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

2013 ◽  
Vol 20 (6) ◽  
pp. 747-750 ◽  
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.

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

2019 ◽  
Vol 116 (34) ◽  
pp. 16955-16960 ◽  
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.

Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort

2013 ◽  
Vol 20 (6) ◽  
pp. 751-753 ◽  
Author(s):  
Caren Ramien ◽  
Annette Pachnio ◽  
Sofia Sisay ◽  
Jusnara Begum ◽  
Alison Leese ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Quantitative Polymerase Chain Reaction ◽  
Hypovitaminosis D ◽  
Nuclear Antigen ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Epstein Barr

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis.

scholarly journals Anti-Epstein–Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel

2011 ◽  
Vol 17 (10) ◽  
pp. 1185-1193 ◽  
Author(s):  
KL Munger ◽  
LI Levin ◽  
EJ O’Reilly ◽  
KI Falk ◽  
A Ascherio
Keyword(s):  
Multiple Sclerosis ◽  
Prospective Study ◽  
Military Personnel ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Antibody Titers ◽  
Race Ethnicity ◽  
Epstein Barr ◽  
A Prospective Study

Background: Elevated Epstein–Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized. Objectives: The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS. Methods: We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks. Results: MS risk increased with increasing titers of anti-EBNA complex ( p < 10−9) and anti-EBNA-1 ( p = 5.8 × 10−9) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6–136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6–23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1. Conclusions: Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.

Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk

2013 ◽  
Vol 20 (3) ◽  
pp. 286-294 ◽  
Author(s):  
K Strautins ◽  
M Tschochner ◽  
I James ◽  
L Choo ◽  
DS Dunn ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Disease Risk ◽  
Human Leukocyte ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Hla Dr ◽  
Epstein Barr ◽  
Antibody Levels

Background: Risk factors for multiple sclerosis (MS) include human leukocyte antigen (HLA)-DR and Epstein-Barr virus (EBV)-specific antibody responses, including an epitope within EBV nuclear antigen 1 (EBNA-1) that is of recent interest. Objective: The objective of this paper is to assess case-control associations between MS risk and anti-EBV antibody levels as well as HLA-DR profiles, gender and age in a population-based cohort. Methods: Serological responses to EBV were measured in 426 MS patients and 186 healthy controls. HLA-DR typing was performed using sequence-based methods. Results: MS patients had significantly higher levels of antibodies against epitope-specific and polyspecific EBNA-1 and viral capsid antigen (VCA), compared with controls (all p < 10−15). In regression analyses, anti-EBNA-1 and anti-VCA antibody levels, protective HLA-DR*04/07/09 alleles and gender (all p < 0.003) contributed independently to a model that classified cases and controls with an odds ratio > 20 (sensitivity 92%, specificity 64%). Notably, the strong influence of high-risk HLA-DR alleles was abrogated after inclusion of EBV serology results. Conclusions: The ability to discriminate MS cases and controls can be substantially enhanced by including anti-EBV serology as well as HLA-DR risk profiles. These findings support the relevance of EBV-specific immunity in MS pathogenesis, and implicate both HLA-dependent and HLA-independent immune responses against EBNA-1 as prominent disease risk factors.

HAUSP/USP7 as an Epstein–Barr virus target

2004 ◽  
Vol 32 (5) ◽  
pp. 731-732 ◽  
Author(s):  
M.N. Holowaty ◽  
L. Frappier
Keyword(s):  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
High Affinity ◽  
Cellular Immortalization ◽  
Epstein Barr ◽  
Epstein Barr Nuclear Antigen

USP7 (also called HAUSP) is a de-ubiquitinating enzyme recently identified as a key regulator of the p53–mdm2 pathway, which stabilizes both p53 and mdm2. We have discovered that the Epstein–Barr nuclear antigen 1 protein of Epstein–Barr virus binds with high affinity to USP7 and disrupts the USP7–p53 interaction. The results have important implications for the role of Epstein–Barr nuclear antigen 1 in the cellular immortalization that is typical of an Epstein–Barr virus latent infection.

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.

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