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.

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.

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.

Correlations between Epstein-Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals

2007 ◽  
Vol 13 (3) ◽  
pp. 420-423 ◽  
Author(s):  
T.R. Nielsen ◽  
M. Pedersen ◽  
K. Rostgaard ◽  
M. Frisch ◽  
H. Hjalgrim
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Immune Globulin ◽  
Epstein Barr Virus ◽  
Female Gender ◽  
Healthy Individuals ◽  
Barr Virus ◽  
Epstein Barr ◽  
Antibody Levels ◽  
Change In Mean

Background Female gender, human leukocyte antigen (HLA) DR2, tobacco smoking and Epstein-Barr virus (EBV) are established risk factors for multiple sclerosis (MS). Their possible interaction however, has been sparsely studied. Objectives To investigate possible associations between EBV antibody levels and a range of other recognized MS risk factors. Design, setting and study population Cross-sectional study undertaken in Denmark based on 517 healthy individuals selected from the Danish population. Methods We measured change in mean log (anti-Epstein-Barr viral capsid antigen (VCA) immune globulin G) using linear regression. Results Anti-Epstein-Barr VCA immune globulin G levels were positively correlated with female gender and HLA DR2. Furthermore, current smoking and cumulative tobacco consumption were positively associated with EBV antibody levels. Conclusion The association between Epstein-Barr VCA antibody levels and non-viral MS risk factors support the view that EBV is critically involved in the etiology of MS. These non-viral MS risk factors may be linked with MS risk through EBV-specific immune responses. Multiple Sclerosis 2007; 13: 420-423. http://msj.sagepub.com

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.

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis

2014 ◽  
Vol 20 (14) ◽  
pp. 1833-1840 ◽  
Author(s):  
Silje Kvistad ◽  
Kjell-Morten Myhr ◽  
Trygve Holmøy ◽  
Søren Bakke ◽  
Antonie G Beiske ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Treatment Response ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Inverse Association ◽  
Barr Virus ◽  
T2 Lesions ◽  
Epstein Barr ◽  
Antibody Levels

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting. Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response. Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model. Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07–8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12–0.84; p = 0.021) with CUA during IFNB treatment. Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response.

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