Epstein-Virus and Multiple Sclerosis

By Easha Vigneswaran 

Multiple Sclerosis (MS) is a chronic neurological disease that causes the demyelination of nerves and neurons due to the immune system mistakenly attacking the central nervous system. At present, it is not exactly clear what the direct cause of the disease is, but for 35 years, scientists have hypothesised that previous infection of the Epstein-Barr Virus (EBV) may be linked to the development of this deteriorating disease. 

EBV is not an uncommon virus, in fact, approximately 90% of the human population is already infected with this herpes virus. The virus itself remains in the host throughout its lifetime causing what is known as glandular fever.¹ Historically, finding a strong link between MS and EBV was difficult due to the lack of a large sample group and the fact the virus is extremely common in the population. However, following the investigation of a large sample group of US military personnel who were monitored over a 20-year period, Bjornevik and his research group were able to find strong links that suggest this EBV infection may increase the pathogenicity of MS.² 

The first reports of MS being linked to EBV infection were in 1980 and then later in a metanalysis review by Almohmeed et al., which showed that 98% of MS subjects were seropositive for EBV antibodies compared to 88% of the controls.³ Numerous other studies in subsequent years also showed a similar correlation between prior EBV infection and the onset of MS.¹ The most recent and extensive study, conducted by Bjornevik et al., concluded the same having analysed serum samples of US military personnel. They found that 35 of the 801 people that developed MS later in life had initially tested negative for the virus. Upon analysis of this personnel with MS 20 years later, 34 out of the 35 had all tested positive for EBV antibodies and only 1 remained seronegative for those antibodies. These new findings have further implicated EBV as a potential cause for MS pathogenicity.²  

The question that follows these findings is why a virus that is associated with infection of B-cells is leading to an inflammatory response in the central nervous system. Studies have found many EBV infected B cells in the brains of MS patients. B cells that have undergone clonal expansion following EBV infection express an integrin called alpha-4 that allows these B cells to move through the bone marrow and thereby cross the blood-brain barrier. Once in the brain, these B-cells produce immunoglobulins that target myelin synthesising glial cells thus damaging the CNS. These immunoglobulins can be detected in the cerebral spinal fluid of MS patients.⁴ 

Another theory surrounding the pathogenicity of EBV in MS is the role of antigenic mimicry. Studies suggest that EBV, upon B-cell infection, produces viral proteins that mimic myelin proteins. One of these proteins is the myelin stress protein alpha B-crystallin. This protein is meant to be protective against autoimmune demyelination but has also been found in MS lesions of patients. Theories suggest that EBV induced alpha B crystallin production in B cells, when presented to T cells, results in an autoimmune attack on the myelin, therefore resulting in CNS damage.⁵ Another theory is that EBV may be inducing changes in B cells whereby there are latent membrane viral proteins that disrupt the signalling pathway of the B cell receptor CD40. LMP1 (EBV protein) mimics CD40 signalling between T and B cells thus causing dysregulation of the immune response and inducing damage on the CNS.⁴ 

EBV contraction linked to the onset of MS can also be linked to vitamin D. It has been previously established that vitamin D deficiency is linked to the development of MS. Vitamin D is known to be important in immune system regulation. Its receptors are found in both healthy and EBV infected B cells, therefore deficiency of vitamin D as well as an EBV infection may increase the risk of B-cell attack on the ,therefore resulting in MS.⁶ 

It is important to say that although those infected with EBV are at risk of developing MS, it remains clear that it is still only a small fraction of the infected population that develop MS. There are numerous genetic factors that greatly increase the risk of developing MS. Gene mutations interacting with EBV proteins can however have large contributing effects to the development of  MS.⁴ In knowing the EBV-MS link exists, it provides a new basis for developing treatments for multiple sclerosis prevention. The EBV vaccine does not currently exist and due to the low incidence of disease induced by EBV infection, there is no necessity for a vaccine. However, with the studies suggesting a causative link between this neurological disease and the virus, it may be that more research efforts should be made to find preventative solutions against EBV infection. This may in turn prove extremely beneficial for those who are pre-disposed to MS as a result of their genetics.⁵

To conclude, it is clear that the vast epidemiological investigation into risk factors of MS have shown a strong correlation that Epstein-Barr Virus may in fact be one of the key drivers for multiple sclerosis pathogenicity in humans. However, it is also evident that further investigation is necessary to understand the extent to which this virus influences the onset of MS which would thereby provide the basis to develop more targeted therapies to reduce the degenerative effects of this chronic disease. 

References:

1. Ruprecht K. The role of Epstein-Barr virus in the etiology of multiple sclerosis: a current review. Expert Review of Clinical Immunology. 2020; 16(12), 1143-1157. doi: 10.1080/1744666X.2021.1847642. 

2. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science (New York, N.Y.). 2022; 375 (6578): 296-301. 10.1126/science.abj8222.
    
3. Almohmeed YH, Avenell A, Aucott L, Vickers MA. Systematic review and meta-analysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One. 2013; 8(4): e61110. doi: 10.1371/journal.pone.0061110. PMID: 23585874; PMCID: PMC3621759.
    
4. Robinson WH, Steinman L. Epstein-Barr virus and multiple sclerosis. Science. 2022; 375(6578):264-265. doi: 10.1126/science.abm7930. Epub 2022 Jan 13. PMID: 35025606. 

5. Bagert BA. Epstein-Barr virus in multiple sclerosis. Curr Neurol Neurosci Rep. 2009; 9(5):405-410. doi: 10.1007/s11910-009-0059-9. PMID: 19664371. 

6. Sintzel MB, Rametta M, Reder AT. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther. 2018; 7(1):59-85. doi: 10.1007/s40120-017-0086-4. Epub 2017 Dec 14. PMID: 29243029; PMCID: PMC5990512.