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Epstein–Barr virus as a potentiator of autoimmune diseases

Nature Reviews Rheumatology volume 20, pages 729–740 (2024)Cite this article

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Abstract

The Epstein–Barr virus (EBV) is epidemiologically associated with development of autoimmune diseases, including systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. Although there is well-established evidence for this association, the underlying mechanistic basis remains incompletely defined. In this Review, we discuss the role of EBV infection as a potentiator of autoimmune rheumatic diseases. We review the EBV life cycle, viral transcription programmes, serological profiles and lytic reactivation. We discuss the epidemiological and mechanistic associations of EBV with systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis and multiple sclerosis. We describe the potential mechanisms by which EBV might promote autoimmunity, including EBV nuclear antigen 1-mediated molecular mimicry of human autoantigens; EBV-mediated B cell reprogramming, including EBV nuclear antigen 2-mediated dysregulation of autoimmune susceptibility genes; EBV and host genetic factors, including the potential for autoimmunity-promoting strains of EBV; EBV immune evasion and insufficient host responses to control infection; lytic reactivation; and other mechanisms. Finally, we discuss the therapeutic implications and potential therapeutic approaches to targeting EBV for the treatment of autoimmune disease.

Key points

  • Epstein–Barr virus (EBV) infection is epidemiologically associated with the autoimmune rheumatic diseases systemic lupus erythematosus, Sjögren syndrome and rheumatoid arthritis, as well as other autoimmune diseases, including multiple sclerosis.

  • There are multiple non-exclusive mechanisms by which EBV might potentiate autoimmunity, including molecular mimicry; B cell reprogramming; genetic factors, including autoimmunity-promoting strains of EBV and host genetics; immune evasion; and lytic reactivation.

  • Ongoing studies are linking EBV infection and EBV reactivation with development of autoimmunity and disease activity.

  • Ongoing studies are defining the molecular and cellular mechanisms by which EBV might mediate autoimmune diseases.

  • Therapeutic targeting of EBV could provide a fundamental treatment approach for EBV-associated autoimmune diseases.

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Fig. 1: EBV life cycle and associations with autoimmunity.
Fig. 2: Mechanisms by which EBV could potentiate autoimmunity.

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Acknowledgements

We thank members of the Robinson, Steinman and Lanz labs for their scientific insights and discussion. We acknowledge funding from NIH R01 AI173189, NIH PATHO-PH2-SUB_17_23, DoD HT9425-23-1-0595 and the Lupus Research Alliance.

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Authors and Affiliations

  1. Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA

    William H. Robinson, Shady Younis, Zelda Z. Love & Tobias V. Lanz

  2. VA Palo Alto Health Care System, Palo Alto, CA, USA

    William H. Robinson, Shady Younis & Zelda Z. Love

  3. Department of Neurology and Neurological Sciences and Paediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Lawrence Steinman

  4. Institute for Immunity Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA

    Tobias V. Lanz

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All authors contributed substantially to review of the literature and discussion of the content. W.H.R. and Z.Z.L. researched data for the article, wrote the article, and W.H.R. edited and revised the article. All authors reviewed and/or edited the manuscript before submission.

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W.H.R. and T.V.L. are consultants for and own equity in Flatiron Bio, and W.H.R. serves on the board of directors of Flatiron Bio. W.H.R., S.Y. and T.V.L. own equity in Ebvio, and W.H.R. serves on the board of directors of Ebvio.

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Robinson, W.H., Younis, S., Love, Z.Z. et al. Epstein–Barr virus as a potentiator of autoimmune diseases. Nat Rev Rheumatol 20, 729–740 (2024). https://doi.org/10.1038/s41584-024-01167-9

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