Multiple sclerosis is an autoimmune, inflammatory disorder in which the body’s own immune system attacks the myelin sheath that forms a protective coating around nerves in the brain and spinal cord and also aids the conduction of nerve signals to the rest of the body. This causes a wide range of problems and disturbances in balance, movement and vision that can become severe over time. Evidence suggests that herpes viruses may play a role in the pathology of demyelination and studies have shown that individuals who have never had Epstein-Barr virus (EBV) have a reduced risk for developing multiple sclerosis compared with individuals who have been infected. In addition, those infected with EBV during adolescence are at less risk of developing multiple sclerosis than those infected at a younger age. EBV is a herpes virus otherwise known of as human herpesvirus 4 (HHV-4). It is most well known for causing glandular fever but research shows that EBV infection is also linked to an increased risk for various autoimmune conditions, including rheumatoid arthritis, dermatomyositis and multiple sclerosis. Scientists are aware that also human herpesvirus 6 (HHV-6) has been found associated with MS onset.
The first evidence for a role of EBV in the pathogenesis of MS came in 1979 when Fraser and others (1979) reported that peripheral blood lymphocytes from patients with clinically active MS have an increased tendency toward spontaneous in vitro EBV-induced B lymphocyte transformation. In the following year, Sumaya and others (1980) reported a higher frequency of EBV seropositivity and higher serumanti-EBV antibody titers in MS patients compared withcontrols. Subsequent studies have shown that MS patients are almost universally seropositive for EBV but not for other viruses. In a meta-analysis of 13 case control studies comparing EBV serology in MS patients and controls, 99.5% of MS patients were EBV seropositive compared with 94% of controls. Serial studies have shown that the risk of developing multiple sclerosis is extremely low among individuals not infected with EBV but increases sharply in the same individuals following EBV infection. These studies suggest that EBV infection is a prerequisite for the development of MS but, by itself, is not enough because the vast majority of people infected with EBV do not develop the disease; at least the HLA-DR15 immune antigen is needed.
The fact that EBV infection is associated with a dramatic increase in MS risk is obscured by the fact that EBV infects such a large proportion (~95%) of the general adult population. In 2009, an Italian team of researchers presented their findings that brain lesions from individuals with multiple sclerosis contained B lymphocytes infected with an abnormal accumulation of EBV. The researchers also demonstrated that the B lymphocytes in the brain are targeted in an immune response that is mounted against them, which causes inflammation and in turn, tissue destruction. Another study currently being carried out at the university of Birmingham in the UK is trying to establish whether or not the immune response to EBV really does cause autoimmune destruction of myelin. Another study looked at the expression of EBV markers in the brains of deceased multiple sclerosis patients. In almost all of the cases examined (21 out of 22), there was evidence of EBV infiltrating B cells and plasma cells in a significant proportion of the brain. In some cases of secondary progressive multiple sclerosis, B cell follicles forming in the cerebral meninges were found to be sites where EBV had persisted.
Latent viral proteins were a regular occurrence in the samples overall, but actual reactivation of the viral particles seemed to be confined to these newly formed B cell follicles. Furthermore, activated cytotoxic T cells were observed along with signs of plasma cell cytotoxicity at these major sites of EBV infection. In 2017 another study published in Neurology found that also like whites, Hispanic and black people who have had mononucleosis may have an increased risk of multiple sclerosis. While being infected at a young age with EBV generally causes few, if any, symptoms, delayed exposure into adolescence or adulthood can cause a severe clinical picture. Previous studies that have found a link between mononucleosis and MS have looked primarily at white populations. Scientists of Kaiser Permanente Southern California in Pasadena, instead, recruited 1,090 black, Hispanic and white people, over a three-year period, with each group having a near balance of healthy people to people with MS or its precursor, called clinically isolated syndrome. Participants had blood tests to check for EBV antibody and were asked whether they had ever had mono.
Researchers found that independent of other factors that could affect MS risk, such as sex, age, smoking and genetic ancestry, the risk of MS for those who had mono was higher than for those who had not. Blacks who had mono were more than four times more likely to develop MS than those who had not, Hispanics were nearly four times more likely and whites were two times more likely. Among blacks 11% with MS had mono in the past, compared to 3% who did not have MS. For Hispanics, 8% of people with MS had mono in the past, compared to 2% who did not have MS. Among whites, 20% of people with MS had mono in the past, compared to 12% of those without the disease. This implies that delaying EBV infection into adolescence or adulthood may be a critical risk factor for MS. One possible limitation of the study is that the control group may not represent the population overall. Although it is unclear whether EBV-infected B cells in the central nervous system cause the development of multiple sclerosis or whether this occurs as result of another unknown process, many researchers believe that EBV persistence and reactivation is an important contributor to MS pathology.
Clearly, this will not apply to all those that got infected with EBV; other genetic factors have surely their impact.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Munger KL et al. Ann Neurol. 2019; 86(3):436-442.
Agostini S et al. J Transl Med. 2018 Mar; 16(1):80.
Olsson T et al. Nat Rev Neurol. 2017; 13(1):25-36.
Lünemann JD et al. Ann Neurol 2010; 67:159–69.
Cepok S et al. J Clin Investig 2005; 115:1352–60.
Wandinger KP et al. Neurology 2000; 55:178–84.
Sumaya CV et al. Annals Neurol 1985; 17:371-77.
Sumaya CV et al. Archives Neurol 1980; 37:94-96.
Fraser KB, Millar JHD et al. Lancet 1979; 314:715.
Dott. Gianfrancesco Cormaci
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