Mechanisms of Epstein-Barr virus-associated autoimmunity: a comparative overview

Abstract

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus, increasingly implicated in the pathogenesis of several autoimmune diseases, such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). These diseases have both, shared and disease-specific immunopathogenic pathways involving EBV. Shared mechanisms include the role of EBV latent proteins in triggering immune dysfunction, molecular mimicry between viral and self-antigens, infection of autoreactive B-cells, and dysfunction of type 1 interferon (IFN-1) responses. In MS, EBV is associated with a CNS-compartmentalized CD8+ T-cell responses, molecular mimicry with neural antigens, and formation of meningeal tertiary lymphoid structures. In SLE, EBV contributes to systemic autoimmunity through mimicry with multiple autoantigens, recurrent viral reactivation, and IFN-driven multi-organ inflammation. In RA, EBV promotes the formation of synovial ectopic lymphoid structures, enhances anti-citrullinated protein antibody production, and drives proinflammatory cytokine dysregulation. Host genetic variations, particularly in HLA alleles, further modulate susceptibility by influencing antigen presentation, viral control and autoreactive T-cell responses. Rather than acting as a uniform and consistent trigger, EBV appears to function as a context-dependent immunological modifier whose pathogenic effects are influenced by factors such as the timing of infection, tissue microenvironment, HLA-associated genetic background, and other environmental exposures. Unravelling the details of these mechanisms may inform targeted preventive and therapeutic strategies for EBV-associated autoimmune diseases.