scholarly journals Epstein Barr Virus Exploits Genetic Susceptibility to Increase Multiple Sclerosis Risk

2021 ◽  
Vol 9 (11) ◽  
pp. 2191
Author(s):  
Fabienne Läderach ◽  
Christian Münz
Keyword(s):  
Multiple Sclerosis ◽  
Mhc Class Ii ◽  
Epstein Barr Virus ◽  
Class Ii ◽  
Barr Virus ◽  
Ebv Infection ◽  
Experimental Systems ◽  
Recent Success ◽  
The Central Nervous System ◽  
Epstein Barr

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) for which both genetic and environmental risk factors have been identified. The strongest synergy among them exists between the MHC class II haplotype and infection with the Epstein Barr virus (EBV), especially symptomatic primary EBV infection (infectious mononucleosis) and elevated EBV-specific antibodies. In this review, we will summarize the epidemiological evidence that EBV infection is a prerequisite for MS development, describe altered EBV specific immune responses in MS patients, and speculate about possible pathogenic mechanisms for the synergy between EBV infection and the MS-associated MHC class II haplotype. We will also discuss how at least one of these mechanisms might explain the recent success of B cell-depleting therapies for MS. While a better mechanistic understanding of the role of EBV infection and its immune control during MS pathogenesis is required and calls for the development of innovative experimental systems to test the proposed mechanisms, therapies targeting EBV-infected B cells are already starting to be explored in MS patients.

scholarly journals Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors

2019 ◽  
Author(s):  
Benjamin M Jacobs ◽  
Gavin Giovannoni ◽  
Jack Cuzick ◽  
Ruth Dobson
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Meta Analysis ◽  
Clinically Isolated Syndrome ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Hla Genotype ◽  
Additive Scale

AbstractBackgroundEBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.ObjectiveTo examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.MethodsPubmed was searched using the terms “multiple sclerosis” AND “Epstein Barr virus”, “multiple sclerosis” AND EBV, “clinically isolated syndrome” AND “Epstein Barr virus” and “clinically isolated syndrome” AND EBV. All abstracts were reviewed for possible inclusion.Results262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10−4; RERI 3.84, p<5×10−3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.ConclusionsEBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis

2021 ◽  
Author(s):  
Asma Hassani ◽  
Narendran Reguraman ◽  
Safa Shehab ◽  
Gulfaraz Khan
Keyword(s):  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Rabbit Model ◽  
Nerve Fibers ◽  
Cns Infection ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Cellular Aggregates ◽  
The Brain

Abstract Background: Epstein-Barr virus (EBV) is a common herpesvirus associated with malignant and non-malignant conditions. An accumulating body of evidence supports a role for EBV in the pathogenesis of multiple sclerosis (MS), a demyelinative disease of the CNS. However, little is known about the details of the link between EBV and MS. One obstacle which has hindered research in this area has been the lack of a suitable animal model recapitulating natural infection in humans. We have recently shown that healthy rabbits are susceptible to EBV infection, and viral persistence in these animals mimics latent infection in humans. Methods: We used the rabbit model to investigate if peripheral EBV infection can lead to infection of the CNS and its potential consequences. We injected EBV intravenously in one group of animals, and PBS in another, with and without immunosuppression. Histopathological changes and viral dynamics were examined in peripheral blood, spleen, brain, and spinal cord, using a range of molecular and histopathology techniques. Results: Our investigations uncovered important findings that could not be previously addressed. We showed that primary peripheral EBV infection can lead to the virus traversing the CNS. Cell associated, but not free virus in the plasma, correlated with CNS infection. The infected cells within the brain were found to be B-lymphocytes. Most notably, animals injected with EBV, but not PBS, developed inflammatory cellular aggregates in the CNS. The incidence of these aggregates increased in the immunosuppressed animals. The cellular aggregates contained compact clusters of macrophages surrounded by reactive astrocytes and dispersed B and T lymphocytes, but not myelinated nerve fibers. Moreover, studying EBV infection over a span of 28 days, revealed that the peak point for viral load in the periphery and CNS coincides with increased occurrence of cellular aggregates in the brain. Finally, peripheral EBV infection triggered temporal changes in the expression of latent viral transcripts and cytokines in the brain. Conclusion: The present study provides the first direct in vivo evidence for the role of peripheral EBV infection in CNS pathology, and highlights a unique model to dissect viral mechanisms contributing to the development of MS.

scholarly journals An Absence of Epstein–Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 487
Author(s):  
Peter A. C. Maple ◽  
Bruno Gran ◽  
Radu Tanasescu ◽  
David I. Pritchard ◽  
Cris S. Constantinescu
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Virus Reactivation ◽  
Serum Samples ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ebv Reactivation ◽  
Epstein Barr

Background: Epstein–Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). Helminth infection can downregulate antiviral immune responses, potentially protecting against MS, but with a theoretical risk for reactivating latent EBV infection. Objective: To investigate parameters of EBV infection and their relationship with disease activity in people with MS (PwMS) therapeutically vaccinated with Necator americanus (hookworm). Methods: Sequential serum samples from 51 PwMS; 26 therapeutically infected (25 larvae) with N. americanus and 25 controls were tested for EBV virus capsid antigen (VCA) IgG and IgM, EBV nuclear antigen-1 (EBNA-1) IgG, and EBV early antigen (EA) IgG. Disease activity was assessed by periodic MRI. Significance was set at p < 0.05. Results: All PwMS were EBV VCA IgG and EBNA-1 IgG positive, and 35.2% were EBV EA IgG positive. EBV antibody levels were generally stable, and EBV reactivation in PwMS was not demonstrated by significant increases in IgG titre over 12 months. Disease activity was most frequent in PwMS possessing high levels of EBV VCA IgG (>600 units/mL) or EBNA-1 IgG (>150 units/mL); however, there was no association with hookworm treatment. Interpretation: Therapeutic hookworm vaccination was not associated with EBV reactivation. Multiple sclerosis disease activity was associated with high levels of EBV VCA IgG or EBNA-1 IgG.

scholarly journals Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1

Blood ◽  
2015 ◽  
Vol 125 (14) ◽  
pp. 2228-2238 ◽  
Author(s):  
Jiun-Han Lin ◽  
Ju-Yin Lin ◽  
Ya-Ching Chou ◽  
Mei-Ru Chen ◽  
Te-Huei Yeh ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Mhc Class Ii ◽  
Epstein Barr Virus ◽  
Class Ii ◽  
Barr Virus ◽  
Key Points ◽  
Cell Gene Expression ◽  
Epstein Barr ◽  
Cell Gene

Key PointsEBV LMP2A alters B-cell gene expression; E47 and PU.1 are repressed by LMP2A, resulting in downregulation of MHC class II expression.

scholarly journals Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis

2014 ◽  
Vol 20 (14) ◽  
pp. 1825-1832 ◽  
Author(s):  
Michael P Pender ◽  
Peter A Csurhes ◽  
Casey MM Pfluger ◽  
Scott R Burrows
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Clinical Course ◽  
Effector Memory ◽  
Barr Virus ◽  
Effector Memory T Cells ◽  
The Central Nervous System ◽  
Epstein Barr

Background: Patients with multiple sclerosis (MS) have a deficiency of circulating CD8+ T cells, which might impair control of Epstein–Barr virus (EBV) and predispose to MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. Based on the expression of CD45RA and CD62L, CD4+ T cells and CD8+ T cells can be subdivided into four subsets with distinct homing and functional properties, namely: naïve, central memory, effector memory (EM) and effector memory re-expressing CD45RA (EMRA) cells. Objective: Our aim was to determine which memory subsets are involved in the CD8+ T cell deficiency and how these relate to clinical course. Methods: We used flow cytometry to analyze the memory phenotypes of T cells in the blood of 118 MS patients and 112 healthy subjects. Results: MS patients had a decreased frequency of EM (CD45RA–CD62L–) and EMRA (CD45RA+CD62L–) CD8+ T cells, which was present at the onset of disease and persisted throughout the clinical course. The frequencies of CD4+ EM and EMRA T cells were normal. Conclusion: Deficiency of effector memory CD8+ T cells is an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV.

scholarly journals Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis

Science ◽  
2022 ◽  
Author(s):  
Kjetil Bjornevik ◽  
Marianna Cortese ◽  
Brian C. Healy ◽  
Jens Kuhle ◽  
Michael J. Mina ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Demyelinating Disease ◽  
Serum Levels ◽  
Unknown Etiology ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Barr Virus ◽  
The Central Nervous System ◽  
Epstein Barr

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

scholarly journals Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions

2019 ◽  
Vol 21 (2) ◽  
pp. 91-99 ◽  
Author(s):  
Lawrence T. C. Ong ◽  
Grant P. Parnell ◽  
Ali Afrasiabi ◽  
Graeme J. Stewart ◽  
Sanjay Swaminathan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
B Cells ◽  
Epstein Barr Virus ◽  
B Lymphocyte ◽  
Sequencing Data ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Activated B Cells

Abstract Epstein–Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines—LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.

Infectious Mononucleosis and Encephalitis: Recovery of EB Virus from Spinal Fluid

PEDIATRICS ◽  
1979 ◽  
Vol 64 (2) ◽  
pp. 257-258
Author(s):  
Crystie C. Halsted ◽  
R. Shihman Chang
Keyword(s):  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Transverse Myelitis ◽  
Spinal Fluid ◽  
Barr Virus ◽  
Ebv Infection ◽  
Direct Invasion ◽  
Neurologic Disorders ◽  
The Central Nervous System ◽  
Epstein Barr

Epstein-Barr virus (EBV), the accepted cause of infectious mononucleosis (IM), has been associated with a variety of neurologic disorders including encephalitis, aseptic meningitis, transverse myelitis, Guillain-Barré syndrome, and Bell's Palsy.1,2 These neurologic syndromes may occur as the sole manifestation of EBV infection or together with the more typical clinical features of IM. It is unclear whether the central nervous manifestations of EBV result from direct invasion of the central nervous system by EBV or from a more indirect mechanism. This report describes the recovery of EBV from the spinal fluid of an 11-year-old boy with IM and encephalitis. CASE REPORT

Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination

2015 ◽  
Vol 22 (3) ◽  
pp. 385-388 ◽  
Author(s):  
Naila Makhani ◽  
Brenda Banwell ◽  
Raymond Tellier ◽  
Carmen Yea ◽  
Suzanne McGovern ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Protective Factor ◽  
Cmv Infection ◽  
Prognostic Information ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Simplex Virus

Epstein–Barr virus (EBV) infection is associated with increased multiple sclerosis (MS) risk. Recently, cytomegalovirus (CMV) infection has been proposed as a protective factor against MS development. We determined EBV, herpes simplex virus, varicella-zoster virus and CMV seroprevalence in 247 prospectively followed children with acquired demyelinating syndromes (ADS). Remote EBV infection was more common in children with MS than those with monophasic ADS while CMV infection was more common in children with monophasic ADS. Children displaying evidence of remote EBV without CMV infection were at highest risk of subsequent MS diagnosis. Viral infection repertoire detected at ADS provides important prognostic information.

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