Epstein-Barr virus and multiple sclerosis: supporting causality

Abstract

Epstein-Barr virus (EBV) is a γ-herpes virus that infects around 95% of individuals worldwide. Although the infection is generally asymptomatic when acquired in childhood, EBV can cause infectious mononucleosis in adolescents and several tumours, like lymphomas and nasopharyngeal carcinoma, in adults. EBV has also been associated with multiple sclerosis, the most common chronic inflammatory disease of the CNS. Robust evidence indicates that the risk of multiple sclerosis is nearly absent in EBV-seronegative individuals, increases considerably after EBV infection, and increases even more after infectious mononucleosis. 1 Jacobs BM Giovannoni G Cuzick J Dobson R Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. Mult Scler. 2020; 26: 1281-1297 Crossref PubMed Scopus (22) Google Scholar Furthermore, people with multiple sclerosis have an increased antibody response to EBV that becomes detectable years before disease onset. 2 Levin LI Munger KL Rubertone MV et al. Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA. 2005; 293: 2496-2500 Crossref PubMed Scopus (334) Google Scholar , 3 Sundström P Juto P Wadell G et al. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology. 2004; 62: 2277-2282 Crossref PubMed Scopus (246) Google Scholar These findings suggest that multiple sclerosis might develop in susceptible individuals due to an alteration of the EBV–host homoeostasis that ordinarily ensures a life-long, pacific coexistence under continuous immune surveillance in healthy EBV carriers. 4 Läderach F Münz C Epstein Barr virus exploits genetic susceptibility to increase multiple sclerosis risk. Microorganisms. 2021; 92191 Crossref Scopus (4) Google Scholar To date, however, most of the available evidence has been correlative in nature and it has been difficult to prove that EBV causes multiple sclerosis. 5 Olsson T Barcellos LF Alfredsson L Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017; 13: 25-36 Crossref PubMed Scopus (458) Google Scholar