Large-scale antibody reactome profiling identifies herpesvirus-autoantigen associations underlying chronic diseases

Area of Science:

• Immunology
• Virology
• Genomics

Background:

• Herpesviruses are ubiquitous and associated with autoimmune and chronic diseases.
• Systematic characterization of herpesvirus-host protein immune interactions at a population scale is lacking.

Purpose of the Study:

• To systematically profile immunoglobulin G (IgG) reactivities against herpesvirus peptides and human proteins.
• To identify and validate viral-autoantigen associations and their link to disease outcomes.
• To define virus-specific immune network architectures in relation to autoimmune diseases.

Main Methods:

• Multiplexed protein display was used to profile IgG reactivities to >4,600 herpesvirus peptides and >15,000 human proteins.
• Two Mass General Brigham Biobank cohorts (discovery n=1,289; replication n=763) with longitudinal electronic health record data were analyzed.
• Statistical methods including FDR correction and independent validation were employed to identify significant associations.

Main Results:

• 3,943 FDR-significant associations were identified and replicated across 93 autoantigens, including novel viral-autoantigen axes.
• Eleven autoantigens were predicted with >85% accuracy by viral peptide reactivities, with some showing sequence homology suggestive of molecular mimicry.
• Virus-specific network architectures were revealed: cytomegalovirus (CMV) formed the largest multimorbid network, Epstein-Barr virus (EBV) converged on autoimmune hubs, and herpes simplex viruses (HSV) formed smaller autoreactive networks.

Conclusions:

• This study establishes a comprehensive herpesvirus-autoantigen-disease network atlas.
• Identified viral-host immune axes provide critical targets for mechanistic investigation into herpesvirus-associated autoimmunity.
• Findings highlight the complex interplay between herpesviruses, host immunity, and autoimmune disease pathogenesis.