Document Type : Review Article
Authors
1 National Institute of Genetic Engineering and Biotechnology.
2 Department of Microbiology, Faculty of Biological Sciences, North Tehran Islamic Azad University, Tehran, Iran.
3 Department of Microbiology, Faculty of Biological Science, North Branch, Islamic Azad University, Tehran, Iran
Abstract
Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Epstein–Barr virus (EBV) is a human DNA herpesvirus infecting more than 90% of the world's population. EBV is the etiological agent of infectious mononucleosis (Pfeiffer's disease). Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). This review summarizes current knowledge on the association between EBV and MS.
Keywords
1.Lassmann H. Multiple sclerosis pathology. Cold Spring Harbor perspectives in medicine. 2018 Mar 1;8(3):a028936.
2.Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Current opinion in neurology. 2018 Dec 1;31(6):752-9.
3.Dobson R, Giovannoni G. Multiple sclerosis–a review. European journal of neurology. 2019 Jan;26(1):27-40.
4.Langille MM, Rutatangwa A, Francisco C. Pediatric multiple sclerosis: a review. Advances in Pediatrics. 2019 Aug 1;66:209-29.
5.Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology. 2018 Feb 1;17(2):162-73.
6.Simonsen CS, Flemmen HØ, Lauritzen T, Berg-Hansen P, Moen SM, Celius EG. The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis. Multiple Sclerosis Journal–Experimental, Translational and Clinical. 2020 Jan;6(1):2055217319901291.
7.Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, Croze E, Aftab BT, Giovannoni G, Joshi MA. Epstein–Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends in molecular medicine. 2020 Mar 1;26(3):296-310.
8.Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging. Neural regeneration research. 2019 Mar;14(3):373.
9.Fernández-Menéndez S, Fernández-Morán M, Fernández-Vega I, Pérez-Álvarez A, Villafani-Echazú J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. Journal of the neurological sciences. 2016 Feb 15;361:213-9.
10.Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Annals of neurology. 2013 Sep;74(3):317-27.
11.Tracy SI, Kakalacheva K, Lünemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. Persistence of Epstein-Barr virus in self-reactive memory B cells. Journal of virology. 2012 Nov 15;86(22):12330-40.
12.Fernández-Menéndez S, Fernández-Morán M, Fernández-Vega I, Pérez-Álvarez A, Villafani-Echazú J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. Journal of the neurological sciences. 2016 Feb 15;361:213-9.
13.Chamberlain SA, Szöcs E. taxize: taxonomic search and retrieval in R. F1000Research. 2013;2.
14.Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology. 2017 Jan;13(1):25-36.
15.Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of viruses in the pathogenesis of multiple sclerosis. Viruses. 2020 Jun;12(6):643.
16.Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Eilers E, Bader V, Haase S, Kaisler J, David C, Schneider R. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell. 2020 Mar 19;180(6):1067-80.
17.Brown J, Quattrochi B, Everett C, Hong BY, Cervantes J. Gut commensals, dysbiosis, and immune response imbalance in the pathogenesis of multiple sclerosis. Multiple Sclerosis Journal. 2021 May;27(6):807-11.
18.Mirza A, Forbes JD, Zhu F, Bernstein CN, Van Domselaar G, Graham M, Waubant E, Tremlett H. Surveying the gut microbiota in multiple sclerosis: a systematic review (2008-2018). InMULTIPLE SCLEROSIS JOURNAL 2018 Oct 1 (Vol. 24, pp. 345-345). 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND: SAGE PUBLICATIONS LTD.
19.Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology. 2016 Mar 15;86(11):1014-21.
20.Azami M, YektaKooshali MH, Shohani M, Khorshidi A, Mahmudi L. Epidemiology of multiple sclerosis in Iran: A systematic review and meta-analysis. PloS one. 2019 Apr 9;14(4):e0214738.
21.Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging. Neural regeneration research. 2019 Mar;14(3):373.
22.Jacobs BM, Giovannoni G, Cuzick J, Dobson R. Systematic review and meta-analysis of the association between Epstein–Barr virus, multiple sclerosis and other risk factors. Multiple Sclerosis Journal. 2020 Oct;26(11):1281-97.
23.Tzellos S, Farrell PJ. Epstein-Barr virus sequence variation—biology and disease. Pathogens. 2012 Dec;1(2):156-74.
24.Münz C, editor. Epstein Barr virus volume 2: one herpes virus: many diseases. Springer; 2015 Oct 1.
25.Correale J, Gaitan MI. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein–Barr virus infection. Acta Neurologica Scandinavica. 2015 Jul;132:46-55.
26.Jouanguy E, Béziat V, Mogensen TH, Casanova JL, Tangye SG, Zhang SY. Human inborn errors of immunity to herpes viruses. Current opinion in immunology. 2020 Feb 1;62:106-22.
27.Hassani A, Khan G. Epstein-Barr virus and miRNAs: partners in crime in the pathogenesis of multiple sclerosis?. Frontiers in Immunology. 2019 Apr 3;10:695.
28.Laurence M, Benito-León J. Epstein–Barr virus and multiple sclerosis: Updating Pender’s hypothesis. Multiple sclerosis and related disorders. 2017 Aug 1;16:8-14.
29.Majerciak V, Yang W, Zheng J, Zhu J, Zheng ZM. A genome-wide Epstein-Barr virus polyadenylation map and its antisense RNA to EBNA. Journal of virology. 2019 Jan 4;93(2):e01593-18.
30.Arrambide G, Tintore M, Espejo C, Auger C, Castillo M, Río J, Castilló J, Vidal-Jordana A, Galán I, Nos C, Mitjana R. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain. 2018 Apr 1;141(4):1075-84.
31.Makhani N, Lebrun C, Siva A, Narula S, Wassmer E, Brassat D, Brenton JN, Cabre P, Carra Dallière C, De Seze J, Durand Dubief F. Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome. Multiple Sclerosis Journal–Experimental, Translational and Clinical. 2019 Mar;5(1):2055217319836664.
32.Veroni C, Serafini B, Rosicarelli B, Fagnani C, Aloisi F. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. Journal of neuroinflammation. 2018 Dec;15(1):1-9.
33.Marcucci SB, Obeidat AZ. EBNA1, EBNA2, and EBNA3 link Epstein-Barr virus and hypovitaminosis D in multiple sclerosis pathogenesis. Journal of Neuroimmunology. 2020 Feb 15;339:577116.
34.Ruprecht K, Wildemann B, Jarius S. Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature. Journal of neurology. 2018 Feb;265(2):239-52.
35.Marrodan M, Alessandro L, Farez MF, Correale J. The role of infections in multiple sclerosis. Multiple Sclerosis Journal. 2019 Jun;25(7):891-901.
36.Ahmed SI, Aziz K, Gul A, Samar SS, Bareeqa SB. Risk of multiple sclerosis in Epstein–Barr virus infection. Cureus. 2019 Sep 19;11(9).
37.Läderach F, Münz C. Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk. Microorganisms. 2021 Nov;9(11):2191.
38.Lünemann JD, Tintoré M, Messmer B, Strowig T, Rovira Á, Perkal H, Caballero E, Münz C, Montalban X, Comabella M. Elevated Epstein–Barr virus‐encoded nuclear antigen‐1 immune responses predict conversion to multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2010 Feb;67(2):159-69.
39.Donati D. Viral infections and multiple sclerosis. Drug Discovery Today: Disease Models. 2020 Sep 1;32:27-33.
40.Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology. 2017 Jan;13(1):25-36.
41.Serafini B, Rosicarelli B, Veroni C, Mazzola GA, Aloisi F. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. Journal of virology. 2019 Nov 26;93(24):e00980-19.
42.Rafiee N, Ravanshad M, Asadi B, Kianfar R, Maleki A. Investigation of IL-2 and IFN-γ to EBV Peptides in Stimulated Whole Blood among Multiple Sclerosis Patients and Healthy Individuals. Intervirology. 2021;64(4):203-8.
43.Houen G, Trier NH, Frederiksen JL. Epstein-Barr Virus and multiple sclerosis. Frontiers in immunology. 2020:3315.
44.Ruprecht K. The role of Epstein-Barr virus in the etiology of multiple sclerosis: a current review. Expert Review of Clinical Immunology. 2020 Dec 1;16(12):1143-57.
45.Balfour HH, Schmeling DO, Grimm-Geris JM. The promise of a prophylactic Epstein–Barr virus vaccine. Pediatric research. 2020 Jan;87(2):345-52.
46.Giovannoni G. Personalized medicine in multiple sclerosis. Neurodegenerative disease management. 2017 Nov;7(6s):13-7.
47.Klineova S, Lublin FD. Clinical course of multiple sclerosis. Cold Spring Harbor perspectives in medicine. 2018 Sep 1;8(9):a028928.
48.Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. The Lancet Neurology. 2016 Feb 1;15(2):198-209.
49.Fugl A, Andersen CL. Epstein-Barr virus and its association with disease-a review of relevance to general practice. BMC family practice. 2019 Dec;20(1):1-8.
50.Laurence M, Benito-León J. Epstein–Barr virus and multiple sclerosis: Updating Pender’s hypothesis. Multiple sclerosis and related disorders. 2017 Aug 1;16:8-14.
2.Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: clinical aspects. Current opinion in neurology. 2018 Dec 1;31(6):752-9.
3.Dobson R, Giovannoni G. Multiple sclerosis–a review. European journal of neurology. 2019 Jan;26(1):27-40.
4.Langille MM, Rutatangwa A, Francisco C. Pediatric multiple sclerosis: a review. Advances in Pediatrics. 2019 Aug 1;66:209-29.
5.Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology. 2018 Feb 1;17(2):162-73.
6.Simonsen CS, Flemmen HØ, Lauritzen T, Berg-Hansen P, Moen SM, Celius EG. The diagnostic value of IgG index versus oligoclonal bands in cerebrospinal fluid of patients with multiple sclerosis. Multiple Sclerosis Journal–Experimental, Translational and Clinical. 2020 Jan;6(1):2055217319901291.
7.Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, Croze E, Aftab BT, Giovannoni G, Joshi MA. Epstein–Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends in molecular medicine. 2020 Mar 1;26(3):296-310.
8.Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging. Neural regeneration research. 2019 Mar;14(3):373.
9.Fernández-Menéndez S, Fernández-Morán M, Fernández-Vega I, Pérez-Álvarez A, Villafani-Echazú J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. Journal of the neurological sciences. 2016 Feb 15;361:213-9.
10.Hauser SL, Chan JR, Oksenberg JR. Multiple sclerosis: prospects and promise. Annals of neurology. 2013 Sep;74(3):317-27.
11.Tracy SI, Kakalacheva K, Lünemann JD, Luzuriaga K, Middeldorp J, Thorley-Lawson DA. Persistence of Epstein-Barr virus in self-reactive memory B cells. Journal of virology. 2012 Nov 15;86(22):12330-40.
12.Fernández-Menéndez S, Fernández-Morán M, Fernández-Vega I, Pérez-Álvarez A, Villafani-Echazú J. Epstein–Barr virus and multiple sclerosis. From evidence to therapeutic strategies. Journal of the neurological sciences. 2016 Feb 15;361:213-9.
13.Chamberlain SA, Szöcs E. taxize: taxonomic search and retrieval in R. F1000Research. 2013;2.
14.Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology. 2017 Jan;13(1):25-36.
15.Tarlinton RE, Martynova E, Rizvanov AA, Khaiboullina S, Verma S. Role of viruses in the pathogenesis of multiple sclerosis. Viruses. 2020 Jun;12(6):643.
16.Duscha A, Gisevius B, Hirschberg S, Yissachar N, Stangl GI, Eilers E, Bader V, Haase S, Kaisler J, David C, Schneider R. Propionic acid shapes the multiple sclerosis disease course by an immunomodulatory mechanism. Cell. 2020 Mar 19;180(6):1067-80.
17.Brown J, Quattrochi B, Everett C, Hong BY, Cervantes J. Gut commensals, dysbiosis, and immune response imbalance in the pathogenesis of multiple sclerosis. Multiple Sclerosis Journal. 2021 May;27(6):807-11.
18.Mirza A, Forbes JD, Zhu F, Bernstein CN, Van Domselaar G, Graham M, Waubant E, Tremlett H. Surveying the gut microbiota in multiple sclerosis: a systematic review (2008-2018). InMULTIPLE SCLEROSIS JOURNAL 2018 Oct 1 (Vol. 24, pp. 345-345). 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND: SAGE PUBLICATIONS LTD.
19.Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology. 2016 Mar 15;86(11):1014-21.
20.Azami M, YektaKooshali MH, Shohani M, Khorshidi A, Mahmudi L. Epidemiology of multiple sclerosis in Iran: A systematic review and meta-analysis. PloS one. 2019 Apr 9;14(4):e0214738.
21.Guan Y, Jakimovski D, Ramanathan M, Weinstock-Guttman B, Zivadinov R. The role of Epstein-Barr virus in multiple sclerosis: from molecular pathophysiology to in vivo imaging. Neural regeneration research. 2019 Mar;14(3):373.
22.Jacobs BM, Giovannoni G, Cuzick J, Dobson R. Systematic review and meta-analysis of the association between Epstein–Barr virus, multiple sclerosis and other risk factors. Multiple Sclerosis Journal. 2020 Oct;26(11):1281-97.
23.Tzellos S, Farrell PJ. Epstein-Barr virus sequence variation—biology and disease. Pathogens. 2012 Dec;1(2):156-74.
24.Münz C, editor. Epstein Barr virus volume 2: one herpes virus: many diseases. Springer; 2015 Oct 1.
25.Correale J, Gaitan MI. Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein–Barr virus infection. Acta Neurologica Scandinavica. 2015 Jul;132:46-55.
26.Jouanguy E, Béziat V, Mogensen TH, Casanova JL, Tangye SG, Zhang SY. Human inborn errors of immunity to herpes viruses. Current opinion in immunology. 2020 Feb 1;62:106-22.
27.Hassani A, Khan G. Epstein-Barr virus and miRNAs: partners in crime in the pathogenesis of multiple sclerosis?. Frontiers in Immunology. 2019 Apr 3;10:695.
28.Laurence M, Benito-León J. Epstein–Barr virus and multiple sclerosis: Updating Pender’s hypothesis. Multiple sclerosis and related disorders. 2017 Aug 1;16:8-14.
29.Majerciak V, Yang W, Zheng J, Zhu J, Zheng ZM. A genome-wide Epstein-Barr virus polyadenylation map and its antisense RNA to EBNA. Journal of virology. 2019 Jan 4;93(2):e01593-18.
30.Arrambide G, Tintore M, Espejo C, Auger C, Castillo M, Río J, Castilló J, Vidal-Jordana A, Galán I, Nos C, Mitjana R. The value of oligoclonal bands in the multiple sclerosis diagnostic criteria. Brain. 2018 Apr 1;141(4):1075-84.
31.Makhani N, Lebrun C, Siva A, Narula S, Wassmer E, Brassat D, Brenton JN, Cabre P, Carra Dallière C, De Seze J, Durand Dubief F. Oligoclonal bands increase the specificity of MRI criteria to predict multiple sclerosis in children with radiologically isolated syndrome. Multiple Sclerosis Journal–Experimental, Translational and Clinical. 2019 Mar;5(1):2055217319836664.
32.Veroni C, Serafini B, Rosicarelli B, Fagnani C, Aloisi F. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. Journal of neuroinflammation. 2018 Dec;15(1):1-9.
33.Marcucci SB, Obeidat AZ. EBNA1, EBNA2, and EBNA3 link Epstein-Barr virus and hypovitaminosis D in multiple sclerosis pathogenesis. Journal of Neuroimmunology. 2020 Feb 15;339:577116.
34.Ruprecht K, Wildemann B, Jarius S. Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature. Journal of neurology. 2018 Feb;265(2):239-52.
35.Marrodan M, Alessandro L, Farez MF, Correale J. The role of infections in multiple sclerosis. Multiple Sclerosis Journal. 2019 Jun;25(7):891-901.
36.Ahmed SI, Aziz K, Gul A, Samar SS, Bareeqa SB. Risk of multiple sclerosis in Epstein–Barr virus infection. Cureus. 2019 Sep 19;11(9).
37.Läderach F, Münz C. Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk. Microorganisms. 2021 Nov;9(11):2191.
38.Lünemann JD, Tintoré M, Messmer B, Strowig T, Rovira Á, Perkal H, Caballero E, Münz C, Montalban X, Comabella M. Elevated Epstein–Barr virus‐encoded nuclear antigen‐1 immune responses predict conversion to multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2010 Feb;67(2):159-69.
39.Donati D. Viral infections and multiple sclerosis. Drug Discovery Today: Disease Models. 2020 Sep 1;32:27-33.
40.Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nature Reviews Neurology. 2017 Jan;13(1):25-36.
41.Serafini B, Rosicarelli B, Veroni C, Mazzola GA, Aloisi F. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. Journal of virology. 2019 Nov 26;93(24):e00980-19.
42.Rafiee N, Ravanshad M, Asadi B, Kianfar R, Maleki A. Investigation of IL-2 and IFN-γ to EBV Peptides in Stimulated Whole Blood among Multiple Sclerosis Patients and Healthy Individuals. Intervirology. 2021;64(4):203-8.
43.Houen G, Trier NH, Frederiksen JL. Epstein-Barr Virus and multiple sclerosis. Frontiers in immunology. 2020:3315.
44.Ruprecht K. The role of Epstein-Barr virus in the etiology of multiple sclerosis: a current review. Expert Review of Clinical Immunology. 2020 Dec 1;16(12):1143-57.
45.Balfour HH, Schmeling DO, Grimm-Geris JM. The promise of a prophylactic Epstein–Barr virus vaccine. Pediatric research. 2020 Jan;87(2):345-52.
46.Giovannoni G. Personalized medicine in multiple sclerosis. Neurodegenerative disease management. 2017 Nov;7(6s):13-7.
47.Klineova S, Lublin FD. Clinical course of multiple sclerosis. Cold Spring Harbor perspectives in medicine. 2018 Sep 1;8(9):a028928.
48.Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. The Lancet Neurology. 2016 Feb 1;15(2):198-209.
49.Fugl A, Andersen CL. Epstein-Barr virus and its association with disease-a review of relevance to general practice. BMC family practice. 2019 Dec;20(1):1-8.
50.Laurence M, Benito-León J. Epstein–Barr virus and multiple sclerosis: Updating Pender’s hypothesis. Multiple sclerosis and related disorders. 2017 Aug 1;16:8-14.
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