Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis

Peferoen, Laura; Lamers, Femke; Lodder, L.; Gerritsen, Wouter; Huitinga, Inge; Melief, Jeroen; Giovannoni, Gavin; Meier, Ute‐Christiane; Hintzen, Rogier Q.; Verjans, Georges M. G. M.; Nierop, Gijsbert P. van; Vos, Wim; Peferoen-Baert, Regina; Middeldorp, Jaap M.; Valk, Paul van der; Amor, Sandra

doi:10.1093/brain/awp296

Cited by 140 publications

(106 citation statements)

References 11 publications

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“…EBV was found in 90% of meningeal B-cell follicles and in perivascular cuffs of patients with MS in one study [Serafini et al 2007] but was either not found or not frequently observed in a number of subsequent studies [Willis et al 2009;Aloisi et al 2010;Lassmann et al 2010;Peferoen et al 2010;Sargsyan et al 2010;Torskilden et al 2010;Owens and Bennett, 2012;Tracy et al 2012]. Nevertheless, latent EBV infection, with residual viral particles possibly remaining chronically in B lymphocytes, may contribute to the inflammatory milieu in active MS lesions by activating an innate and adaptive immune response, including B-cell activation and proinflammatory IFNα production [Serafini et al 2010;Tzartos et al 2012;Ascherio et al 2012a].…”

Section: Genetic Risk Factors For Multiple Sclerosis Possibly Involvimentioning

confidence: 99%

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Pierrot‐Deseilligny

Souberbielle

2013

Ther Adv Neurol Disord

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Abstract:The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.

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Section: Genetic Risk Factors For Multiple Sclerosis Possibly Involvimentioning

confidence: 99%

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Pierrot‐Deseilligny

Souberbielle

2013

Ther Adv Neurol Disord

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“…The more active lesions also showed evidence of lytic infection and cytotoxic responses to EBV-infected B cells, suggesting that these cells drive MS pathology. Several discordant reports (Willis et al 2009;Peferoen et al 2010;Sargsyan et al 2010) raised questions on these findings (Ascherio and Bar-Or 2010), but the presence of latently infected EBV-positive cells in perivascular infiltrate of all active MS lesions has been recently confirmed in a new rigorous investigation (Tzartos et al 2012). By itself, the presence of EBV-positive cells in MS lesions does not prove that these cells have a causal role, because these cells could be attracted to areas of inflammation by locally produced cytokines, but when considered in the context of the epidemiological evidence, it provides a plausible scenario of MS causation.…”

Section: Potential Mechanisms Relating Ebv To Msmentioning

confidence: 99%

EBV and Autoimmunity

Ascherio

Munger

2015

Current Topics in Microbiology and Immunology

103

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Although a role of EBV in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been possible only for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE), whereas evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify the conclusion that EBV is a component cause of MS and SLE and possible mechanisms underlying these effects.

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“…6 -9 Our findings are in line with previous reports, which describe the presence of EBERϩ cells in the MS lesions 6 and the observation that active EBV infection is not a characteristic feature of the MS brain. [7][8][9] However, our study included a novel preselection strategy and focused only on white matter MS lesions rather than meningeal areas. We believe that there are 2 primary reasons for the discrepancies in previous reports: the sensitivity and specificity of the methodology and the clinical material used.…”

Section: Is Cerebral Expression Of Ebers Restricted To Ms?mentioning

confidence: 99%

“…4,5 Furthermore, EBV infection was found to be a characteristic feature of the MS brain 6 ; however, these findings were countered by other studies. [7][8][9] EBV infects predominantly B lymphocytes and persists in the blood in rare memory B cells. The gold standard for detecting EBV in tissue is in situ hybridization for the EBERs, 2 small EBV-RNAs (EBER1 and EBER2), abundant in EBV-infected cells (10 6 -10 7 copies/infected cell nucleus) 10 with immunomodulatory effects upon secretion and TLR3 ligation on neighboring cells.…”

mentioning

confidence: 99%

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

Tzartos¹,

Khan²,

et al. 2012

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Objective: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain. Methods:White matter postmortem MS (n ϭ 10) and control tissue (n ϭ 11) was analyzed for the expression of the proinflammatory cytokine interferon ␣ (IFN␣) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization. Results:We detected overexpression of IFN␣ in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFN␣ in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFN␣ was overexpressed in these preselected active MS lesions. EBERϩ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFN␣ production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFN␣ production in vitro. Conclusion:These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFN␣ production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases. Neurology ® 2012;78:15-23 GLOSSARY ds ϭ double-stranded; EBER ϭ EBV-encoded RNA; EBNA-1 ϭ EBV nuclear antigen 1; EBV ϭ Epstein-Barr virus; FCS ϭ fetal calf serum; H&E ϭ hematoxylin & eosin; HEK ϭ human embryonic kidney; HLA ϭ human leukocyte antigen; HSE ϭ herpes simplex encephalitis; IFN␣ ϭ interferon ␣; IgG ϭ immunoglobulin G; ISH ϭ in situ hybridization; LFB ϭ Luxol fast blue; mAb ϭ monoclonal antibody; MS ϭ multiple sclerosis; OHL ϭ oral hairy leukoplakia; PBS ϭ phosphate-buffered saline; pDC ϭ plasmacytoid dendritic cell; PLP ϭ protein lipid protein; SLE ϭ systemic lupus erythematosus; SSPE ϭ subacute sclerosing panencephalitis; TLR3 ϭ Toll-like receptor-3.The innate immune response is an essential part of the host response to many infections and type I interferon (IFN) is produced within hours of systemic infection.1 Our previous findings showed that Toll-like receptor-3 (TLR3) stimulation of human microglia with the viral-mimic polyIC led to IFN␣ production and downstream Th1 polarization of CD4ϩ helper T cells, 2 which may impact on CNS immunity.

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Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis

Cited by 140 publications

References 11 publications

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

EBV and Autoimmunity

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

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