Epstein-Barr virus in oral shedding of children with multiple sclerosis

Yea, Carmen; Tellier, Raymond; Chong, Pele; Westmacott, Garrett; Marrie, Ruth Ann; Bar‐Or, Amit; Banwell, Brenda

doi:10.1212/wnl.0b013e3182a841e4

Cited by 51 publications

(50 citation statements)

References 35 publications

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“…Prior EBV infection is thus far the strongest and most consistent environmental factor associated with pediatric and adult‐onset MS 9, 10, 11, 12, 13, 20, 21. We observed that this association with pediatric MS is seen regardless of race and ethnicity, although the association is stronger in whites, as recently reported in adult‐onset MS 14.…”

Section: Discussionsupporting

confidence: 82%

“…Although several other studies investigated the association of prior viral infections and pediatric MS risk,9, 10, 11, 12, 13 very few studies examining the risk of MS in relation to previous viral exposures and the possible interactions with age, race and ethnicity have been conducted 14. Using a large case–control study, we aimed to assess the heterogeneity of association between remote infections with common herpesviruses and the risk of pediatric MS in children with a diverse racial and ethnic background.…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWhile prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections.MethodsCases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status.ResultsA total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status.Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Nourbakhsh

Rutatangwa

Waltz

et al. 2018

Ann Clin Transl Neurol

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“…In all cases, the consensus sequence deriving from deep sequencing coincided with the one determined by Sanger sequencing, confirming the cosegregation of newly identified variants with the known EBNA2 alleles. We also found one or more variable positions in all HDs (1-17) and individuals with MS (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). For all couples of variants lying on the same read (coverage $50), the hypothesis of independent segregation, indicative of random sequencing errors, was rejected through a x 2 test (p , 0.05), thus supporting the coexistence of different genotypes.…”

Section: Resultsmentioning

confidence: 67%

“…7 To disclose possible MS-related EBV strains, various groups have followed a candidate-gene approach. [8][9][10][11][12][13][14] Along the same line, we chose to investigate EBV variability in MS by studying Epstein-Barr nuclear antigen 2 (EBNA2). EBNA2 is, in principle, the best candidate for this kind of study because it is the most polymorphic among all EBV genes: 5 major alleles of the EBV type 1 strain, the most frequent strain in the general Caucasian population, 15 have been identified based on nucleotide variations within the most variable region of EBNA2, which is also involved in the interaction with host proteins.…”

mentioning

confidence: 99%

“…; more frequent EBNA2 type 1 and 2 coinfection in patients than in healthy subjects 14 ; and a broader range of genetic variants in children with MS in the context of an increased rate of EBV reactivation. 15 Different patterns of EBV genetic variations in different geographic regions could account for inconsistencies, as suggested by the different geographic distributions of EBV-related malignancies.…”

mentioning

confidence: 99%

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Epstein-Barr virus genetic variants are associated with multiple sclerosis

et al. 2015

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Objective: We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development. 84-14.32; p 5 0.016) and underrepresentation of 1.3B allele (OR 5 0.23; 95% CI 0.08-0.51; p 5 0.0006). We identified new genetic variants, mostly 1.2 allele-and MS-associated (especially amino acid variation at position 245; OR 5 9.4; 95% CI 1.19-78.72; p 5 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features. MethodsConclusions: Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development. Despite converging evidence supporting an etiologic role for Epstein-Barr virus (EBV) in multiple sclerosis (MS), we still do not know through which mechanisms the virus may contribute to disease development. 1 The potential pathogenic role of EBV genetic variants in MS may be in keeping with epidemiologic observations, in particular the geographic gradient of MS and the change in MS risk in migrants, 2 and with the reported association between virus genetic variants and EBV-related malignancies with different geographic distribution.3-5 Also, the discrepancy between the global diffusion of EBV infection and the low prevalence of MS could be at least in part explained by EBV genomic diversity that differently affects MS development.Major methodologic difficulties hinder the study of EBV variants through sequencing of the whole viral genome. To date, only 8 complete genome sequences have been described: 5 from patients with EBV-related diseases and 3 from healthy individuals.6 This is mainly attributable

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Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism

2023

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The link between Epstein-Barr virus (EBV) and multiple sclerosis (MS) has puzzled researchers since it was first discovered over 40 years ago. Until that point, EBV was primarily viewed as a cancer-causing agent, but the culmination of evidence now shows that EBV has a pivotal role in development of MS. Early MS disease is characterised by episodic neuroinflammation and focal lesions in the central nervous system (CNS) that over time develop into progressive neurodegeneration and disability. Risk of MS is vanishingly low in EBV seronegative individuals, history of infectious mononucleosis (acute symptomatic primary infection with EBV) significantly increases risk and elevated antibody titres directed against EBV antigens are well-characterised in patients. However, the underlying mechanismor mechanismsresponsible for this interplay remains to be fully elucidated; how does EBV-induced immune dysregulation either trigger or drive MS in susceptible individuals? Furthermore, deep understanding of virological and immunological events during primary infection and long-term persistence in B cells will help to answer the many questions that remain regarding MS pathogenesis. This review discusses the current evidence and mechanisms surrounding EBV and MS, which have important implications for the future of MS therapies and prevention.

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Epstein-Barr virus in oral shedding of children with multiple sclerosis

Abstract: Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV.

Cited by 51 publications

References 35 publications

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Heterogeneity in association of remote herpesvirus infections and pediatric MS

Epstein-Barr virus genetic variants are associated with multiple sclerosis

Epstein–Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism

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