Exploring the Association between Epstein-Barr Virus and Systemic Lupus Erythematosus: Insights into Viral Triggers

Ling Zhong; Xiao Zhang

doi:10.53941/hm.2025.100012

Abstract

Epstein-Barr virus (EBV) is ubiquitous in humans, which infects more than 90% of adults globally. Beyond its established association with malignancies, EBV infection is linked to several autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis and Sjögren syndrome. SLE is characterized by systemic inflammation and multiorgan damage with unpredictable relapsing-remitting clinical course. Although significant evidence supports EBV infection as a contributing factor in SLE pathogenesis, the exact mechanisms linking EBV to SLE onset remain to be fully elucidated. Molecular mimicry is among the potential factors that may drive SLE development. Importantly, given this association, development of therapies targeting EBV is promising for novel SLE treatment.

References

1.
Zhong, L.; Krummenacher, C.; Zhang, W.; Hong, J.; Feng, Q.; Chen, Y.; Zhao, Q.; Zeng, M.S.; Zeng, Y.X.; Xu, M.; et al. Urgency and necessity of Epstein-Barr virus prophylactic vaccines. NPJ Vaccines 2022, 7, 159. https://doi.org/10.1038/s41541-022-00587-6.
2.
Odumade, O.A.; Hogquist, K.A.; Balfour, H.H., Jr. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin. Microbiol. Rev. 2011, 24, 193–209. https://doi.org/10.1128/CMR.00044-10.
3.
Damania, B.; Kenney, S.C.; Raab-Traub, N. Epstein-Barr virus: Biology and clinical disease. Cell 2022, 185, 3652–3670. https://doi.org/10.1016/j.cell.2022.08.026.
4.
Burton, E.M.; Goldbach-Mansky, R.; Bhaduri-McIntosh, S. A promiscuous inflammasome sparks replication of a common tumor virus. Proc. Natl. Acad. Sci. USA 2020, 117, 1722–1730. https://doi.org/10.1073/pnas.1919133117.
5.
Kraus, R.J.; Yu, X.; Cordes, B.A.; Sathiamoorthi, S.; Iempridee, T.; Nawandar, D.M.; Ma, S.; Romero-Masters, J.C.; McChesney, K.G.; Lin, Z.; et al. Hypoxia-inducible factor-1alpha plays roles in Epstein-Barr virus’s natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter. PLoS Pathog. 2017, 13, e1006404. https://doi.org/10.1371/journal.ppat.1006404.
6.
Laichalk, L.L.; Thorley-Lawson, D.A. Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J. Virol. 2005, 79, 1296–1307. https://doi.org/10.1128/JVI.79.2.1296-1307.2005.
7.
Van Sciver, N.; Ohashi, M.; Pauly, N.P.; Bristol, J.A.; Nelson, S.E.; Johannsen, E.C.; Kenney, S.C. Hippo signaling effectors YAP and TAZ induce Epstein-Barr Virus (EBV) lytic reactivation through TEADs in epithelial cells. PLoS Pathog. 2021, 17, e1009783. https://doi.org/10.1371/journal.ppat.1009783.
8.
Liu, J.; Gao, H.; Xu, L.P.; Mo, X.D.; Liu, R.; Liang, S.; Wu, N.; Wang, M.; Wang, Z.; Chang, Y.J.; et al. Immunosuppressant indulges EBV reactivation and related lymphoproliferative disease by inhibiting Vdelta2(+) T cells activities after hematopoietic transplantation for blood malignancies. J. Immunother. Cancer 2020, 8, e000208. https://doi.org/10.1136/jitc-2019-000208.
9.
Hatayama, Y.; Hashimoto, Y.; Motokura, T. Frequent co-reactivation of Epstein-Barr virus in patients with cytomegalovirus viremia under immunosuppressive therapy and/or chemotherapy. J. Int. Med. Res. 2020, 48, 300060520972880. https://doi.org/10.1177/0300060520972880.
10.
Robinson, W.H.; Younis, S.; Love, Z.Z.; Steinman, L.; Lanz, T.V. Epstein-Barr virus as a potentiator of autoimmune diseases. Nat. Rev. Rheumatol. 2024, 20, 729–740. https://doi.org/10.1038/s41584-024-01167-9.
11.
Rahman, A.; Isenberg, D.A. Systemic lupus erythematosus. N. Engl. J. Med. 2008, 358, 929–939. https://doi.org/10.1056/NEJMra071297.
12.
Gao, S.; Yu, Z.; Ma, X.; Sun, J.; Ren, A.; Gao, S.; Gong, M.; Zhou, X.; Ma, M.; Song, H. Childhood-onset systemic lupus erythematosus in China, 2016–2021: A nationwide study. Lancet Child Adolesc. Health 2024, 8, 762–772. https://doi.org/10.1016/S2352-4642(24)00172-X.
13.
Evans, A.S.; Rothfield, N.F.; Niederman, J.C. Raised antibody titres to E.B. virus in systemic lupus erythematosus. Lancet 1971, 1, 167–168. https://doi.org/10.1016/s0140-6736(71)91937-4.
14.
James, J.A.; Kaufman, K.M.; Farris, A.D.; Taylor-Albert, E.; Lehman, T.J.; Harley, J.B. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J. Clin. Investig. 1997, 100, 3019–3026. https://doi.org/10.1172/JCI119856.
15.
James, J.A.; Neas, B.R.; Moser, K.L.; Hall, T.; Bruner, G.R.; Sestak, A.L.; Harley, J.B. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. Arthritis Rheum. 2001, 44, 1122–1126. https://doi.org/10.1002/1529-0131(200105)44:5<1122::AID-ANR193>3.0.CO;2-D.
16.
Chen, C.J.; Lin, K.H.; Lin, S.C.; Tsai, W.C.; Yen, J.H.; Chang, S.J.; Lu, S.N.; Liu, H.W. High prevalence of immunoglobulin A antibody against Epstein-Barr virus capsid antigen in adult patients with lupus with disease flare: Case control studies. J. Rheumatol. 2005, 32, 44–47.
17.
Lau, C.S.; Yuen, K.Y.; Chan, K.H.; Wong, R.W. Lack of evidence of active lytic replication of Epstein-Barr and cytomegaloviruses in patients with systemic lupus erythematosus. Chin. Med. J. 1998, 111, 660–665.
18.
Kang, I.; Quan, T.; Nolasco, H.; Park, S.H.; Hong, M.S.; Crouch, J.; Pamer, E.G.; Howe, J.G.; Craft, J. Defective control of latent Epstein-Barr virus infection in systemic lupus erythematosus. J. Immunol. 2004, 172, 1287–1294. https://doi.org/10.4049/jimmunol.172.2.1287.
19.
Moon, U.Y.; Park, S.J.; Oh, S.T.; Kim, W.U.; Park, S.H.; Lee, S.H.; Cho, C.S.; Kim, H.Y.; Lee, W.K.; Lee, S.K. Patients with systemic lupus erythematosus have abnormally elevated Epstein-Barr virus load in blood. Arthritis Res. Ther. 2004, 6, R295–R302. https://doi.org/10.1186/ar1181.
20.
Tu, J.; Wang, X.; Geng, G.; Xue, X.; Lin, X.; Zhu, X.; Sun, L. The Possible Effect of B-Cell Epitopes of Epstein-Barr Virus Early Antigen, Membrane Antigen, Latent Membrane Protein-1, and -2A on Systemic Lupus Erythematosus. Front. Immunol. 2018, 9, 187. https://doi.org/10.3389/fimmu.2018.00187.
21.
Yadav, P.; Tran, H.; Ebegbe, R.; Gottlieb, P.; Wei, H.; Lewis, R.H.; Mumbey-Wafula, A.; Kaplan, A.; Kholdarova, E.; Spatz, L. Antibodies elicited in response to EBNA-1 may cross-react with dsDNA. PLoS ONE 2011, 6, e14488. https://doi.org/10.1371/journal.pone.0014488.
22.
Yadav, P.; Carr, M.T.; Yu, R.; Mumbey-Wafula, A.; Spatz, L.A. Mapping an epitope in EBNA-1 that is recognized by monoclonal antibodies to EBNA-1 that cross-react with dsDNA. Immun. Inflamm. Dis. 2016, 4, 362–375. https://doi.org/10.1002/iid3.119.
23.
Csorba, K.; Schirmbeck, L.A.; Tuncer, E.; Ribi, C.; Roux-Lombard, P.; Chizzolini, C.; Huynh-Do, U.; Vanhecke, D.; Trendelenburg, M. Anti-C1q Antibodies as Occurring in Systemic Lupus Erythematosus Could Be Induced by an Epstein-Barr Virus-Derived Antigenic Site. Front. Immunol. 2019, 10, 2619. https://doi.org/10.3389/fimmu.2019.02619.
24.
McClain, M.T.; Heinlen, L.D.; Dennis, G.J.; Roebuck, J.; Harley, J.B.; James, J.A. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nat. Med. 2005, 11, 85–89. https://doi.org/10.1038/nm1167.
25.
Sabbatini, A.; Bombardieri, S.; Migliorini, P. Autoantibodies from patients with systemic lupus erythematosus bind a shared sequence of SmD and Epstein-Barr virus-encoded nuclear antigen EBNA I. Eur. J. Immunol. 1993, 23, 1146–1152. https://doi.org/10.1002/eji.1830230525.
26.
James, J.A.; Gross, T.; Scofield, R.H.; Harley, J.B. Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B’-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity. J. Exp. Med. 1995, 181, 453–461. https://doi.org/10.1084/jem.181.2.453.
27.
James, J.A.; Scofield, R.H.; Harley, J.B. Lupus humoral autoimmunity after short peptide immunization. Ann. N. Y. Acad. Sci. 1997, 815, 124–127. https://doi.org/10.1111/j.1749-6632.1997.tb52054.x.
28.
Sundar, K.; Jacques, S.; Gottlieb, P.; Villars, R.; Benito, M.E.; Taylor, D.K.; Spatz, L.A. Expression of the Epstein-Barr virus nuclear antigen-1 (EBNA-1) in the mouse can elicit the production of anti-dsDNA and anti-Sm antibodies. J. Autoimmun. 2004, 23, 127–140. https://doi.org/10.1016/j.jaut.2004.06.001.
29.
Rovin, B.H.; Furie, R.; Latinis, K.; Looney, R.J.; Fervenza, F.C.; Sanchez-Guerrero, J.; Maciuca, R.; Zhang, D.; Garg, J.P.; Brunetta, P.; et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012, 64, 1215–1226. https://doi.org/10.1002/art.34359.
30.
Mackensen, A.; Muller, F.; Mougiakakos, D.; Boltz, S.; Wilhelm, A.; Aigner, M.; Volkl, S.; Simon, D.; Kleyer, A.; Munoz, L.; et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat. Med. 2022, 28, 2124–2132. https://doi.org/10.1038/s41591-022-02017-5.
31.
Monaco, M.C.G.; Soldan, S.S.; Su, C.; Clauze, A.; Cooper, J.F.; Patel, R.J.; Lu, F.; Hughes, R.J.; Messick, T.E.; Andrada, F.C.; et al. EBNA1 Inhibitors Block Proliferation of Spontaneous Lymphoblastoid Cell Lines From Patients With Multiple Sclerosis and Healthy Controls. Neurol. Neuroimmunol. Neuroinflamm. 2023, 10, e200149. https://doi.org/10.1212/NXI.0000000000200149.

Scilight Press

Author Information

Abstract

Keywords

References

About Scilight

Journals

Publishing Policies

Contact Us