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

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.

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Systematic review and meta-analysis of the association between Epstein–Barr virus, multiple sclerosis and other risk factors

Multiple Sclerosis Journal ◽

10.1177/1352458520907901 ◽

2020 ◽

Vol 26 (11) ◽

pp. 1281-1297 ◽

Cited By ~ 4

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

Background: Epstein–Barr virus (EBV) 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. Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. Methods: Pubmed 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. Results: A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 × 10−4). Previous infectious mononucleosis (IM) was associated with increased odds ratio (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. Conclusion: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

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HLA‐DRB1*15:01 is a coreceptor for Epstein‐Barr virus, linking genetic and environmental risk factors for multiple sclerosis

European Journal of Immunology ◽

10.1002/eji.202149179 ◽

2021 ◽

Author(s):

Jennifer Menegatti ◽

David Schub ◽

Marco Schäfer ◽

Friedrich A. Grässer ◽

Klemens Ruprecht

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Environmental Risk ◽

Epstein Barr Virus ◽

Environmental Risk Factors ◽

Barr Virus ◽

Epstein Barr

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Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis

Medical Hypotheses ◽

10.1016/j.mehy.2007.04.030 ◽

2008 ◽

Vol 70 (1) ◽

pp. 66-69 ◽

Cited By ~ 43

Author(s):

Trygve Holmøy

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Vitamin D ◽

Immune Response ◽

Synergistic Effect ◽

Epstein Barr Virus ◽

Vitamin D Status ◽

Barr Virus ◽

Epstein Barr

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

10.21203/rs.3.rs-792416/v1 ◽

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.

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Epstein–Barr virus infection after adolescence and human herpesvirus 6A as risk factors for multiple sclerosis

European Journal of Neurology ◽

10.1111/ene.14597 ◽

2020 ◽

Cited By ~ 1

Author(s):

M. Biström ◽

D. Jons ◽

E. Engdahl ◽

R. Gustafsson ◽

J. Huang ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Virus Infection ◽

Epstein Barr Virus ◽

Human Herpesvirus ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Epstein Barr ◽

Barr Virus Infection

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

Vaccines ◽

10.3390/vaccines8030487 ◽

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.

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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1902623116 ◽

2019 ◽

Vol 116 (34) ◽

pp. 16955-16960 ◽

Cited By ~ 13

Author(s):

Katarina Tengvall ◽

Jesse Huang ◽

Cecilia Hellström ◽

Patrick Kammer ◽

Martin Biström ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

T Cell ◽

Epstein Barr Virus ◽

Molecular Mimicry ◽

Nuclear Antigen ◽

Immune Reactivity ◽

Barr Virus ◽

Epstein Barr ◽

Antibody Levels

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

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Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515626598 ◽

2016 ◽

Vol 22 (13) ◽

pp. 1655-1664 ◽

Cited By ~ 25

Author(s):

Yuan Zhou ◽

Gu Zhu ◽

Jac C Charlesworth ◽

Steve Simpson ◽

Rohina Rubicz ◽

...

Keyword(s):

Multiple Sclerosis ◽

Genetic Risk ◽

Epstein Barr Virus ◽

Meta Analysis ◽

Nuclear Antigen ◽

Genetic Loci ◽

Polygenic Risk ◽

Barr Virus ◽

Genome Wide ◽

Epstein Barr

Background: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). Objective: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. Methods: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size ( Neff) = 5555) and a large MS GWAS ( Neff = 15,231). Results: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 ( p = 4.11 × 10−9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP ( p = 3.32 × 10−20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance ( p < 5 × 10−8). Conclusions: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

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The interaction between smoking and Epstein-Barr virus as multiple sclerosis risk factors may depend on age

Multiple Sclerosis Journal ◽

10.1177/1352458513507820 ◽

2013 ◽

Vol 20 (6) ◽

pp. 747-750 ◽

Cited By ~ 15

Author(s):

Jonatan Salzer ◽

Hans Stenlund ◽

Peter Sundström

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Epstein Barr Virus ◽

Nuclear Antigen ◽

Positive Interaction ◽

Barr Virus ◽

Older Subjects ◽

Epstein Barr ◽

A Prospective Study ◽

Epstein Barr Nuclear Antigen

The multiple sclerosis (MS) risk factors smoking and remote Epstein-Barr virus (EBV) infection have been suggested to interact statistically, but the results are conflicting. In a prospective study on 192 MS cases and 384 matched controls, we analysed levels of cotinine as a marker of smoke exposure, and Epstein-Barr Nuclear Antigen-1 antibody reactivity. We assessed interaction on the additive and multiplicative scales, and estimated the effects of the risk factors across strata of each other. The results suggest that a negative interaction may be present in samples drawn at a young age, and a positive interaction among older subjects.

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