Impact of genetic variation in the molecular mimicry between Anoctamin-2 and Epstein-Barr virus nuclear antigen 1 in Multiple Sclerosis

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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Multiple sclerosis: The elevated antibody response to Epstein–Barr virus primarily targets, but is not confined to, the glycine–alanine repeat of Epstein–Barr nuclear antigen-1

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2014.04.005 ◽

2014 ◽

Vol 272 (1-2) ◽

pp. 56-61 ◽

Cited By ~ 17

Author(s):

Klemens Ruprecht ◽

Benjamin Wunderlich ◽

René Gieß ◽

Petra Meyer ◽

Madlen Loebel ◽

...

Keyword(s):

Multiple Sclerosis ◽

Antibody Response ◽

Epstein Barr Virus ◽

Nuclear Antigen ◽

Barr Virus ◽

Epstein Barr ◽

Epstein Barr Nuclear Antigen

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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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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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Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458510368051 ◽

2010 ◽

Vol 16 (7) ◽

pp. 883-887 ◽

Cited By ~ 19

Author(s):

Massimiliano Castellazzi ◽

Carmine Tamborino ◽

Alice Cani ◽

Elena Negri ◽

Eleonora Baldi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Disorders ◽

Epstein Barr Virus ◽

Serum Levels ◽

Nuclear Antigen ◽

Enzyme Linked Immunosorbent Assay ◽

Barr Virus ◽

Epstein Barr ◽

Multiple Sclerosis Patients

Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein—Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing—remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis ( p < 0.0001) and NIND ( p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND ( p < 0.01) and in OIND than in NIND ( p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis ( p < 0.05) and in MRI inactive than in MRI active multiple sclerosis ( p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND ( p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively ( p < 0.05) and inversely ( p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.

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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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Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility

Neurology ◽

10.1212/wnl.0000000000004412 ◽

2017 ◽

Vol 89 (13) ◽

pp. 1330-1337 ◽

Cited By ~ 29

Author(s):

Annette Langer-Gould ◽

Jun Wu ◽

Robyn Lucas ◽

Jessica Smith ◽

Edlin Gonzales ◽

...

Keyword(s):

Multiple Sclerosis ◽

Ethnic Groups ◽

Lower Risk ◽

Epstein Barr Virus ◽

Hygiene Hypothesis ◽

Nuclear Antigen ◽

Barr Virus ◽

Epstein Barr ◽

Incident Cases ◽

Racial Ethnic

Objective:To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.Methods:Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.Results:Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.Conclusions:The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

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