Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis

Levin, Lynn I.; Munger, Kassandra L.; Rubertone, Mark V.; Peck, Charles A.; Lennette, Evelyne T.; Spiegelman, Donna; Ascherio, Alberto

doi:10.1001/jama.293.20.2496

Cited by 403 publications

(339 citation statements)

References 32 publications

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“…Although EBNA-1-specific IgG are markers of latent EBV infection, VCA-specific IgG titers increase after EBV reactivation [28] and correlate with the EBV viral load [29]. However, in the blood of MS patients, authors have reported that EBNA-1 IgG are markedly increased whereas VCA IgG titers are normal [5][6][7][8]. Therefore, our findings, which are consistent with other reports [9,13,14], indicate that EBV may show more signs of reactivation in the CSF than in the blood at MS clinical onset.…”

Section: Discussionmentioning

confidence: 99%

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Intrathecal immune responses to EBV in early MS

et al. 2010

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EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8 1 CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8 1 CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV-nor CMV-specific CD8 1 CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

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Section: Discussionmentioning

confidence: 99%

“…Among the latter, the g-herpesvirus EBV has been repeatedly associated with this disease [2][3][4]. Large seroepidemiological studies [5][6][7][8] and cellular immune response assessments [9][10][11][12] have demonstrated enhanced EBV-specific immune responses in the blood of MS patients.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal immune responses to EBV in early MS

et al. 2010

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“…Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. The precise etiology of MS remains elusive with a complex interplay between environmental factors, genetic susceptibility, and age-dependant exposure to viral infection postulated [1]. A significant genetic component has been demonstrated by studies examining familial concordance rates with risk being up to 300-fold increased in monozygotic twins and 20-40-fold increased for first-degree relatives as compared to a general population prevalence of 0.1% [2].…”

Section: Introductionmentioning

confidence: 99%

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort

Szvetko

Fowdar

Nelson

et al. 2007

Journal of the Neurological Sciences

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Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the α = 0.05 level (MTRR χ 2 = 0.005, P = 0.95, MTHFR χ 2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS.

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“…Some papers, published several years ago [5,6], have already reported that the titres of certain antibodies against EBV (EBNA-1, EBNA-2 and EA-D) are higher in blood samples obtained from future patients before the onset of MS than in those from age-and sex-matched controls. Recently, four longitudinal studies [7][8][9][10] provided strong support for these findings. In 2005, Levin et al [7] measured the titres of various antibodies against EBV in serial blood samples from 83 patients with MS and controls, using banked blood samples and archived data maintained by the US Army.…”

Section: Introductionmentioning

confidence: 88%

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

Csuka

Simon

Hóbor

et al. 2013

Clinical and Experimental Immunology

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SummarySeveral studies suggest that infection by Epstein-Barr virus (EBV) might be one of the environmental factors which facilitates the development of autoimmune disorders in genetically susceptible individuals. Recent data indicate that high anti-Epstein-Barr nuclear antigen 1 (EBNA)-1 immunoglobulin (Ig)G titre is a strong risk factor for multiple sclerosis (MS) in patients both with and without the main genetic predisposing trait, human leucocyte antigen (HLA)-DRB1*15:01. Because no similar studies have been published in systemic lupus erythematosus (SLE) patients, we determined the HLA-DRB1*15:01 carrier state and the serum titres against the whole EBNA-1 and its small fragments aa35-58 and aa398-404 in 301 SLE patients, 135 MS patients and in 345 healthy controls. The carrier state of the HLA-DRB1*15:01 allele was deduced from genotyping of a tagSNP (rs3135388) by applying a Taqman-based assay. The serum concentrations of antibodies to EBNA-1 and its aa35-58 or aa398-404 fragments were determined using a commercial assay (ETI-EBNA-G) and home-made enzyme-linked immunosorbent assays, respectively. The serum concentration of anti-EBNA-1 antibodies was significantly (P < 0·001) higher both in MS and SLE patients than in controls. Similar significant differences were found both in HLA-DRB1*15:01 carriers and non-carriers. Furthermore, titres of antibodies against the aa35-58 EBNA-1 fragment were elevated both in MS and SLE patients. By contrast, the levels of aa398-404 EBNA-1 antibodies were elevated significantly only in the SLE patients. These findings indicate that high anti-EBNA-1 IgG titres are HLA-DRB1*15:01-independent risk factors not only for MS, but also for SLE, while high antibody titres against the aa398-404 fragment are characteristic for SLE.

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Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis

Cited by 403 publications

References 32 publications

Intrathecal immune responses to EBV in early MS

Intrathecal immune responses to EBV in early MS

No association between MTHFR A1298C and MTRR A66G polymorphisms, and MS in an Australian cohort

Serum concentration of immunoglobulin G-type antibodies against the whole Epstein–Barr nuclear antigen 1 and its aa35–58 or aa398–404 fragments in the sera of patients with systemic lupus erythematosus and multiple sclerosis

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