van Luijn, Marvin M.

‘t Hart, Bert A.

English

EUR Research Repository

BA ‘t Hart and MM van Luijn journals.sagepub.com/home/msj 485sclerosis genetic risk loci: Insights into disease pathogenesis and therapeutic opportunities. Clin Transl Immunol 2023; 12(6): e1454. 5. Mechelli R, Manzari C, Policano C, et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology 2015; 84(13): 1362–1368. 6. 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. 7. Thomas OG, Bronge M, Tengvall K, et al. Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis. Sci Adv 2023; 9(20): eadg3032. 8. Veroni C and Aloisi F. The CD8 T cell-Epstein-Barr virus-B cell trialogue: a central issue in multiple sclerosis pathogenesis. Front Immunol 2021; 12: 665718. 9. Schneider-Hohendorf T, Gerdes LA, Pignolet B, et al. Broader Epstein-Barr virus-specific T cell receptor repertoire in patients with multiple sclerosis. J Exp Med 2022; 219(11): e20220650. 10. Soldan S, Su C, Monaco MC, et al. Unstable EBV latency drives inflammation in multiple sclerosis patient derived spontaneous B cells. Res Sq 2023; 3: rs.3.rs-2398872.Visit SAGE journals online journals.sagepub.com/home/msj journalsEBV infection drives MS pathology: NoBert A ‘t Hart1 and Marvin M van Luijn2OpinionThe seminal Science publication by Ascherio and coworkers1 leaves little room for doubts about the essential contribution of Epstein–Barr virus (EBV) to the pathogenic process in multiple sclerosis (MS). However, via which mechanisms EBV enhances the risk of an individual to develop MS is debated. EBV could drive the disease by serving as antigen to which immune cells and antibodies react. Cross-reactivity between viral and central nervous system (CNS) anti-gens has been demonstrated (molecular mimicry), but current evidence that this phenomenon directly drives MS pathology is inconclusive. A less explored alter-native mechanism is that EBV alters peripheral immune cells in such a way that subsets cross the blood–brain barrier (BBB) and interact with antigens released from a primary lesion inside the CNS.2 Conceptually, the subsequent accumulation of patho-genic immune subsets drives low-grade smoldering MS pathology. In this controversy, we argue that EBV rather amplifies the contribution of pathogenic lym-phocyte subsets to MS, than directly drives MS pathology.ArgumentationSeveral aspects of EBV tropism and anti-EBV responses are difficult to align with epidemiological and experimental observations in MS. First, EBV infection is common, while MS is relatively rare. It remains incompletely understood how a virus that is almost ubiquitous in the human population (>90% infection prevalence) triggers a disease with a preva-lence in global high-risk areas of around 0.1%. A pre-sumed explanation is involvement of a genetic susceptibility factor, but studies are needed for better understanding why, nevertheless, MS concordance in genetically identical monozygotic twins is only 30%.Classical mechanisms explaining the connection between virus infection and autoimmune disease (such as MS) are molecular mimicry, bystander acti-vation, and epitope spreading. The relevance of each phenomenon for the initiation and/or perpetuation of CNS pathology is particularly clear in murine MS models (e.g. EAE), but still needs to be firmly proven for the human disease. It has also been proposed that EBV-infected B cells form ectopic lymphoid struc-tures inside the CNS, in which EBV-specific pro-inflammatory T cells can be reactivated to cause damage. However, others could not detect EBV in MS brain or cerebrospinal fluid (CSF)3 and anti-EBV antibodies have rarely been reported to be present in MS CSF, in contrast to blood. The recently revealed genetic architecture of MS disability progression does not point to anti-viral responses as an underlying mechanism, nor shows an association with Human Leukocyte Antigen (HLA) polymorphisms as seen in Correspondence to:  BA ‘t Hart  Department of Anatomy and Neurosciences, Amsterdam University Medical Center, VUMC, Vrije Universiteit Amsterdam, de Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. mog3556@gmail.comBert A ‘t Hart  Department of Anatomy and Neurosciences, Amsterdam University Medical Center, VUMC, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsMarvin M van Luijn Department of Immunology, MS Center ErasMS, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The NetherlandsMultiple Sclerosis Journal2024, Vol. 30(4-5) 485 –487DOI: 10.1177/ 13524585241235833© The Author(s), 2024.  Article reuse guidelines:  sagepub.com/journals-permissionsMultiple Sclerosis Journal 30(4-5)486 journals.sagepub.com/home/msjMS susceptibility. In our view, these observations argue against EBV as dominant driver of MS pathol-ogy, but rather suggest a more complex interplay between virus, immune system, and target organ.Alternative viewA well-documented orchestrating role of B cells in MS pathogenesis is that of an antigen-presenting cell (APC). B cells are exquisitely capable of capturing low amounts of antigens through highly specific sur-face-expressed immunoglobulins. After internaliza-tion and processing, naive B cells present antigenic peptides to CD4+ T cells via polymorphic HLA class II molecules to get help for differentiation into mem-ory or antibody-secreting cells. Since peripheral selection of autoreactive naïve B cells is impaired in people with MS,4 the presence of the major MS risk allele HLA-DRB1*1501 may already be an important determinant of this process due to the presentation of different types of viral and/or self-peptides. In addi-tion, after primary infection EBV can hijack the acti-vation program of naïve B cells, which could trigger alternative processing of antigens for presentation5 and further empower their APC potential due to direct interaction of EBV antigen with genetic risk variants. Probably as a consequence, memory B cells promote CD4+ T cells to infiltrate the MS brain, especially in individuals carrying HLA-DRB1*1501. Notably, such CD4+ T cells are highly responsive to EBV,6 suggest-ing that certain subsets indeed preferentially interact with EBV-infected memory B cells. Together with their possible escape from peripheral control by CD8+ T cells in HLA class I risk carriers, B cells instruct Th17.1 cells that can activate and migrate through the BBB as a possible first pathogenic event leading to MS.7 This way of BBB activation enables other path-ogenic immune subsets such as (non-EBV-specific) B cells and CD8+ T cells to immigrate the CNS and cause pathology. Results obtained in a valid MS ani-mal model in marmoset monkeys revealed that EBV-infected B cells directly activate autoaggressive CD8+ effector memory cytotoxic T cells. Upon entry into the CNS these were found to induce widespread MS-like pathology in white and cortical gray matter.5B cells also receive signals such as IFN-γ from inter-acting CD4+ T cells to induce expression of transcrip-tion factor T-bet and chemokine receptor CXCR3, which can be potentiated by EBV and guides their entry into the CNS. To drive MS pathology, the accu-mulation of EBV-infected CXCR3+ B cells in the perivascular space of people with MS may also give rise to clones that produce autoantibodies or post-translationally modified (myelin) peptides that can form toxic amyloid-like aggregates,8,9 yet this hypoth-esis needs to be further tested. Although CD8+ T cells are enriched in the MS brain, their exhausted features in risk HLA (and their cytotoxic capacity in protective HLA) carriers could further promote local B-cell mat-uration and persistence.10As the frequency of B cells containing EBV is very low during the latency phase (between 1 and 50 per 106 B cells), it is tempting to speculate that the wide prevalence gap between EBV infection and MS (a factor ~700) may be explained by the low chance that a B cell with relevant specificity and function in MS (as explained above) contains the virus. Alternatively, and maybe also more likely, it is not the latency but the primary infection phase when occurring at adoles-cent age (infectious mononucleosis) in which EBV-infected B cells are shaped to drive pathology with an MS diagnosis in later years.Summary and concluding remarksThe central pathogenic role of EBV infection in the initiation and perpetuation of MS is undeniable, but incompletely understood. We posit here that the path-ogenic process within the CNS is not driven by EBV itself or by immune reactions against the virus, but by CNS-homing T cells that have acquired pathogenic functionality from EBV-infected B cells in the periph-ery. We posit that probably during and shortly after the primary infection phase, EBV-infected B cells escape from peripheral control and serve as overly potent memory APCs to promote CD4+ T cells to interrupt the BBB. After this first event, pathogenic B and T cells gradually enter and accumulate in the CNS to, irrespective of relapse occurrence and EBV reactivity, instigate MS pathology.Data Availability StatementData sharing not applicable to this article as no data sets were generated or analyzed during the current study.AcknowledgementsThe authors thank Dr Joost Smolders MD, PhD (Erasmus University Medical Center and MS center ErasMS), for critically reading the manuscripts.Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of inter-est with respect to the research, authorship, and/or publication of this article.FundingThe author(s) received no financial support for the research, authorship, and/or publication of this article.journals.sagepub.com/home/msj 487M Cortese and A AscherioReferences 1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science 2022; 375: 296–301. 2. ‘t Hart BA, Luchicchi A, Schenk GJ, et al. Mechanistic underpinning of an inside-out concept for autoimmunity in multiple sclerosis. Ann Clin Transl Neurol 2021; 8(8): 1709–1719. 3. Willis SN, Stadelmann C, Rodig SJ, et al. Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 2009; 132: 3318–3328. 4. Kinnunen T, Chamberlain N, Morbach H, et al. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 2013; 123(6): 2737–2741. 5. ‘t Hart BA, Kap YS, Morandi E, et al. EBV infection and multiple sclerosis: Lessons from a marmoset model. Trends Mol Med 2016; 22(12): 1012–1024. 6. Wang J, Jelcic I, Muhlenbruch L, et al. HLA-DR15 molecules jointly shape an autoreactive T cell repertoire in multiple sclerosis. Cell 2020; 183: 1264–1281.e1220. 7. Hoeks C, Puijfelik FV, Koetzier SC, et al. Differential Runx3, Eomes, and T-bet expression subdivides MS-associated CD4(+) T cells with brain-homing capacity. Eur J Immunol. Epub ahead of print 7 November 2023. DOI: 10.1002/eji.202350544. 8. Araman C, van Gent ME, Meeuwenoord NJ, et al. Amyloid-like behavior of sitespecifically citrullinated myelin oligodendrocyte protein (MOG) peptide fragments inside EBV-infected B-cells influences their cytotoxicity and autoimmunogenicity. Biochemistry 2019; 58: 763–775. 9. Bogers L, Engelenburg HJ, Janssen M, et al. Selective emergence of antibody-secreting cells in the multiple sclerosis brain. EBioMedicine 2023; 89: 104465. 10. van Langelaar J, Rijvers L, Smolders J, et al. B and T cells driving multiple sclerosis: Identity, mechanisms and potential triggers. Front Immunol 2020; 11: 760.EBV infection drives MS pathology: CommentaryMarianna Cortese  and Alberto AscherioThe discovery that infection with the Epstein–Barr virus (EBV) is the leading cause of MS calls into question the optimality of current treatments, which target EBV only indirectly, have broad immuno-suppressive effects, and, while markedly reducing relapses and onset of demyelinating lesions, do not halt disability progression, nor eliminate fatigue and other disabling symptoms.1,2 Could therapeutics directly and selectively targeting EBV be safer and more effective? Resolving the controversy in the cur-rent journal issue on whether and how EBV drives MS pathology is key to answering this question and has transcending implications for millions of people with MS. In the scenario proposed by Aloisi and Sal-vetti, in which EBV-specific cytotoxic T-cells target-ing lytic antigens are the primary effector, prevention of EBV lytic reactivation—a lower hanging fruit than the complete elimination of EBV infection—could be effective in MS. Such interventions, however, would be ineffective if latently EBV-infected B-cells, acting primarily as antigen-presenting cells, activate non-EBV-specific cytotoxic T-cells that cause tissue dam-age without further viral stimulation, as proposed by t’Hart and van Luijn. There is support for both sets of mechanisms, which are not mutually exclusive, but evidence remains inconclusive because of the diffi-culty of discerning critical effects from epiphenomena in observational human studies, or of extrapolating from animal models to human disease. Considering that EBV infection is active and persistent throughout the lifetime of the host, and that an increased MS risk is observed for 20 or more years after primary EBV infection,3 it may seem unlikely that the presence of the virus, which periodically reactivates and is a continuous source of antigenic stimulation, becomes irrelevant to MS progression, but it is nevertheless possible considering the complex genetic and epige-netic effects of EBV in infected cells.4,5Correspondence to: A Ascherio  Department of Nutrition, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA. aascheri@hsph.harvard.eduMarianna Cortese  Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USAAlberto Ascherio  Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA/Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA/Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USAMultiple Sclerosis Journal2024, Vol. 30(4-5) 487 –488DOI: 10.1177/ 13524585241235837© The Author(s), 2024.  Article reuse guidelines:  sagepub.com/journals-permissionsVisit SAGE journals online journals.sagepub.com/home/msj journals

EBV infection drives MS pathology:No

https://pure.eur.nl/files/144447492/EBV_infection_drives_MS_pathology.pdf

EBV infection drives MS pathology:No

Abstract

Similar works

Full text

Available Versions

EUR Research Repository