Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain

Willis, Simon N.; Stadelmann, Christine; Rodig, Scott J.; Caron, Tyler; Gattenloehner, Stefan; Mallozzi, Scott S.; Roughan, Jill E.; Almendinger, Stefany; Blewett, Megan M.; Brück, Wolfgang; Hafler, David A.; O’Connor, Kevin

doi:10.1093/brain/awp200

Cited by 247 publications

(209 citation statements)

References 56 publications

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“…An increased EBV-specific CD8 1 CTL response in one MS patient [15], as well as a higher EBV-specific proliferation of CD4 1 T cell lines in two out of three MS patients [16] in the CSF as compared with paired blood, has been reported. Although these data are controversial [17], EBVinfected B cells located in neo-follicles in the meninges have been detected in patients with MS, but not with other inflammatory neurological diseases (OIND). Activated CD8 1 T cells present in the vicinity of these neo-follicles were suggestive of ongoing cytotoxic activity against EBV-infected B cells [18].…”

Section: Introductionmentioning

confidence: 99%

Intrathecal immune responses to EBV in early MS

et al. 2010

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EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8 1 CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8 1 CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV-nor CMV-specific CD8 1 CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

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Section: Introductionmentioning

confidence: 99%

Intrathecal immune responses to EBV in early MS

et al. 2010

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“…It has been proposed that failure to control latent EBV infection in an immune privileged site, such as the subarachnoid space, could lead to recurrent intrathecal reactivation of EBV and tissue damage in the nearby grey matter 62,63 . However, a number of other studies have been unable to detect EBV in the brain or lesions of MS patients 64,65 and this remains a highly debated controversy 66 . The different results found in these studies are likely to be due to the different types of tissues and MS cases used, the variable preservation of meningeal tissues in the samples, and differences in the sensitivity of the techniques used to detect EBV infection 67 .…”

Section: Inflammatory Grey Matter Damagementioning

confidence: 99%

“…As has previously been discussed, this disparity may be a result of differences in the technical approaches used, such as different procedures of tissue processing, cutting and staining, and cohort choice. 65,101 .…”

Section: Role Of Meningeal Inflammatory Infiltratesmentioning

confidence: 99%

Exploring the origins of grey matter damage in multiple sclerosis

et al. 2015

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Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage. DOI: https://doi.org/10.1038/nrn3900Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-111099 Accepted Version Originally published at: Calabrese, Massimiliano; Magliozzi, Roberta; Ciccarelli, Olga; Geurts, Jeroen J G; Reynolds, Richard; Martin, Roland (2015). Exploring the origins of grey matter damage in multiple sclerosis. Nature Reviews Neuroscience, 16 (3) AbstractMultiple sclerosis is characterised at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, in recent years it has become clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage has been suggested to have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. This review will summarize and highlight important histological, immunological, and neuroimaging results from this rapidly expanding field and will address the most recent hypotheses on the pathogenesis of grey matter damage.

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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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Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain

Cited by 247 publications

References 56 publications

Intrathecal immune responses to EBV in early MS

Intrathecal immune responses to EBV in early MS

Exploring the origins of grey matter damage in multiple sclerosis

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

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