Unraveling the Epstein-Barr virus enigma: The puzzling role in multiple sclerosis development

In a recent article published in the Clinical and Translational Immunology journal, researchers pursuing multiple sclerosis (MS) therapies and preventive interventions reviewed the current evidence and mechanisms linking MS with Epstein–Barr virus (EBV).

Study: Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism. Image Credit: Kateryna Kon / ShutterstockStudy: Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism. Image Credit: Kateryna Kon / Shutterstock


Recent evidence suggests that EBV plays a pivotal role in MS development. Previously, researchers viewed EBV as a cancer-causing agent, and the link between EBV and MS appeared puzzling. 

However, accumulating data suggests that acute symptomatic primary EBV infection significantly increases MS risk, a disease characterized by progressive neurodegeneration and disability. Also, its risk is low in EBV seronegative individuals.

However, scientists have no clarity about the virological and immunological events that occur during primary EBV infection or how EBV-induced immune dysregulation drives MS. It is crucial to elucidate the underlying mechanisms governing EBV-induced MS to gather a deep understanding of MS pathogenesis.

MS, a chronic disease of the central nervous system (CNS), is common among women aged between 20 and 40 years. Over time, a relapsing–remitting disease course is taken over by neurodegenerative mechanisms, resulting in a steady loss of brain function and volume.

Warner and Carp first suggested a role for EBV in MS in 1981 based on epidemiological observations that showed a rare incidence of asymptomatic EBV infection in nonaffluent countries, whereas delayed and symptomatic infection in affluent Caucasians. Both were reminiscent of MS – a disease more common in Westernized societies.

Much later, in 2010, Alberto Ascherio et al. showed a possible link between primary EBV infection and MS among US military recruits. It was much more compelling evidence because this study cohort was much more extensive.

Due to the unique lifestyle of EBV, a γ-1 herpesvirus harboring many unique genes in its >170 Kb double-stranded deoxyribonucleic acid (DNA) genome, there is a lack of robust animal models to study EBV immunobiology. Thus, studies primarily depend on the natural host to examine EBV infection in infectious mononucleosis (IM) patients. These people develop lymphoproliferative disease (LPD) characterized by extensive expansion of T cells in the blood. 

Overall, the current understanding of EBV biology, and its association with the host immune response, especially in the context of MS, remains incomplete. However, multiple studies have shown that EBV seropositivity always invariably precedes the onset of MS. The largest investigation to date in this context surveyed 10 million people and showed that EBV seroconversion increased the risk of MS by 32-fold. In addition, EBV seronegative individuals have a small MS odds ratio (OR), an effect unique to EBV infections.

Further studies showed a delay between the resolution of primary infection and the MS onset by several months, suggesting that EBV drives MS pathogenesis rather than the acute infection. These observations do not rule out the role of other environmental or genetic factors in MS development.

Multiple independent and longitudinal studies have confirmed a robust correlation between antibody responses to EBV nuclear antigens (EBNA) and MS risk. Accordingly, individuals with the highest antibody titers showed up to an eight- and 36-fold increased risk of MS onset, respectively.

Intriguingly, EBV seroconversion in adolescence carries the highest risk of onset of MS. Moreover, EBV viral loads in MS patients mostly remain unaltered or increase slightly in the peripheral blood compared with healthy controls, indicating that they had transitioned into a persistent EBV carrier state before developing MS.

The exact neuroinflammatory mechanism through which EBV mediates MS pathogenesis remains unknown. One theory suggests that uncontrolled EBV replication decreases T-cell immunosurveillance and that MS-related damage to the CNS is due to infected B cells gaining entry into the CNS. These B cells serve a pathogenic role and stimulate altered T-cell responses in MS patients; thus, researchers have shifted focus to studying T cell–B cell interactions outside lymphoid organs. Multiple other theories have surfaced to elucidate this interaction; however, none thoroughly explains MS-related epidemiological and clinical observations.

To date, molecular mimicry appears to be the most convincing theory implicating EBV in MS. Recent studies showed that antibodies are generated against EBNA1-bound homologous epitopes from human proteins, e.g., anoctamin-2 (ANO2).

Researchers have discovered multiple cross- or autoreactive antibodies in MS patients; however, only in a subset of patients, raising the possibility that they are biomarkers of pathogenic T-cell responses which drive MS.

Missing links, learnings, and future directions

Antibody and T-cell responses to EBV and autoantigens in individuals are the key to understanding the role of EBV adaptive immunity in MS, thus, warrants further study. Further research is warranted to ascertain how EBV infection affects the immunopeptidome on the B-cell surface.

A better understanding of IM might be critical in uncovering EBV's role in the development of MS because a history of IM is one of the foremost drivers of interest in a possible link between EBV and MS. Moreover, researchers seek clarity on why MS is becoming increasingly prevalent in developed countries only.

EBV immunology will likely guide the development of personalized MS therapies in the future. However, first, studies must better characterize the virological events in MS. For instance, genetic analysis of large cohorts of individuals showing EBV seroconversion might shed light on how virus and host interactions affect the immune compartment at different stages of development. 

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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