Multiple Sclerosis: How is it Associated with Epstein-Barr Virus?
In the past, Multiple Sclerosis (MS) has been associated with many virus infections. But causation has been hard to establish for any specific virus. The association to Epstein-Barr Virus (EBV) comes from a recent study involving a large military cohort (> 10 million adults) in which there were 955 cases of MS. The risk of MS was increased 32-fold after infection with Epstein-Barr virus (EBV), but not increased after infection with other viruses, including cytomegalovirus, herpes simplex virus type 1 (HSV-1), and various adeno- and rhinoviruses, as judged by VirScan assays for antibodies to viral peptides (1). Serum samples from 801 MS cases made it possible to assess EBV infectious status, and of these, only one MS patient was EBV-antibody negative at the onset of MS. So, the authors concluded that their findings could not be explained by any known risk factor for MS and suggest EBV infection to be the leading cause of MS.
MS is the most common immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). MS is characterized pathologically by multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring. Axonal injury is also a prominent pathologic feature, especially in the later stages. MS is considered an autoimmune disease caused by antibodies directed to surface structures of the CNS myelinating oligodendrocytes. Treatment of MS patients with anti-CD20 monoclonal antibody, which depletes B cells from circulation, is the most efficacious MS treatment. In the MS lesions there is neuroinflammation with infiltrating lymphocytes and macrophages causing the death of oligodendrocytes. These lesions are perivenularly localized within the CNS.
It should be noted, however, that MS is an unpredictable disease, and the disease progression can vary substantially from person to person. There are four different clinical courses for MS: clinically isolated syndrome (CIS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and relapsing-remitting MS (RRMS). Of these, RRMS is the most common, accounting for approximately 85% of MS cases. With the RRMS disease course, the patient will have periodic exacerbations of the disease, which are followed by remission periods (2).
Perhaps MS should be considered a syndrome rather than a single-cause disease entity. After all, its pathogenesis may differ from patient to patient and so is probably multifactorial. For example, the risk of MS is heritable with family clustering, and siblings have a seven times higher risk of developing MS (3). In addition, the disease is polygenic: there are 233 distinct genetic risk variants of which 32 independent variants are in the major histocompatibility complex locus. But these genetic risk factors overlap with those for other autoimmune diseases and implicate both the innate and adaptive immune system in MS. Curiously, none of these genetic risk variants are related to the oligodendrocytes or neurons targeted in MS (3).
For these and other reasons, MS is often referred to as “The graveyard of virologists.” However, virologists should keep investigating possible virus involvement in the pathogenesis of MS with the following three questions in mind.
- If an infection with EBV is involved in the pathogenesis of MS, is it a direct cause or an obligatory prerequisite for suffering from MS?
Acquisition of EBV at adolescence or later—as was the case for most of the patients in the aforementioned study (1)—indicates an upbringing sheltered from infection. In accordance with this, people migrating after the age of around 15 from a country with a high risk of acquiring MS (usually high-income countries) to a country with a low risk of MS maintain their risk for MS of the country of origin, while those migrating as young children have the risk of their new country of residence (4-7). Furthermore, infectious mononucleosis, which is caused by an EBV infection usually at adolescence or later, has previously been reported to increase the risk for MS (8-12). - If there’s cross-immunity—for example to an EBV protein like EBNA (13, 14) and an oligodendrocyte surface structure—why Is there not a disseminated demyelination throughout the entire CNS like in experimental allergic encephalitis (EAE) but rather very localized perivenular lesions?
Despite the detection of EBV-specific oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) and the finding that OCBs from patients with MS bind to specific EBV proteins (13), the actual presence of the virus in the CNS of these patients has not been well established and studies have yielded contradicting results (15). - What activates exacerbations? Upper respiratory tract infections have been associated with MS relapses (16). Do such infections reactivate latent EBV to cause a lytic infection or do they by other means trigger the immune system to attack the oligodendrocystic cells (such as by reactivating another latent herpes virus)?
HSV-1 infection in experimental animals has been shown to cause lesions of demyelination in the CNS like those in MS (17-19). Also, reactivation of latent HSV-1 in mice caused such CNS lesions followed by remyelination resembling exacerbations and remissions of MS (20). HSV-1 has also been isolated from serospinal fluid taken during the first attack of multiple sclerosis (21), and acyclovir treatment for two years reduced number of exacerbations in patients with RRMS (22). Furthermore, Bell’s palsy (idiopathic facial palsy), which is highly associated with HSV-1 infection (23-26), has signs of ongoing brainstem damage (27-29) and demyelination (30, 31) rather than in the peripheral facial nerve. Lately, expression of human endogenous retroviruses (HERV) and infection with human herpesvirus 6 (HHV6) have also been associated with MS (32).
Clinical studies targeting EBV are currently underway (33). For example, a phase I trial employs autologous EBV-specific T-cell therapy in patients with progressive MS and clinically isolated syndromes (CIS), demonstrating promising results regarding safety and efficacy in reducing disability. Additionally, studies on the noncyclic nucleoside analogue tenofovir alafenamide have revealed its ability to inhibit EBV DNA polymerase. Based on these findings, a clinical trial is currently underway to assess the use of this drug as an add-on to ocrelizumab, evaluating its efficacy in alleviating MS symptoms and promoting neuroprotection (34).
Owing to the suggested primary role of EBV in the pathogenesis of MS, new prophylactic vaccines against the virus are also being tested in healthy young adults (35). The main aim of the vaccines should be to prevent EBV infection. But a vaccine that controls the immune response to EBV could also reduce the frequency of MS. Of course, research on vaccines is complicated due to potential adverse events such as an aberrant immune response that could trigger autoimmunity or transient protection against EBV that could only delay—rather than prevent— the infection and the onset of MS (1).
References:
(1) Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. K. Bjornevik et al. Science 375, 296-301 (2022).
(2) Types of Multiple Sclerosis, National Multiple Sclerosis Society, website accessed 1 August 2023
(3) Genetics of multiple sclerosis: lessons from polygenicity. Goris A, Vandebergh M, McCauley JL, Saarela J, Cotsapas C Lancet Neurol. 2022 Sep;21(9):830-842. DOI: 10.1016/S1474-4422(22)00255-1 PMID: 35963264
(4) Annual incidence, prevalence and mortality of MS in white South African-born and in white immigrants to South Africa. Dean G BMJ 2:724-730, 1967
(5) Risk of multiple sclerosis related to age of immigration to Israel. Alter M et al. Arch. Neurol. 25:234-237, 1966
(6) Multiple sclerosis and age at migration. Detels et al American Journal of Epidemiology 108 (5): 386-393, 1978
(7) High risk of MS in Iranian immigrants in Gothenburg, Sweden. Ahlgren et al Multiple Sclerosis Journal 16 (9) 1079-1082, 2010
(8) A case-control study of multiple sclerosis. Operskalski EA, Visscher BR, Malmgren RM, Detels R Neurology 1989 Jun;39(6):825-9. DOI: 10.1212/wnl.39.6.825 PMID: 2725877
(9) Epidemiological investigation of the association between infectious mononucleosis and multiple sclerosis. Lindberg C, Andersen O, Vahlne A, Dalton M, Runmarker B. Neuroepidemiology 1991;10(2):62-5. DOI: 10.1159/000110248 PMID: 2062419
(10) Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Thacker EL, Mirzaei F, Ascherio A. Ann Neurol. 2006 Mar;59(3):499-503. DOI: 10.1002/ana.20820 PMID: 16502434
(11) Multiple sclerosis and age at infection with common viruses. Hernán MA, Zhang SM, Lipworth L, Olek MJ, Ascherio A Epidemiology 2001 May;12(3):301-6. DOI: 10.1097/00001648-200105000-00009 PMID: 11337603
(12) Infectious mononucleosis and multiple sclerosis – Updated review on associated risk. Sheik-Ali S. Mult. Scler. Relat. Disord. 2017 DOI: 10.1016/j.msard.2017.02.019 PMID: 28619433
(13) Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Lanz TV et al Nature 2022 Mar;603(7900):321-327 DOI: 10.1038/s41586-022-04432-7 PMID: 35073561
(14) Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Thomas OG et alSci Adv. 2023 May 19;9(20):eadg3032. DOI: 10.1126/sciadv.adg3032 PMID: 37196088
(15) Epstein-Barr virus in the multiple sclerosis brain: A controversial issue–report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM, Neuropro MiSe EBV Working Group Brain 2011;134(9):2772–2786. DOI: 10.1093/brain/awr197.
(16) Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. Andersen O, Lygner PE, Bergström T, Andersson M, Vahlne A J. Neurol. 1993 Jul;240(7):417-22. DOI: 10.1007/BF00867354 PMID: 8410082
(17) Neural spread of herpes simplex virus types 1 and 2 in mice after corneal or subcutaneous (footpad) inoculation K Kristensson, Vahlne A, Persson LA, Lycke E J. Neurol Sci. 1978 Feb;35(2-3):331-40 DOI: 10.1016/0022-510x(78)90013-8 PMID: 632838
(18) The relationship of astrocytes and macrophages to CNS demyelination after experimental herpes simplex virus infection. Townsend JJ J. Neuropathol Exp Neurol. 1981 Jul;40(4):369-79 DOI: 10.1097/00005072-198107000-00002 PMID: 7252523
(19) Virus-induced demyelination in herpes simplex virus-infected mice. Kristensson K, Svennerholm B, Vahlne A, Nilheden E, Persson L, Lycke E J. Neurol Sci. 1982 Feb;53(2):205-16 DOI: 10.1016/0022-510x(82)90006-5 PMID: 7057211
(20) Latent herpes simplex virus trigeminal ganglionic infection in mice and demyelination in the central nervous system. Kristensson K, Svennerholm B, Persson L, Vahlne A, Lycke E. J. Neurol Sci. 1979 Oct;43(2):253-63. DOI: 10.1016/0022-510x(79)90119-9 PMID: 316000
(21) Isolation of herpes simplex virus type 1 during first attack of multiple sclerosis. Bergström T, Andersen O, Vahlne A. Ann. Neurol. 1989 Aug;26(2):283-5 DOI: 10.1002/ana.410260218
(22) Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. Lycke J, Svennerholm B, Hjelmquist E, Frisén L, Badr G, Andersson M, Vahlne A, Andersen O. J. Neurol. 1996 Mar;243(3):214-24 DOI: 10.1007/BF00868517 PMID: 8936350
(23) Herpes simplex virus in idiopathic facial paralysis (Bell palsy). Adour KK, Bell DN, Hilsinger Jr. RL JAMA 1975 Aug 11;233(6):527-30 PMID: 167209
(24) Bell’s palsy and herpes simplex virus. Vahlne A, Edström S, Arstila P, Beran M, Ejnell H, Nylén O, Lycke E Arch. Otolaryngol. 1981 Feb;107(2):79-81. DOI: 10.1001/archotol.1981.00790380009003 PMID: 6258547
(25) Herpes-simplex virus as a cause of Bell’s palsy. McCormick DP Lancet 1972 Apr 29;1(7757):937-9. DOI: 10.1016/s0140-6736(72)91499-7 PMID: 4112101
(26) Virology studies and Bell’s palsy. Brodie SW Laryngol. Otol. 1979 Jun;93(6):563-8 DOI: 10.1017/s0022215100087417 PMID: 224123
(27) Auditory brain stem response abnormalities in patients with Bell’s palsy. Rosenhall U, Edström S, Hanner P, Badr G, Vahlne A Otolaryngol Head Neck Surg. 1983 Aug;91(4):412-6 DOI: 10.1177/019459988309100413 PMID: 6415590
(28) Auditory brain stem response and audiologic tests in idiopathic facial nerve paralysis. Hendrix RA, Melnick W Otolaryngol Head Neck Sur. 1983 Dec;91(6):686-90 DOI: 10.1177/019459988309100617 PMID: 6420751
(29) Auditory brain-stem evoked potentials in Bell’s palsy. Uri N, Schuchman G, Pratt H Arch Otolaryngol 1984 May;110(5):301-4 DOI: 10.1001/archotol.1984.00800310025005 PMID: 6712518
(30) Elevated levels of myelin basic protein in CSF in relation to auditory brainstem responses in Bell’s palsy. Edström S, Hanner P, Andersen O, Rosenhall U, Vahlne A, Karlsson B. Acta Otolaryngol 1987 Mar-Apr;103(3-4):198-203 PMID: 2437760
(31) Possible association of herpes simplex virus infection with demyelinating disease. Vahlne A, Edström S, Hanner P, Andersen O, Svennerholm B, Lycke E. Scand J Infect Dis Suppl 1985;47:16-21 PMID: 3868023
(32) Risk of a first clinical diagnosis of central nervous system demyelination in relation to human herpesviruses in the context of Epstein-Barr virus. Lucas RM, Lay MJ, Grant J, Cherbuin N, Toi CS, Dear K, Taylor BV, Dwyer DE, Ausimmune Investigator Group, Ponsonby AL Eur J Neurol 2023 Jun 12 DOI: 10.1111/ene.15919 PMID: 37306550
(33) Epstein-Barr virus as a cause of multiple sclerosis: Opportunities for prevention and therapy. Aloisi F, Giovannoni G, Salvetti M Lancet Neurol 2023;22:338–349 DOI: 10.1016/S1474-4422(22)00471-9
(34) Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers. Ortega-Hernandez OD, Martínez-Cáceres EM, Presas-Rodríguez S, Ramo-Tello C Int. J. Mol. Sci. 2023;24:7407. DOI: 10.3390/ijms24087407
(35) A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice. Wei CJ, Bu W, Nguyen LA, Batchelor JD, Kim J, Pittaluga S, Fuller JR, Nguyen H, Chou TH, Cohen JI, et al Sci. Transl. Med. 2022;14:eabf3685. DOI: 10.1126/scitranslmed.abf3685