Shortly after World War II, Irish surgeon Denis Parsons Burkitt noticed the appearance of jaw and facial bone tumors in an unusually large number of children whilst working in Uganda. In early 1960s London, pathologist Michael Anthony Epstein, along with Yvonne Barr and Bert Achong, identified a new virus from the Herpesviridae family in tumour cells sent from Uganda. This virus became known as Epstein-Barr virus, and a malignant disease identified in Uganda as Burkitt’s lymphoma.
What is EBV?
Epstein-Barr virus (EBV) is a double-stranded DNA virus that infects B-lymphocytes. It is transmitted mainly via saliva (most often by sharing food and kissing) which contains virus-infected epithelial cells. Nearly 95% of adults worldwide have been infected with EBV at some point. The envelope of this virus has glycoproteins essential for binding and entry into the host cell (B-lymphocytes and epithelial cells). EBV uses B-lymphocytes to replicate its viral genome. These B-lymphocytes then differentiate into memory B-cells, which can then enter the circulation or remain dormant until some trigger reactivates them.
EBV is causally associated with multiple malignant and non-malignant diseases. It is best known as the cause of mononucleosis. Malignancies associated with it include Burkitt’s lymphoma, hemophagocytic lymphohistiocytosis, Hodgkin’s lymphoma, and nasopharyngeal and gastric cancers. Some studies have also found a link between EBV and various autoimmune diseases, such as systemic lupus erythematosus, dermatomyositis, and rheumatoid arthritis. It is important to know that much remains unclear, so the cause-and-effect relationship between this virus and the aforementioned diseases is not entirely clear. According to new studies from 2022, multiple sclerosis is included in the set of diseases associated with EBV.
What is multiple sclerosis?
Multiple sclerosis is one of the leading causes of physical disability, whose rates are rising in both the developed world and the developing world. The aetiology of this disease is still unclear. In addition to some genes, the occurrence and development of MS are influenced by some environmental factors: exposure to sunlight, obesity and smoking. Three key pathophysiological characteristics are the formation of lesions in the central nervous system, inflammatory processes and demyelinating processes. These three work together in a complex and not entirely clarified way, causing a range of symptoms. These include visual disturbances, paresthesias, general weakness, spasticity, urinary incontinence, and cognitive impairment. The course of the disease depends on the type of multiple sclerosis that the patient suffers from, and includes alternating periods of relapse and remission, and often worsening of the situation over time. However, in general, the course of the disease is highly variable and unpredictable. There is a growing number of drugs that can be used to treat multiple sclerosis, which include mechanisms of action that were not previously thought to be crucial in the development of the disease (e.g. drugs that target B-lymphocytes).
How to conduct research?
Clarifying the factors that lead to the occurrence of multiple sclerosis is thus becoming an increasingly relevant issue. Scientists have long considered EBV to be an important causative factor. However, as 95% of people are infected with the virus, and as the number of people infected with multiple sclerosis is 1 in 330 (in the US), it was difficult to design a study that would monitor two groups of people (one infected and the other uninfected) and measure in which group cases of multiple sclerosis would occur.
However, one such study was conducted on recruits in the U.S. military, a group of more than 10 million people. At the beginning of their service and every two years thereafter, samples of their blood serums were collected and tested for HIV, and stored. Thus, researchers from Harvard University tested samples collected from 1993 to 2013. They identified cases of multiple sclerosis among soldiers in active service, and tested their sera. Of the 801 soldiers with multiple sclerosis, 800 were positive for EBV. They then analyzed serum samples from a randomly selected group with similar characteristics (age, sex, race). At the time of collecting the first sample, 35 people who now have multiple sclerosis were negative. In the control group, 107 people were negative. At the time of the last test, all but one person with MS were positive for the virus today, unlike only 57% of those without multiple sclerosis.
Significance of discovery
In theory, this means that people who do not have EBV have practically no chance of getting multiple sclerosis, i.e. that after EBV infection the risk of developing multiple sclerosis increases 30 times. In another study, published shortly after, another team of scientists from Stanford University tried to explain the pathological mechanisms of the association between EBV and multiple sclerosis. According to them, the point is in molecular mimicry. Namely, the Epstein-Barr virus produces proteins that are similar to the proteins that can be found in myelin, so when antibodies attack the virus, they also attack their own central nervous system. However, this explanation is only possible for a minority of cases of multiple sclerosis, and one should be careful with the claim that EBV causes multiple sclerosis, especially when the vast majority of people with EBV still do not develop it. It would be more accurate to say that EBV seems to be a necessary condition for the development of multiple sclerosis, and that genetic and environmental factors are still likely to be crucial for the onset of the disease.
These findings motivate diverse teams of scientists to learn more about the field, and open up the possibility of developing therapeutic options for both multiple sclerosis and mononucleosis, either to prevent mononucleosis transmission, prevent mononucleosis from being a predisposing factor for MS, or treat MS through some targets associated with response to Epstein-Barr virus.
Translation by Vanda Petrak
1 Lanz TV et al. Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM. Nature, 2022
2 Bjornevik K et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 2022, 375/6578: 296-301 3
Dobson R, Giovannoni G. Multiple Sclerosis – A Review. Eur J. Neurol. 2019, 26(1), 27-40
4 Fugl A, Andersen CL. Epstein-Barr virus and its association with disease – a review of relevance to general practice. BMC Farm Pract. 2019, 20, 62
5 Multipla skleroza, www.msd-prirucnici.placebo.hr, pristupljeno 1.3.2022.