open access

Vol 56, No 3 (2022)
Research Paper
Submitted: 2022-03-16
Accepted: 2022-05-24
Published online: 2022-06-21
Get Citation

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients

Michael Fleischer12, Helene Schuh12, Nela M. Bickmann12, Tim Hagenacker12, Karlgeorg Krüger3, Thomas Skripuletz4, Melanie Fiedler5, Christoph Kleinschnitz12, Refik Pul12, Jelena Skuljec12
·
Pubmed: 35726751
·
Neurol Neurochir Pol 2022;56(3):236-245.
Affiliations
  1. Department of Neurology, University Medicine Essen, Essen, Germany
  2. Centre for Translational Neuro- and Behavioural Sciences (C-TNBS), University Medicine Essen, Essen, Germany
  3. Diavero Diagnosis Centre, Essen, Germany
  4. Department of Neurology, Hanover Medical School, Hanover, Germany
  5. Institute for Virology, University Medicine Essen, Essen, Germany

open access

Vol 56, No 3 (2022)
RESEARCH PAPERS — LEADING TOPIC
Submitted: 2022-03-16
Accepted: 2022-05-24
Published online: 2022-06-21

Abstract

Introduction. Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients.

Aim of the study. We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue.

Material and methods. A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters.

Results. A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG.

Conclusions and clinical implications. Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.

Abstract

Introduction. Fatigue is the most frequent symptom in multiple sclerosis (MS), although it is still poorly understood due to its complexity and subjective nature. There is an urgent need to identify reliable biomarkers to improve disease prognosis and therapeutic strategies. Epstein-Barr virus (EBV) is the major environmental risk factor associated with MS aetiology, and trials with EBV-targeted T cell therapies have reduced fatigue severity in MS patients.

Aim of the study. We investigated whether the serum amount of immunoglobulin (Ig)G-specific for EBV antigens could be a suitable prognostic marker for the assessment of MS-related fatigue.

Material and methods. A total of 194 MS patients were enrolled. We quantified EBV nuclear antigen 1 (EBNA1) and EBV viral capsid antigen (VCA) immunoglobulin (Ig) G levels and B cell-activating factor of the tumour necrosis factor family (BAFF) concentration in the serum of patients with relapsing-remitting MS (RRMS) and chronic progressive MS (CPMS), and we analysed their correlation with aspects of fatigue and other clinical disease parameters.

Results. A complete EBV seropositivity could be detected in our cohort. After adjusting for confounding variables and covariates, neither EBNA1 nor VCA antibody titres were associated with levels of fatigue, sleepiness, depression, or with any of the clinical values such as expanded disability status scale, lesion count, annual relapse rate, or disease duration. However, patients with RRMS had significantly higher EBNA1 IgG titre than those with CPMS, whereas this was not the case under therapies targeting CD20+ cells. BAFF levels in serum were inversely proportional to anti-EBNA1 IgG.

Conclusions and clinical implications. Our results show that EBNA1 IgG titre is not associated with the presence or level of fatigue. Whether the increased EBNA1 titre in RRMS plays a direct role in disease progression, or is only a consequence of excessive B cell activation, remains to be answered in future studies.

Get Citation

Keywords

multiple sclerosis, RRMS, progressive MS, EBV, EBNA1, fatigue, BAFF

Supp./Additional Files (3)
Supplementary Figure 1
View
2MB
Suppl. Figure 1_caption
Download
12KB
Supplementary Table 1
Download
6KB
About this article
Title

Anti-EBNA1 IgG titre is not associated with fatigue in multiple sclerosis patients

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 56, No 3 (2022)

Article type

Research Paper

Pages

236-245

Published online

2022-06-21

Page views

4967

Article views/downloads

799

DOI

10.5603/PJNNS.a2022.0043

Pubmed

35726751

Bibliographic record

Neurol Neurochir Pol 2022;56(3):236-245.

Keywords

multiple sclerosis
RRMS
progressive MS
EBV
EBNA1
fatigue
BAFF

Authors

Michael Fleischer
Helene Schuh
Nela M. Bickmann
Tim Hagenacker
Karlgeorg Krüger
Thomas Skripuletz
Melanie Fiedler
Christoph Kleinschnitz
Refik Pul
Jelena Skuljec

References (47)
  1. Adamczyk-Sowa M, Adamczyk B, Kułakowska A, et al. Secondary progressive multiple sclerosis - from neuropathology to definition and effective treatment. Neurol Neurochir Pol. 2020; 54(5): 384–398.
  2. Absinta M, Lassmann H, Trapp BD. Mechanisms underlying progression in multiple sclerosis. Curr Opin Neurol. 2020; 33(3): 277–285.
  3. Bar-Or A, Pender MP, Khanna R, et al. Epstein-Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol Med. 2020; 26(3): 296–310.
  4. Mrozek-Gorska P, Buschle A, Pich D, et al. Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc Natl Acad Sci U S A. 2019; 116(32): 16046–16055.
  5. Mulero P, Midaglia L, Montalban X. Ocrelizumab: a new milestone in multiple sclerosis therapy. Ther Adv Neurol Disord. 2018; 11: 1756286418773025.
  6. Myhr KM, Torkildsen Ø, Lossius A, et al. B cell depletion in the treatment of multiple sclerosis. Expert Opin Biol Ther. 2019; 19(3): 261–271.
  7. Steri M, Orrù V, Idda ML, et al. Overexpression of the cytokine BAFF and autoimmunity risk. N Engl J Med. 2017; 376(17): 1615–1626.
  8. Burnard S, Lechner-Scott J, Scott RJ. EBV and MS: Major cause, minor contribution or red-herring? Mult Scler Relat Disord. 2017; 16: 24–30.
  9. Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022; 603(7900): 321–327.
  10. Gieß R, Pfuhl C, Behrens J, et al. Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis. PLOS ONE. 2017; 12(4): e0175279.
  11. Kvistad S, Myhr KM, Holmøy T, et al. Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Multiple Sclerosis Journal. 2014; 20(14): 1833–1840.
  12. Lünemann JD, Tintoré M, Messmer B, et al. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol. 2010; 67(2): 159–169.
  13. Munger KL, Fitzgerald KC, Freedman MS, et al. No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT. Neurology. 2015; 85(19): 1694–1701.
  14. Zivadinov R, Chin J, Horakova D, et al. Humoral responses to herpesviruses are associated with neurodegeneration after a demyelinating event: results from the multi-center set study. J Neuroimmunol. 2014; 273(1-2): 58–64.
  15. Zivadinov R, Zorzon M, Weinstock-Guttman B, et al. Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009; 80(6): 620–625.
  16. Broch L, Simonsen CS, Flemmen HØ, et al. High prevalence of fatigue in contemporary patients with multiple sclerosis. Mult Scler J Exp Transl Clin. 2021; 7(1).
  17. Manjaly ZM, Harrison NA, Critchley HD, et al. Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019; 90(6): 642–651.
  18. Weiland TJ, Jelinek GA, Marck CH, et al. Clinically significant fatigue: prevalence and associated factors in an international sample of adults with multiple sclerosis recruited via the internet. PLoS One. 2015; 10(2): e0115541.
  19. Billones R, Liwang JK, Butler K, et al. Dissecting the fatigue experience: A scoping review of fatigue definitions, dimensions, and measures in non-oncologic medical conditions. Brain Behav Immun Health. 2021; 15: 100266.
  20. Berger JR, Pocoski J, Preblick R, et al. Fatigue heralding multiple sclerosis. Mult Scler. 2013; 19(11): 1526–1532.
  21. Levin LI, Munger KL, O'Reilly EJ, et al. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010; 67(6): 824–830.
  22. Ioannides ZA, Csurhes PA, Douglas NL, et al. Sustained Clinical Improvement in a Subset of Patients With Progressive Multiple Sclerosis Treated With Epstein-Barr Virus-Specific T Cell Therapy. Front Neurol. 2021; 12: 652811.
  23. Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018; 3(22).
  24. Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994; 18 Suppl 1: S79–S83.
  25. Häuser W, Almouhtasseb R, Muthny FA, et al. [Validation of a German Version of the Fatigue Impact Scale FIS-D]. Z Gastroenterol. 2003; 41(10): 973–982.
  26. Tabuse H, Kalali A, Azuma H, et al. The new GRID Hamilton Rating Scale for Depression demonstrates excellent inter-rater reliability for inexperienced and experienced raters before and after training. Psychiatry Res. 2007; 153(1): 61–67.
  27. Serafini B, Severa M, Columba-Cabezas S, et al. Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation. J Neuropathol Exp Neurol. 2010; 69(7): 677–693.
  28. Topping J, Dobson R, Lapin S, et al. The effects of intrathecal rituximab on biomarkers in multiple sclerosis. Mult Scler Relat Disord. 2016; 6: 49–53.
  29. Flensner G, Ek AC, Landtblom AM, et al. Fatigue in relation to perceived health: people with multiple sclerosis compared with people in the general population. Scand J Caring Sci. 2008; 22(3): 391–400.
  30. Braley TJ, Chervin RD. Fatigue in multiple sclerosis: mechanisms, evaluation, and treatment. Sleep. 2010; 33(8): 1061–1067.
  31. Braley TJ, Boudreau EA. Sleep Disorders in Multiple Sclerosis. Curr Neurol Neurosci Rep. 2016; 16(5): 50.
  32. Popp RFJ, Fierlbeck AK, Knüttel H, et al. Daytime sleepiness versus fatigue in patients with multiple sclerosis: A systematic review on the Epworth sleepiness scale as an assessment tool. Sleep Med Rev. 2017; 32: 95–108.
  33. Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005; 76(4): 469–475.
  34. Baker D, Marta M, Pryce G, et al. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine. 2017; 16: 41–50.
  35. Mameli G, Cocco E, Frau J, et al. Serum BAFF levels, Methypredsinolone therapy, Epstein-Barr Virus and Mycobacterium avium subsp. paratuberculosis infection in Multiple Sclerosis patients. Scientific Reports. 2016; 6(1).
  36. The Wearing-off Phenomenon of Ocrelizumab in Patients With Multiple Sclerosis [2000]. https://clinicaltrials.gov/ct2/show/record/NCT04478591 (16.02.2022).
  37. Abrahamyan S, Eberspächer B, Hoshi MM, et al. German Competence Network Multiple Sclerosis (KKNMS), Other members of the KKNMS that acted as collaborators in this study. Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis. J Neurol Neurosurg Psychiatry. 2020; 91(7): 681–686.
  38. Dobson R, Kuhle J, Middeldorp J, et al. Epstein-Barr–negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm. 2017; 4(2): e318.
  39. Jacobs BM, Giovannoni G, Cuzick J, et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. Mult Scler. 2020; 26(11): 1281–1297.
  40. Mescheriakova JY, van Nierop GP, van der Eijk AA, et al. EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution. Neurol Neuroimmunol Neuroinflamm. 2020; 7(6).
  41. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375(6578): 296–301.
  42. Zivadinov R, Cerza N, Hagemeier J, et al. Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. Neurol Neuroimmunol Neuroinflamm. 2016; 3(1): e190.
  43. Ramroodi N, Niazi AA, Sanadgol N, et al. Evaluation of reactive Epstein-Barr Virus (EBV) in Iranian patient with different subtypes of multiple sclerosis (MS). Braz J Infect Dis. 2013; 17(2): 156–163.
  44. Cencioni M, Mattoscio M, Magliozzi R, et al. B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies. Nature Reviews Neurology. 2021; 17(7): 399–414.
  45. Gingele S, Jacobus TL, Konen FF, et al. Ocrelizumab depletes CD20⁺ t cells in multiple sclerosis patients. Cells. 2018; 8(1).
  46. Möhn N, Konen FF, Pul R, et al. Experience in multiple sclerosis patients with COVID-19 and disease-modifying therapies: a review of 873 published cases. J Clin Med. 2020; 9(12).
  47. Adamczyk B, Morawiec N, Arendarczyk M, et al. Multiple sclerosis immunomodulatory therapies tested for effectiveness in COVID-19. Neurol Neurochir Pol. 2021; 55(4): 357–368.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
tel.:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: viamedica@viamedica.pl