A recent longitudinal analysis suggests that infection with Epstein-Barr virus (EBV) increases the risk of developing multiple sclerosis (MS) by more than 30 times, placing EBV as the leading cause of MS (1).

MS is a debilitating chronic autoimmune disease affecting more than 2.8 million people worldwide (2). In MS, the neurodegenerative demyelination of the central nervous system is caused by immune-mediated chronic inflammation. At present, while there is no known cause for MS, patients with the disease seem to have a genetic vulnerability to certain environmental factors that could trigger this condition, such as EBV (3,4).

EBV is a human gamma-herpesvirus and is one of the most ubiquitous viruses, infecting up to 95% of the global population. EBV is usually asymptomatic when contracted in childhood; however, if the primary infection occurs in adolescence or adulthood, it can lead to infectious mononucleosis (IM) (5). After infection, it remains in the body throughout life in a latent form inside B-cells but can be periodically reactivated and it has been linked to certain cancers (6) and autoimmune diseases (7,8).

EBV has been associated with MS through epidemiological and serological studies (9,10,11,12). However, results from pathology studies have been conflicting, with some but not all studies detecting EBV in MS demyelinated lesions (13,14,15,16). Evidence of causality remains inconclusive, primarily due to the high frequency of EBV, the rarity of MS, and the lengthy delay between EBV infection and MS onset (1).

The current study included blood sample data collected over a 20-year period (1993 – 2013) from over 10 million people actively serving in the US military. For 801 (out of 995) individuals who developed MS during the study, and for 1,566 matched controls, multiple serum samples taken before the date of diagnosis were available. These samples were analysed for EBV antibodies to determine the soldiers' EBV status at the time of first sample and the relationship between EBV infection and MS onset during the period of active duty.

At baseline, 35 MS cases and 107 controls were EBV-negative. Thirty-four of the MS cases became infected with EBV during the follow-up, and all seroconverted before the onset of MS. In comparison, only 57% of controls became EBV-seropositive over the same period. These results indicate that the risk of developing MS increased 32 times in those who became positive for EBV infection, which is higher than any other known risk factor.

EBV seropositivity was nearly ubiquitous at the time of MS development, with only one of 801 MS cases being EBV seronegative at the time of MS onset. On average, individuals who developed MS became symptomatic 5 years after infection with EBV.

Serum concentrations of neurofilament light chain (sNfL), a biomarker of nerve cell damage, were assessed in a subset of samples. sNfL levels are known to increase as early as 6 years before clinical MS onset and may be a more accurate marker of the time of initiation of the disease process (17). The sNfl levels only increased after EBV seroconversion in individuals who developed MS, suggesting that EBV infection occurs before both the onset of MS symptoms and the neurodegeneration inherent in MS.

Antibodies against cytomegalovirus (CMV) were also assessed to determine whether other infections were associated with the development of MS. In contrast to results with EBV, MS risk was lower amongst CMV-positive individuals compared to CMV-negative individuals. Virome screening, which assessed the immune response of samples to approximately 200 human pathogenic viruses, did not identify any links between other viruses and MS risk.

Although the findings implicate EBV as a major initiator for MS, the study does not prove causation and does not identify confounders that may explain why only a small percentage of people infected with EBV develop MS. In addition, research suggests that other factors such as genetic susceptibility and environmental factors (e.g., smoking, vitamin D deficiency) are important in MS pathogenesis (18,19,20).

The study strengthens the scientific consensus that EBV infection is a trigger for MS and creates new research opportunities for MS diagnosis, management, and possible clinical treatments targeting EBV infection. In addition, the findings have ramifications for research into other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, which have also been significantly associated with EBV infection in epidemiologic studies (7,21).