Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Background: Epstein-Barr virus (EBV) infection is a known trigger and risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we found enhanced IgG reactivity to EBV EBNA4 and EBNA6 arginine-rich sequences in postinfectious ME/CFS (piME/CFS). Objective: This study aims to investigate IgG responses to arginine-rich (poly-R) EBNA4 and EBNA6 sequences and homologous human sequences in PCS and ME/CFS. Methods: The IgG responses against poly-R EBNA4 and EBNA6 and corresponding homologous human 15-mer peptides and respective full-length proteins were analyzed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Sera of 45 PCS patients diagnosed according to WHO criteria, with 26 patients fulfilling the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 healthy controls (HC) were investigated. Results: Autoantibodies to poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, angiogenic regulator TSPYL5, as well as to full-length α-adrenergic receptor (ADRA) proteins were more frequent in patients. Several autoantibodies were positively associated with key symptoms of autonomic dysfunction, fatigue, cognition, and pain. Conclusion: Collectively, we identified autoantibodies with new antigen specificities with a potential role in PCS and ME/CFS. Clinical Implication: These finding should prompt further studies on the function of these autoantibodies, their exploitation for diagnostic use, and of drugs targeting autoantibodies. Capsule summary: Our study reveals elevated autoantibodies to EBV-related poly-R sequences and their human homologues in PCS and ME/CFS patients associated with symptom severity, suggesting a potential role in disease pathogenesis.