to delineate both shared and disease-specific autoantibodies using autoantigen microarray.

Results: Widespread autoantibody signatures were observed, and 384 and 69 IgG and IgA autoantibodies were identified in IMID, predominantly targeting proteins involved in cytokine signaling and T cell-related pathways. Notably, most IMIDs have the common pathways of cell apoptosis and proliferation, and each IMID has its unique pathways. The identified autoantibody signatures achieved area under the curve values of 0.6 to 1.0 for individual IMIDs and 0.996 for all IMIDs compared with healthy controls. The autoantibodies against SULF1 and HDAC3 were further validated in an independent rheumatoid arthritis cohort, and the overexpression of these two autoantigens was detected at the transcriptomic and protein levels.

Conclusion: These findings provide an exploratory autoantibody-based resource for IMID and identify candidate signatures that may inform future studies of disease stratification, diagnostic refinement, and mechanistic investigation. Nevertheless, owing to the relatively small sample sizes for each disease subgroup, the observed predictive performances should be regarded as preliminary, necessitating further verification in larger independent patient cohorts.