EBV Causes Multiple Sclerosis

Smokers are more likely to have been infected by EBV, for socioeconomic reasons. The Surgeon General report of 2014 (Ch. 10, p. 569) makes no mention at all of EBV in MS, therefore it is a deliberate act of scientific fraud.

Epstein-Barr virus antibodies in multiple sclerosis. CV Sumaya, LW Myers, GW Ellison. Arch Neurol 1980 Feb;37(2):94-96. 2 / 157 (1.3%) patients, versus 5 / 81 controls (6.2%) lacked antibodies to EBV. "In the subjects with antibodies, the prevalence of high titers (greater than or equal to 1:160) was significantly greater in patients, 69 (44.5%), than in control subjects, 22 (28.9%). The geometric mean titer of antibodies to EBV was significantly higher in patients, 107.0, than in control subjects, 77.1. There was no association between antibody titers and duration or activity of the disease."

Sumaya - Arch Neurol 1980 abstract / PubMed

Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis. PF Bray, LC Bloomer, VC Salmon, MH Bagley, PD Larsen. Arch Neurol 1983 Jul;40(7):406-408. 313 consecutive patients nd 406 controls. "Using a standardized immunofluorescent antibody (IFA) technique, we found a significantly higher prevalence of Epstein-Barr virus (EBV) infection and a higher level of serum viral capsid antigen IgG antibody titer in the MS population than in the controls. The MS population had a lower cytomegalovirus (CMV) infection rate and lower CMV complement fixing antibody production than controls."

Bray - Arch Neurol 1983 abstract / PubMed

Epstein-Barr nuclear antigen and viral capsid antigen antibody titers in multiple sclerosis. PD Larsen, LC Bloomer, PF Bray. Neurology 1985 Mar;35(3):435-438. 93 age- and sex-matched pairs of MS patients and controls. "The seropositivity rate of both anti-EBVCA and anti-EBNA in MS patients was 100%, compared with 84% in controls (p less than 0.0001). Both anti-EBVCA and anti-EBNA titers were significantly higher in MS patients than in controls (p less than 0.0001)."

Larsen - Neurology 1985 abstract / PubMed

A case-control study of multiple sclerosis. EA Operskalski, BR Visscher, RM Malmgren, R Detels. Neurology 1989 Jun;39(6):825-829. 145 MS patients, 145 friend controls. "The most striking finding was a strong positive association for history of infectious mononucleosis (IM), suggesting older age at exposure to Epstein-Barr virus, the most common etiologic agent of IM. We also found significant positive associations for number of different domiciles before adulthood and for visits outside the United States; both would be compatible with an increased likelihood among cases of exposures to uncommon viruses or to multiple strains of a common agent."

Operskalski - Neurology 1989 abstract / PubMed

Increased risk of multiple sclerosis after late Epstein-Barr virus infection: a historical prospective study. S Haahr, N Koch-Henriksen, A Mřller-Larsen, LS Eriksen, HM Andersen. Mult Scler 1995 Jun;1(2):73-77. "16 cases of MS which met the diagnostic criteria were found with onset of MS after the year of the HA test and before follow-up on 1 January 1991. The expected number for a Danish population, matched by sex, age and year at start of observation, was 5.70 (P < 0.05), the risk ratio being 2.81. No patient had developed MS before contracting IM. Among the HA-negative persons 12 were registered with onset of MS after the year of the HA test and before follow-up, the expected number being 10.47 (P > > 0.05)."

Haahr - Mult Scler 1995 abstract / PubMed

The significance of Epstein-Barr virus seropositivity in multiple sclerosis patients? M Munch, K Riisom, T Christensen, A Mřller-Larsen, S Haahr. Acta Neurol Scand 1998 Mar;97(3):171-174. 137 of 138 MS patients and 124 of 138 healthy controls were seropositive.

Munch - Acta Neurol Scand 1998 abstract / PubMed

Epstein-Barr virus and multiple sclerosis. A Ascherio, M Munch. Epidemiology 2000 Mar;11(2):220-224. In a meta-analysis of published investigations, "The summary odds ratio of MS comparing EBV seropositive individuals with EBV seronegative individuals was 13.5 (95% CI = 6.3-31.4)."

Ascherio - Epidemiology 2000 abstract / PubMed

Epstein-Barr Virus Antibodies and Risk of Multiple Sclerosis. A Prospective Study. A Ascherio, KL Munger, ET Lennette, D Spiegelman, MA Hernan, MJ Olek, SE Hankinson, DJ Hunter. Journal of the American Medical Association 2001 Dec 26;286(24):3083-3086. This study found that "serum antibodies to EBV were consistently higher among women with MS compared to their matched controls," and that elevated antibody levels occurred before the development of clinical evidence of multiple sclerosis. They also note that "In a meta-analysis of published investigations, we estimated that the odds of disease are more than 10 times higher among EBV-positive than EBV-negative persons."

Ascherio / JAMA 2001 full article

In view of this, the 2001 study in the American Journal of Epidemiology co-authored by Hernan, Oleky, and Ascherio, which pretended that "smoking is associated with an increased risk of MS" was either a despicable fraud or flagrant incompetence, because anyone who knew what they were doing would know 1) that EBV infection is very strongly associated with socioeconomic class, as is smoking, and 2) that ORs over 10 such as they found in their 2000 meta-analysis easily produce bogus "smoking risks" of the magnitude they pretended, due to residual confounding (Cigarette smoking and incidence of multiple sclerosis. MA Hernan, MJ Oleky, A Ascherio. Am J Epidemiol 2001 Jul 1;154(1):69-74.)

Hernan - Am J Epidemiol 2001 abstract / PubMed
EBV and Socioeconomic Status

Notice of Retraction: "Multiple Sclerosis and Epstein-Barr Virus" A Ascherio, M Rubertone, D Spiegelman, L Levin, K Munger, C Peck, E Lennette. (JAMA 2003;289:1533-1536.) In: JAMA 2005 May 25;293(20). "Several dates of blood collection, however, were erroneously assigned, obscuring important temporal variations in antibody titers among the cases. Overall, analyses of the correct data still support the strong and highly significant association between anti–EB nuclear antigen titers and risk of MS as we originally reported, but it has become apparent that this association is strongly modified by age. Antibody titers of cases and controls were virtually identical in samples collected before age 20 years. However, while titers in controls remained constant, antibody titers of the cases increased, reaching a maximum between ages 25 and 29 years, followed by a plateau. As discussed in the article based on the corrected data, this is a new and important finding that may be critical to the understanding of the relation between EBV and MS." (Repost: MS Diagnosed Forums.)

Notice of Retraction / MS Diagnosed

AAN: Child-Onset Multiple Sclerosis More Likely to Have epstein-barr virus Antibodies than Controls. By Paula Moyer. Doctor's Guide 2003 Apr 8. Re BL Banwell et al, Viral Studies in Multiple Sclerosis, presented at the 55th Annual Meeting of the American Academy of Neurology. 25 children with MS compared with 75 age-matched controls. "EBV seropositivity differed markedly between paediatric MS patients and age-matched controls. Although 89% of paediatric MS patients were positive for EBV-VCA and EBV-EBNA, which indicated a temporally remote infection, 31% of controls had such infections (p 0.0004). Among the MS patients, 3 (12%) were negative for all three EBV antigens."

Banwell / Doctor's Guide 2003 article

The immune response against herpesvirus is more prominent in the early stages of MS. P Villoslada, C Juste, M Tintore, V Llorenc, G Codina, P Pozo-Rosich, X Montalban. Neurology 2003 Jun 24;60(12):1944-1948. "A strong association was found between anti-HHV-6 immunoglobulin M antibodies and early MS (clinically isolated syndromes at high risk for MS, and short duration active relapsing-remitting MS) when compared with healthy controls and secondary progressive MS. Moreover, in this group of patients, titers for anti-EBV immunoglobulin G were also elevated."

Villoslada - Neurology 2003 abstract / PubMed

Epstein-Barr virus in pediatric multiple sclerosis. S Alotaibi, J Kennedy, R Tellier, D Stephens, B Banwell. JAMA 2004 Apr 21;291(15):1875-1879. 30 pediatric MS patients, 90 emergency department controls, 53 healthy controls. "Serological evidence for remote EBV infection was present in 83% of pediatric MS patients compared with 42% of emergency department and healthy controls (P<.001). Five pediatric MS patients were negative for all 3 EBV antigens."

Alotaibi / JAMA 2004 full article

An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. P Sundstrom, P Juto, G Wadell, G Hallmans, A Svenningsson, L Nystrom, J Dillner, L Forsgren. Neurology 2004 Jun 22;62(12):2277-2282. "All cases showed signs of past EBV infection. High activity to EBNA-1 and HHV-6 significantly (borderline significance for HHV-6) increased the risk for MS in prospective sera. A discrepancy between activities to EBNA-1 and VCA was striking in MS samples collected less than 5 years before relapsing-remitting MS onset, where high activity to EBNA-1 significantly increased, and high VCA activity significantly decreased the risk for MS."

Sundstrom - Neurology 2004 abstract / PubMed

Plasma viral load of Epstein-Barr virus and risk of multiple sclerosis. HJ Wagner, KL Munger, A Ascherio. Eur J Neurol 2004 Dec;11(12):833-834. "Presence of EBV in plasma was associated with an increased risk of MS (relative risk = 2.5, 95% CI 0.78-7.8, P = 0.12). Adjusting for smoking, ancestry, and latitude of residence at birth did not materially change this result."

Wagner - Eur J Neurol 2004 abstract / PubMed

Temporal relationship between elevation of epstein-barr virus antibody titers and and initial onset of neurological symptoms in multiple sclerosis. LI Levin, KL Munger, MV Rubertone, CA Peck, ET Lennette, D Spiegelman, A Ascherio. JAMA 2005 May 25;293(20):2496-2500. In 83 cases from US military personnel, raised levels of antibodies to EBV predicted the development of MS.

Levin - JAMA 2005 abstract / PubMed

In patients who joined a health plan between 1965 and 1974, "The average concentration of anti–Epstein-Barr virus antibodies was significantly higher among individuals who had developed MS than among those who hadn't -- those with four times the level of antibodies were approximately twice as likely to develop MS. The elevated levels became evident between 15 and 20 years before patients first experienced the neurological symptoms of MS and remained higher afterward, the researchers reported." (Epstein-Barr Virus May Be Associated with Multiple Sclerosis. Doctor's Guide News, April 11, 2006. Re: Gerald N. DeLorenze et al., to be published in Archives of Neurology, June 2006.) "The relative risk of MS associated with a 4-fold increase in antibody titers was 2.1 (95% confidence interval, 1.1-3.8) for the EBNA complex and 1.8 (95% confidence interval, 1.1-2.9) for EBNA-1. Elevations of antibody titers to the EBNA complex and EBNA-1 among MS cases first occurred between 15 to 20 years before the onset of symptoms and persisted thereafter." (Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. GN DeLorenze, KL Munger, ET Lennette, N Orentreich, JH Vogelman, A Ascherio. Arch Neurol 2006 Jun;63(6):839-844.)

DG News, Apr. 11, 2006 / Doctors Guide
DeLorenze - Arch Neurol 2006 abstract / PubMed
DeLorenze / Arch Neurol 2006 full article

High seroprevalence of Epstein-Barr virus in children with multiple sclerosis. D Pohl, B Krone, K Rostasy, E Kahler, E Brunner, M Lehnert, HJ Wagner, J Gärtner, F Hanefeld. Neurology 2006 Dec 12;67(11):2063-2065. In 147 pediatric patients with multiple sclerosis (MS) and paired controls, "The children with MS showed a near-complete seropositivity for EBV antibody against virus capsid antigen (98.6% vs 72.1% in controls, p = 0.001) but did not display serologic evidence for a recent EBV infection. EBV antibody concentrations of pediatric patients with MS were significantly higher vs controls."

Pohl - Neurology 2006 abstract / PubMed

Correlations between Epstein-Barr virus antibody levels and risk factors for multiple sclerosis in healthy individuals. TR Nielsen, M Pedersen, K Rostgaard, M Frisch, H Hjalgrim. Mult Scler 2007 Apr;13(3):420-423. In a cross-sectional study in Denmark of 517 healthy individuals, "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."

Nielsen - Mult Scler 2007 abstract / PubMed

Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. B Banwell, L Krupp, J Kennedy, R Tellier, S Tenembaum, J Ness, A Belman, A Boiko, O Bykova, E Waubant, JK Mah, C Stoian, M Kremenchutzky, MR Bardini, M Ruggieri, M Rensel, J Hahn, B Weinstock-Guttman, EA Yeh, K Farrell, M Freedman, M Iivanainen, M Sevon, V Bhan, ME Dilenge, D Stephens, A Bar-Or. Lancet Neurol 2007 Sep;6(9):773-781. "Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons)."

Banwell - Lancet Neurol 2007 abstract / PubMed

The relationship between HLA-DRB1 alleles and optic neuritis in Irish patients and the risk of developing multiple sclerosis. I Tuwir, C Dunne, J Crowley, T Saddik, R Murphy, L Cassidy. Br J Ophthalmol 2007 Oct;91(10):1288-1292. 78 patients with a clinical diagnosis of acute optic neuritis versus 250 healthy bone marrow donors. "An ON/MS positive patient was 3.4 times more likely than an ON/MS negative patient to be DRB1*15 positive... Female gender was significantly increased among ON/MS positive patients with a p value of 0.0053."

Tuwir - Br J Ophthalmol 2007 abstract / PubMed

[Deliberate anti-smoker fraud exploiting confounding by infection] Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Y Mikaeloff, G Caridade, M Tardieu, S Suissa; KIDSEP study group. Brain 2007 Oct;130(Pt 10):2589-2995. This study included no data on EBV infection.

Mikaeloff - Brain 2007 abstract / PubMed

"Contrary to an earlier report, smoking appears to have no effect on the progression of multiple sclerosis (MS), according to a study published in the October 9, 2007, issue of Neurology, the medical journal of the American Academy of Neurology. Researchers in the Netherlands surveyed 364 people at both the initial and secondary stages of MS, 263 of whom were smokers... 'Because the cause of MS as well as reasons for progression is generally unknown, there have been many genetic and environmental factors tested,' said study author Marcus W. Koch, MD, with the University of Groningen in the Netherlands.'Cigarette smoking is one more factor we can rule out.' Koch says the finding is in conflict with a previous study that suggested cigarette smoking increased the rate of MS progress. 'Differences in that study's size and methodology may account for this discrepancy. Since our study involved more people, and participants were personally interviewed, we feel it makes our results more accurate.'" (Smoking Has No Effect on Progression of Multiple Sclerosis. DGNews, Oct. 8, 2007; Re: Cigarette smoking and progression in multiple sclerosis. M Koch, A van Harten, M Uyttenboogaart, J De Keyser. Neurology 2007 Oct 9;69(15):1515-1520.)

Smoking Has No Effect on Progression of Multiple Sclerosis, Oct. 8, 2007 / Doctors Guide
Koch - Neurol 2007 abstract / PubMed

Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. B Serafini, B Rosicarelli, D Franciotta, R Magliozzi, R Reynolds, P Cinque, L Andreoni, P Trivedi, M Salvetti, A Faggioni, F Aloisi. J Exp Med 2007 Nov 26;204(12):2899-2912. "Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8+ T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells."

Serafini - J Exp Med 2007 abstract / PubMed

Integrating risk factors. HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. PL De Jager, KC Simon, KL Munger, JD Rioux, DA Hafler, A Ascherio. Neurology 2008 Mar 25;70(13 Pt 2):1113-1118. "The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers."

De Jager - Neurology 2008 abstract / PubMed

Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. S Jilek, M Schluep, P Meylan, F Vingerhoets, L Guignard, A Monney, J Kleeberg, G Le Goff, G Pantaleo, RA Du Pasquier. Brain 2008 Jul;131(Pt 7):1712-1721. "In the whole cohort, the rate of EBV and CMV infections were 99% and 51%, respectively. The frequency of IFN-gamma secreting EBV-specific CD8+ T cells in patients with clinically isolated syndrome (CIS) was significantly higher than that found in patients with relapsing-remitting MS (RR-MS), secondary-progressive MS, primary-progressive MS, patients with other neurological diseases and healthy controls. The shorter the interval between MS onset and our assays, the more intense was the EBV-specific CD8+ T-cell response. Confirming the above results, we found that EBV-specific CD8+ T-cell responses decreased in 12/13 patients with CIS followed prospectively for 1.0 +/- 0.2 years. In contrast, there was no difference between categories for EBV-specific CD4+ T cell, or for CMV-specific CD4+ and CD8+ T-cell responses."

Jilek / Brain 2008 full article

EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. JD Lünemann, I Jelcić, S Roberts, A Lutterotti, B Tackenberg, R Martin, C Münz. J Exp Med 2008 Aug 4;205(8):1763-1773. 24 untreated patients with MS and 24 healthy virus carriers matched for MS-associated HLA alleles. "MS patients showed selective increase of T cell responses to the EBV nuclear antigen 1 (EBNA1), the most consistently recognized EBV-derived CD4(+) T cell antigen in healthy virus carriers, but not to other EBV-encoded proteins. In contrast, influenza and human cytomegalovirus-specific immune control was unchanged in MS. The enhanced response to EBNA1 was mediated by an expanded reservoir of EBNA1-specific central memory CD4(+) T helper 1 (Th1) precursors and Th1 (but not Th17) polarized effector memory cells. In addition, EBNA1-specific T cells recognized myelin antigens more frequently than other autoantigens that are not associated with MS. Myelin cross-reactive T cells produced IFN-gamma, but differed from EBNA1-monospecific cells in their capability to produce interleukin-2, indicative of a polyfunctional phenotype as found in controlled chronic viral infections."

Lünemann - J Exp Med 2008 full article / PubMed CentralLünemann / J Exp Med 2008 full article

Gene-environment interactions between HLA B7/A2, EBV antibodies are associated with MRI injury in multiple sclerosis. R Zivadinov, B Weinstock-Guttman, M Zorzon, L Uxa, M Serafin, A Bosco, A Bratina, C Maggiore, A Grop, MA Tommasi, B Srinivasaraghavan, M Ramanathan. Neuroimmunol 2009 Apr 30;209(1-2):123-130. 93 MS patients (62 females; 31 males) and 122 healthy controls. "The presence of HLA B7 was associated with increased T1-LV and trends indicating increased anti-EBV VCA IgG levels, higher disability (EDSS) and more destructive MRI parameters (increased T2-LV and decreased BPF). The presence of HLA A2 was associated with lower EDSS and a trend toward decreased anti-EBV VCA IgG levels; the associations with MRI variables were not significant. The HLA B7-A2 haplotype was significantly associated with higher T2-LV and T1-LV and a trend toward lower BPF was observed."

Zivadinov - Neuroimmunol 2009 abstract / PubMed

Serum IgG repertoire in clinically isolated syndrome predicts multiple sclerosis. H Zéphir, D Lefranc, S Dubucquoi, J de Seze, L Boron, L Prin, P Vermersch. Mult Scler 2009 May;15(5):593-600. IgG of 50 patients with clinically isolated syndrome, 82 MS patients, 27 healthy controls, and 42 patients with other inflammatory neurological diseases. "About 78% of scores obtained from CIS patients were located in the 'MS area.' During the follow-up (3.5 +/- 1.3 years), 28 patients fulfilled the McDonald criteria for MS, 15 patients remained CIS, and 7 patients developed OIND. Among the patients with an LDA score in the 'MS area,' 61.5% converted to MS."

Zéphir - Mult Scler 2009 abstract / PubMed

Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis. R Zivadinov, M Zorzon, B Weinstock-Guttman, M Serafin, A Bosco, A Bratina, C Maggiore, A Grop, MA Tommasi, B Srinivasaraghavan, M Ramanathan. J Neurol Neurosurg Psychiatry 2009 Jun;80(6):620-625. 135 patients with MS (86 women, 49 men). "The results suggest that the presence of anti-EBV antibodies is associated with MRI markers of [grey matter] atrophy in MS and with increased loss of brain volume over 3 years."

Zivadinov - J Neurol Neurosurg Psychiatry 2009 abstract / PubMed

Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. RA Farrell, D Antony, GR Wall, DA Clark, L Fisniku, J Swanton, Z Khaleeli, K Schmierer, DH Miller, G Giovannoni. Neurology 2009 Jul 7;73(1):32-38. 5-year prospective of 50 clinically isolated syndrome, 25 relapsing-remitting, and 25 primary progressive MS patients. "All subjects had serologic evidence of previous EBV infection, but no lytic reactivation was detected. Significant differences in EBNA-1 IgG titers were found between subgroups, highest in the RRMS cohort compared with PPMS (p < 0.001) and CIS (p < 0.001). Gd-enhancing lesions on MRI correlated with EBNA-1 IgG (r = 0.33, p < 0.001) and EBNA-1:VCA IgG ratio (r = 0.36, p < 0.001). EBNA-1 IgG also correlated with change in T2 lesion volume (r = 0.27, p = 0.044) and Expanded Disability Status Scale score (r = 0.3, p = 0.035)."

Farrell - Neurology 2009 abstract / PubMed

Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. SN Willis, C Stadelmann, SJ Rodig, T Caron, S Gattenloehner, SS Mallozzi, JE Roughan, SE Almendinger, MM Blewett, W Brück, DA Hafler, KC O'Connor. Brain 2009 Dec;132(Pt 12):3318-3328. "EBV could not be detected in any of the multiple sclerosis specimens containing white matter lesions by any of the methods employed" (in situ hybridization, immunohistochemistry and two independent real-time polymerase chain reaction (PCR) methodologies).

Willis - Brain 2009 abstract / PubMed

Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. JD Lünemann, M Tintoré, B Messmer, T Strowig, A Rovira, H Perkal, E Caballero, C Münz, X Montalban, M Comabella. Ann Neurol 2010 Feb;67(2):159-169. 147 patients with clinically isolated syndrome, 50 controls. "Compared with controls, CIS patients showed increased humoral (p < 0.0001) and cellular (p = 0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins... EBNA1 was the only viral antigen with which immune responses correlated with number of T2 lesions (p = 0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p = 0.012 at both 1 and 5 years), presence of new T2 lesions (p = 0.003 and p = 0.028 at 1 and 5 years), and Expanded Disability Status Scale score (p = 0.015 and p = 0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria (hazard ratio [95% confidence interval], 2.2 [1.2-4.3]; p = 0.003)."

Lünemann - Ann Neurol 2010 abstract / PubMed

Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. KC Simon, IAF van der Mei, KL Munger, A Ponsonby, J Dickinson, T Dwyer, P Sundström, and A Ascherio. Neurology 2010 Apr 27;74(17):1365-1371. 442 cases and 865 controls from 3 MS case-control studies (Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study). Key finding: "The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers." From the Harvard School of Public Health, the mothership of charlatanism, this study was published for the sole purpose of anti-smoking hate propaganda which omitted this key observation. Instead, they claimed that "the effect of high Epstein-Barr antibody levels was stronger among past or current smokers." (MS Risk Linked to Smoking and Viral Antibodies. By Michael Smith. MedPage Today, Apr. 7, 2010.) And their claim of interaction between EBNA1 IgG and smoking was not replicated.

Simon / Neurology 2010 abstract
MS Risk Linked to Smoking and Viral Antibodies / MedPage 2010

Ascherio's anti-smoking propaganda funding from NINDS: $628,142 for "Vitamin D, Epstein-Barr virus infection, and cigarette smoking and risk of multiple sclerosis" in FY2011. He already believes that cigarette smoking is an important risk factor for MS. From the Finnish Mortality Cohort, "The specific hypotheses to be tested among the mothers are that pre-diagnostic low vitamin D levels, elevated EBV IgG antibody titers, and elevated cotinine levels are associated with an increased risk of MS, and similarly among the offspring that in utero exposure to low vitamin D levels, elevated EBV antibody titers, and elevated cotinine will be associated with an increase risk of MS as an adult... The proposed project is expected to contribute to the identification of modifiable risk factors for MS, such as vitamin D and smoking, and their interaction with Epstein-Barr virus infection." In other words, another piece of deceitful propaganda just like the previous one. (Project Number 1R01NS073633-01, at the Harvard School of Public Health.)

Project Number 1R01NS073633-01 / National Institutes of Health

Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. LI Levin, KL Munger, EJ O'Reilly, KI Falk, A Ascherio. Ann Neurol 2010 Jun;67(6):824-830. 305 individuals who developed MS and 610 matched controls from the Department of Defense Serum Repository. "Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008). We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection."

Levin - Ann Neurol 2010 abstract / PubMed

Upregulation of Immunoglobulin-related Genes in Cortical Sections from Multiple Sclerosis Patients. O Torkildsen, C Stansberg, SM Angelskĺr, EJ Kooi, JJ Geurts, P van der Valk, KM Myhr, VM Steen, L Bř. Brain Pathol 2010 Jul;20(4):720-729. "We observed a massive upregulation of immunoglobulin (Ig)-related genes in cortical sections of MS patients. Using immunohistochemistry, the activation of Ig genes seems to occur within plasma cells in the meninges... we screened the brain samples for the presence of EBV by real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry, but no evidence of active or latent EBV infection was detected. This study demonstrates that genes involved in the synthesis of Igs are upregulated in MS patients and that this activation is caused by a small number of meningeal plasma cells that are not infected by EBV."

Torkildsen - Brain Pathol 2010 abstract / PubMed

Relation between Epstein-Barr virus and multiple sclerosis: analytic study of scientific production. O Santiago, J Gutierrez, A Sorlozano, J de Dios Luna, E Villegas, O Fernandez. Eur J Clin Microbiol Infect Dis 2010 Jul;29(7):857-866. Meta-analysis of 30 published studies. "We found an association between MS and an exposure to EBV, studied by determining the anti-VCA IgG antibodies (odds ratio [OR] = 5.5; 95% confidence interval [CI] = 3.37-8.81; p < 0.0001), anti-complex EBNA IgG (OR = 5.4; 95% CI = 2.94-9.76; p < 0.0001) and anti-EBNA-1 IgG (OR = 12.1; 95% CI = 3.13-46.89; p < 0.0001). No significant association could be found when studying anti-EA IgG (OR = 1.3; 95% CI = 0.68-2.35; p = 0.457), EBV DNA in serum (OR = 1.8; 95% CI = 0.99-3.36; p = 0.051) and DNA in brain tissues and in cerebrospinal fluid (CSF) (OR = 0.9; 95% CI = 0.38-2.01; p = 0.768)."

Santiago - Eur J Clin Microbiol Infect Dis 2010 abstract / PubMed

No evidence for intrathecal IgG synthesis to Epstein Barr virus nuclear antigen-1 in multiple sclerosis. N Jafari, GP van Nierop, GM Verjans, AD Osterhaus, JM Middeldorp, RQ Hintzen. J Clin Virol 2010 Sep;49(1):26-31. 114 MS patients, 62 disease controls. "No difference was observed in the overall anti-EBV antibody diversity, but EBNA-1 reactivity was increased in MS patients versus controls for immunoblot and ELISA (p<0.0001)... Anti-EBNA-1(394-451) IgG levels in serum and CSF were significantly higher in MS patients compared to controls. However, normalization for total IgG content of paired serum and CSF samples abrogated this disease association."

Jafari - J Clin Virol 2010 abstract / PubMed

Controversial role of epstein-barr virus in multiple sclerosis. N Fatima, MP Toscano, SB Hunter, C Cohen. Appl Immunohistochem Mol Morphol 2011 May;19(3):246-252. Seventeen MS (16 brain biopsies and 1 autopsy brain) and 12 autopsy brains with no pathologic abnormalities; 11 brain biopsies of encephalitis and 4 brain biopsies of progressive multifocal leukoencephalopathy. None were positive for LMP1 or EBER.

Fatima - Appl Immunohistochem Mol Morphol 2011 abstract / PubMed

Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. B Banwell, A Bar-Or, DL Arnold, D Sadovnick, S Narayanan, M McGowan, J O'Mahony, S Magalhaes, H Hanwell, R Vieth, R Tellier, T Vincent, G Disanto, G Ebers, K Wambera, MB Connolly, J Yager, JK Mah, F Booth, G Sebire, D Callen, B Meaney, ME Dilenge, A Lortie, D Pohl, A Doja, S Venketaswaran, S Levin, EA Macdonald, D Meek, E Wood, N Lowry, D Buckley, C Yim, M Awuku, P Cooper, F Grand'maison, JB Baird, V Bhan, RA Marrie. Lancet Neurol 2011 May;10(5):436-445. 302 children in Canada. "Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis."

Banwell - Lancet Neurol 2011 abstract / PubMed

Common viruses associated with lower pediatric multiple sclerosis risk. E Waubant, EM Mowry, L Krupp, T Chitnis, EA Yeh, N Kuntz, J Ness, D Chabas, J Strober, J McDonald, A Belman, M Milazzo, M Gorman, B Weinstock-Guttman, M Rodriguez, JR Oksenberg, JA James; US Pediatric MS Network. Neurology 2011 Jun 7;76(23):1989-1995. 189 MS patients, 66 controls. "Epstein-Barr nuclear antigen-1 seropositivity was associated with an increased odds of MS (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.52-9.38, p=0.004) in analyses adjusted for age, sex, race, ethnicity, and HLA-DRB1*1501/1503 status. In multivariate analyses including EBV status, a remote infection with CMV (OR 0.27, 95% CI 0.11-0.67, p=0.004) was associated with a lower risk of developing MS. Although a remote infection with HSV-1 was not associated with an increased odds of MS, a strong interaction was found between HSV-1 status and HLA-DRB1 in predicting MS (p<0.001). HSV-1 was associated with an increased risk of MS in those without a DRB1*15 allele (OR 4.11, 95% CI 1.17-14.37, p=0.03), whereas the effect was reversed in those who were DRB1*15-positive (OR 0.07, 95% CI 0.02-0.32, p=0.001)."

Waubant - Neurology 2011 full article / PubMed Central

Current and past Epstein-Barr virus infection in risk of initial CNS demyelination. RM Lucas, AL Ponsonby, K Dear, P Valery, MP Pender, JM Burrows, SR Burrows, C Chapman, A Coulthard, DE Dwyer, T Dwyer, T Kilpatrick, ML Lay, AJ McMichael, BV Taylor, IA van der Mei, D Williams. Neurology 2011 Jul 26;77(4):371-379. 282 incident cases, 558 matched controls. "There were no significant case-control differences in the proportion with detectable EBV DNA (55.8% vs 50.5%, respectively, p = 0.28), or in quantitative EBV DNA load (p = 0.33). Consistent with previous work, higher anti-EBV-specific immunoglobulin G (IgG) titers and a history of infectious mononucleosis were associated with increased FCD risk and there was an additive interaction with HLA-DRB1*1501 status."

Lucas - Neurology 2011 abstract / PubMed

Epstein-Barr virus in the multiple sclerosis brain: a controversial issue--report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Lassmann H, Niedobitek G, Aloisi F, Middeldorp JM; NeuroproMiSe EBV Working Group. Brain 2011 Sep;134(Pt 9):2772-2786. Review.

Lassmann - Brain 2011 full article / PubMed Central

Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel. K Munger, L Levin, E O'Reilly, K Falk, A Ascherio. Mult Scler 2011 Oct;17(10):1185-1193. "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."

Munger - Mult Scler 2011 abstract / PubMed

Epstein-Barr virus nuclear antigen-1 B-cell epitopes in multiple sclerosis twins. R Mechelli, J Anderson, D Vittori, G Coarelli, V Annibali, S Cannoni, F Aloisi, M Salvetti, J James, G Ristori. Mult Scler 2011 Nov;17(11):1290-1294. 12 pairs of monozygotic (MZ) twins (9 MS-discordant, 3 healthy), 3 non-twin patients and 2 healthy subjects. "Compared with healthy individuals, and similarly to what has been described in infectious mononucleosis (IM) patients, affected co-twins and non-twin patients had a significantly increased response to another EBNA-1 epitope (aa. 401-411)."

Mechelli - Mult Scler 2011 abstract / PubMed

High frequency of co-infection by Epstein-Barr virus types 1 and 2 in patients with multiple sclerosis. A Santón, E Cristóbal, M Aparicio, A Royuela, LM Villar, JC Alvarez-Cermeńo. Mult Scler 2011 Nov;17(11):1295-1300. "EBV was detected in 70 out of 75 patients (93.3%) and in 123 of 186 controls (66.1%). Among positive cases, type 1 was found in 6 patients (8.6%) and 40 controls (32.5%), type 2 in 1 patient (1.4%) and 37 controls (30.1%), and dual-infections by both EBV types were detected in 63 patients (90%) and 46 controls (37.4%). Logistic regression models showed that MS was significantly associated with the presence of EBV (p<0.001) and also with dual type infections (p<0.001)."

Santón - Mult Scler 2011 abstract / PubMed

Epstein-Barr virus and multiple sclerosis: interaction with HLA. E Sundqvist, P Sundström, M Lindén, AK Hedström, F Aloisi, J Hillert, I Kockum, L Alfredsson, T Olsson. Genes Immun 2012 Jan;13(1):14-20. "IM showed association with MS, odds ratio (OR)=1.89 (1.45-2.48% confidence interval (CI)), as did raised EBNA1 IgG OR=1.74 (1.38-2.18 95%CI). All EBNA1 fragment IgGs were associated with MS risk. However, EBNA1 fragment 385-420 IgG levels were more strongly associated to MS than total EBNA1 IgG, OR=3.60 (2.75-4.72 95%CI), and also interacted with both DRB1(*)15 and absence of A(*)02, AP 0.60 (0.45-0.76 95%CI) and AP 0.39 (0.18-0.61 95%CI), respectively. The observed interaction between HLA class I and II genotype and reactivity to EBV-related epitopes suggest that the mechanism through which HLA genes influence the risk of MS may, at least in part, involve the immune control of EBV infection."

Sundqvist - Genes Immun 2012 abstract / PubMed

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. JS Tzartos, G Khan, A Vossenkamper, M Cruz-Sadaba, S Lonardi, E Sefia, A Meager, A Elia, JM Middeldorp, M Clemens, PJ Farrell, G Giovannoni, UC Meier. Neurology 2012 Jan 3;78(1):15-23. "We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains." They also determined that "EBERs elicited IFNα production in vitro."

Tzartos - Neurology 2012 abstract / PubMed

HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis. S Jilek, M Schluep, A Harari, M Canales, A Lysandropoulos, A Zekeridou, G Pantaleo, RA Du Pasquier. J Immunol 2012 May 1;188(9):4671-4680. "We found that MS patients had a lower or a higher prevalence of HLA-A2 and HLA-B7, respectively. Using HLA class I tetramers in HLA-B7(+) MS patients, there was a higher prevalence of MS patients with HLA-B*0702/EBV(RPP)-specific CD8(+) T cells ex vivo. However, the magnitude of the HLA-B*0702/EBV(RPP)-specific and HLA-B*0702/CMV(TPR)-specific CD8(+) T cell response (i.e., the percentage of tetramer(+) CD8(+) T cells in a study subject harboring CD8(+) T cells specific for the given epitope) was lower in MS patients. No differences were found using other tetramers. After stimulation with the HLA-B*0702/EBV(RPP) peptide, the production of IL-2, perforin, and granzyme B and the cytotoxicity of HLA-B*0702/EBV(RPP)-specific CD8(+) T cells were decreased."

Jilek - J Immunol 2012 abstract / PubMed

Assessment of Epstein-Barr virus in blood from patients with multiple sclerosis. GM Hon, MS Hassan, SJ van Rensburg, RT Erasmus, TE Matsha. Metab Brain Dis 2012 Sep;27(3):311-318. "Anti-EBV-VCA IgM positive cases were significantly increased in patients (controls: 23.3%; patients; 41.9%; P = 0.046). The IgM to IgG immune status ratio was near-significantly higher in patients with relapse episodes in the year preceding blood sampling (P = 0.058)."

Hon - Metab Brain Dis 2012 abstract / PubMed

Epstein-Barr virus peptide presented by HLA-E is predominantly recognized by CD8(bright) cells in multiple sclerosis patients. PB Jřrgensen, AH Livbjerg, HJ Hansen, T Petersen, P Höllsberg. PLoS One 2012;7(9):e46120. Relapsing remitting MS patients "had increased frequency of CD8(bright) cells recognizing HLA-E/A2 (p=0.006) and HLA-E/BZLF1 (p=0.016). Conversely, MS-RR had fewer CD8(dim) cells that recognized HLA-E/BZLF1 (p=0.001), but this could be attributed to the overall lower number of CD8(dim) cells in MS-RR... Whereas HLA-E/A2 was predominantly recognized by CD8(dim) cells, HLA-E/BZLF1 was predominantly recognized by CD8(bright) cells in MS-RR and MS-PP, but not in HC."

Jřrgensen - PLoS One 2012 full article / PubMed Central
Jřrgensen / PLoS One 2012 full article

Genetic and Infectious Profiles of Japanese Multiple Sclerosis Patients. S Yoshimura, N Isobe, T Yonekawa, T Matsushita, K Masaki, S Sato, Y Kawano, K Yamamoto, JI Kira; the South Japan Multiple Sclerosis Genetics Consortium. PLoS One 2012;7(11):e48592. 145 MS patients and 367 healthy controls. 71/71 (100.0% ) of HLA-DRB1*0405-negative patients, 48/56 (85.71%) of HLA-DRB1*0405-positive patients, and 143/156 (91.67%) of healthy controls were positive for EBNA by ELISA. DRB1*0405-positive patients had a younger age at onset and a more benign course.

Yoshimura / PLoS One 2012 full article

Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis. E Sundqvist, P Sundström, M Lindén, AK Hedström, F Aloisi, J Hillert, I Kockum, L Alfredsson, T Olsson. Neurology 2012 Sep 25;79(13):1363-1368. "[W]e observed interactions on the additive scale between EBNA1 IgG and DRB1*15 (AP = 0.34, 95% confidence interval 0.11-0.57, p = 5 × 10(-3)) and between EBNA1 IgG and absence of A*02 (AP = 0.36, 0.13-0.59, p = 2 × 10(-3)) but not between smoking and DRB1*15 and EBNA1 IgG. The interaction between EBNA1 IgG and DRB1*15 was not significant in the conditional analysis. CONCLUSION: We did not observe any interaction between EBNA1 IgG and smoking, regardless of scale used, and thus did not replicate the observations from Simon et al."

Sundqvist - Neurology 2012 abstract / PubMed

The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. J Pakpoor, G Disanto, JE Gerber, R Dobson, UC Meier, G Giovannoni, SV Ramagopalan. Mult Scler 2013 Feb;19(2):162-166. Twenty-two adult and three paediatric studies. "The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13-0.26)) and for paediatric MS was 0.18 (95% CI 0.11-0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03-0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22-0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0-0.43). CONCLUSION: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail."

Pakpoor - Mult Scler 2013 abstract / PubMed

Association of Epstein-Barr virus infection with multiple sclerosis in India. L Pandit, C Malli, A D'Cunha, R Shetty, B Singhal. J Neurol Sci 2013 Feb 15;325(1-2):86-89. 140 MS patients and 140 matched controls. "A modest difference was observed for EBNA1 (p=0.02) and EBV-VCA (p=0.03) titres in MS patients as compared to healthy controls. There was no association between EBNA1 titres and MS. High EBNA1 titre (>99.75U/l) was significantly associated with HLA DRBI*15:01 (OR=4.92. CI=1.07-22.57) status in MS patients but not in healthy controls (OR=1.19, CI=0.53-2.63)."

Pandit - J Neurol Sci 2013 abstract / PubMed

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. D Csuka, D Simon, R Hóbor, K Uray, Z Prohászka, Z Bánlaki, PK Jani, A Szilágyi, F Hudecz, K Rajczy, G Beke, A Boros Major, A Tordai, Z Illés, T Berki, L Czirják, G Füst. Clin Exp Immunol 2013 Mar;171(3):255-262. 301 SLE patients, 135 MS patients and 345 healthy controls. "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."

Csuka - Clin Exp Immunol 2013 abstract / PubMed

Evaluation of reactive Epstein-Barr Virus (EBV) in Iranian patient with different subtypes of multiple sclerosis (MS). N Ramroodi, AA Niazi, N Sanadgol, Z Ganjali, V Sarabandi. Braz J Infect Dis 2013 Mar-Apr;17(2):156-163. 78 MS patients and 123 controls. "Our results demonstrated increased titer of both anti-Epstein-Barr virus-IgG and IgM antibodies in patients (91.02% vs 82.11% in controls, p<0.001 and 14.1% vs 4.06% in controls, p<0.001, respectively). Overall, Epstein-Barr virus reactivation was found in 68.75% of subtypes of multiple sclerosis, 4.54% of multiple sclerosis primary subtype, and in only 3.25% of healthy control subjects. Moreover, in samples of patients with disease relapse (exacerbation) cell free viral DNA was elevated in contrast to other patients (p<0.001)."

Ramroodi - Braz J Infect Dis 2013 abstract / PubMed

Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. E Waubant, EM Mowry, L Krupp, T Chitnis, EA Yeh, N Kuntz, J Ness, A Belman, M Milazzo, M Gorman, B Weinstock-Guttman, M Rodriguez, JA James. Mult Scler 2013 Jun;19(7):891-895. 189 cases, 38 controls. "The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals (p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals."

Waubant - Mult Scler 2013 author manuscript / PubMed Central

Radioactive in situ hybridization for Epstein-Barr virus-encoded small RNA supports presence of Epstein-Barr virus in the multiple sclerosis brain. B Serafini, L Muzio, B Rosicarelli, F Aloisi. Brain 2013 Jul;136(7):e233. Letter.

Serafini / Brain 2013 extract

Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes. B Weinstock-Guttman, D Horakova, R Zivadinov, M Tamańo-Blanco, D Badgett, M Tyblova, M Vaneckova, Z Seidl, J Krasensky, N Bergsland, DP Ramasamy, J Hagemeier, E Havrdova, M Ramanathan. J Neuroimmunol 2013 Oct 15;263(1-2):121-127. 118 CIS patients. "Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti-EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C."

Weinstock-Guttman - J Neuroimmunol 2013 abstract / PubMed

Epstein-Barr virus in oral shedding of children with multiple sclerosis. C Yea, R Tellier, P Chong, G Westmacott, RA Marrie, A Bar-Or, B Banwell; On behalf of the Canadian Pediatric Demyelinating Disease Network. Neurology 2013 Oct 15;81(16):1392-1399. 22 patients, 77 controls. "Nineteen of the 22 (86.4%) children with MS were seropositive for remote EBV infection compared to 35 out of 77 (45.5%) healthy controls (p = 0.008). Baseline analysis of mouth swabs revealed a higher proportion of EBV-positive samples from EBV-seropositive patients with MS compared to EBV-seropositive healthy controls (52.6% vs 20%, p = 0.007). Longitudinal analysis of monthly swabs revealed average EBV detection rates of 50.6% in patients with MS and 20.4% in controls (p = 0.01)... Changes in the predominant EBV genetic variants were detected more frequently in patients with MS; however, no specific EBV genetic variant was preferentially associated with MS."

Yea - Neurology 2013 abstract / PubMed

EBNA-1 IgG titers in Sardinian multiple sclerosis patients and controls. G Mameli, D Cossu, E Cocco, S Masala, J Frau, MG Marrosu, LA Sechi. J Neuroimmunol 2013 Nov 15;264(1-2):120-122. Number of patients not given in abstract. "Our results show a higher serum prevalence of EBNA-1 IgG in MS patients compared to healthy controls. Moreover, analyzing a subset of patients treated for 6 months with IFN-β, we observed a decrease in their EBNA-1 specific IgG titers."

Mameli - J Neuroimmunol 2013 abstract / PubMed

Combining HLA-DR risk alleles and anti-Epstein-Barr virus antibody profiles to stratify multiple sclerosis risk. K Strautins, M Tschochner, I James, L Choo, D Dunn, M Pedrini, A Kermode, W Carroll, D Nolan. Mult Scler 2014 Mar;20(3):286-294. 426 MS patients and 186 healthy controls. "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."

Strautins - Mult Scler 2014 abstract / PubMed

Epstein-Barr virus in multiple sclerosis. HS Abdelrahman, HS Selim, MH Hashish, LI Sultan. J Egypt Public Health Assoc 2014 Aug;89(2):90-95. 75 MS patients and non-MS controls. "Seventy MS patients (93.3%) were positive for EBNA1 IgG compared with 68 controls (90.7%). In MS patients, the mean EBNA1 IgG serum level was 310.91 (±131.05) U/ml; meanwhile, among controls the mean serum EBNA IgG level was 177.81 (±104.98) U/ml.All patients with MS were positive for VCA IgG, whereas only 60 (80.0%) controls were positive. In the MS group, the VCA IgG mean level was 302.19 (±152.11) U/ml compared with 167.94 (±111.79) U/ml in controls. The differences in the serum levels of both markers between the two groups were statistically significant (P<0.001)."

Abdelrahman - J Egypt Public Health Assoc 2014 abstract / PubMed

Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies. M Castellazzi, C Contini, C Tamborino, F Fasolo, G Roversi, S Seraceni, R Rizzo, E Baldi, M Tola, T Bellini, E Granieri, E Fainardi. J Neuroinflammation 2014 Nov 13;11(1):188. 100 relapsing-remitting MS patients and 200 controls with other inflammatory and noninflammatory neurological disorders. "Levels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed."

Castellazzi - J Neuroinflammation 2014 full article / PubMed Central
Castellazzi / J Neuroinflammation 2014 full article

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. S Kvistad, KM Myhr, T Holmřy, S Bakke, AG Beiske, KS Bjerve, H Hovdal, K Lřken-Amsrud, F Lilleĺs, R Midgard, G Njřlstad, T Pedersen, JS Benth, S Wergeland, O Torkildsen. Mult Scler 2014 Dec;20(14):1833-1840. 87 MS patients followed for two years. "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)."

Kvistad - Mult Scler 2014 abstract / PubMed

Targeting Epstein-Barr virus infection as an intervention against multiple sclerosis. D Jons, P Sundström, O Andersen. Acta Neurol Scand 2015 Feb;131(2):69-79. Review. "There is an important immunogenetic etiological factor for multiple sclerosis. However, a general assumption is that immune defense genes are activated by the environment, basically by infections. We contend that the relationship between infectious mononucleosis and multiple sclerosis cannot be completely explained by genetics and inverse causality. Epstein-Barr infection as indicated by positive serology is an obligatory precondition for multiple sclerosis, which is a stronger attribute than a risk factor only... A cohort in which intervention against Epstein-Barr infections was performed should be the object of neurological follow-up."

Jons - Acta Neurol Scand 2015 abstract / PubMed

Risk factors for multiple sclerosis and associations with anti-EBV antibody titers. TH Mouhieddine, H Darwish, L Fawaz, B Yamout, H Tamim, SJ Khoury. Clin Immunol 2015 Mar 21;158(1):59-66. 249 MS patients, 230 cpntrols. "EBV seropositivity was higher in MS patients compared to controls for both anti-VCA (99.5%; 97.2%) and anti-EBNA-1 (96.3%; 89.4%), and the titers were significantly higher in MS patients. MS patients had a significantly lower vitamin D level (15.5±8.3ng/ml) compared to controls (20.4±11.3ng/ml)."

Mouhieddine - Clin Immunol 2015 abstract / PubMed

Gender influence in EBV antibody response in multiple sclerosis patients from Kuwait. R Al-Temaimi, R Alroughani, S Jacob, F Al-Mulla. J Neuroimmunol 2015 Aug 15;285:57-61. 141 MS patients and 40 healthy controls. "Antibody titers against EBV were significantly elevated in MS patients compared to healthy controls (anti-EBNA1, p=0.008; anti-VCA, p=0.028). MS males had higher antibody titers to EBNA1 than healthy male controls (p=0.005) and female MS patients (p=0.03). HLA-DRB1*1501 haplotype genotypes failed to generate a risk association with MS or EBV antibody titers (p=0.6)."

Al-Temaimi - J Neuroimmunol 2015 abstract / PubMed

Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. R Zivadinov, N Cerza, J Hagemeier, E Carl, D Badgett, DP Ramasamy, B Weinstock-Guttman, M Ramanathan. Neurol Neuroimmunol Neuroinflamm 2016 Jan 7;3(1):e190. 539 patients with MS, 66 patients with clinically isolated syndrome, 63 patients with other neurologic diseases, and 178 controls. "More than 30% of patients with MS and CIS presented with the highest quartile of anti-EBV-VCA and -EBNA-1 status compared to ≤10% of HC (p < 0.001)... Patients with MS with the highest quartile of anti-EBV-VCA showed significantly increased T2 lesion volume (p = 0.001), T1 lesion number (p = 0.002), and T1 lesion volume (p = 0.04) and decreased gray matter (p = 0.041) and cortical (p = 0.043) volumes compared to patients with MS with lower quartiles." There were no significant differences of MRI outcomes in other groups.

Zivadinov - Neurol Neuroimmunol Neuroinflamm 2016 abstract / PubMed

Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Y Zhou, G Zhu, JC Charlesworth, S Simpson Jr, R Rubicz, HH Göring, NA Patsopoulos, C Laverty, F Wu, A Henders, JJ Ellis, I van der Mei, GW Montgomery, J Blangero, JE Curran, MP Johnson, NG Martin, DR Nyholt, BV Taylor; ANZgene consortium. Mult Scler 2016 Jan 27 [Epub ahead of print]. 3599 cases from family cohort, plus 15,231 other MS cases. "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."

Zhou - Mult Scler 2016 abstract / PubMed

Serostatus of Epstein-Barr virus in Iranian MS patients. S Karampoor, H Zahednasab, AA Pirkouh, SH Monavari, S Ramagopalan, H Keyvani. Acta Neurol Belg 2016 Mar;116(1):43-46. 60 patients with MS and 50 healthy controls. "All MS patients to be seropositive for EBV as compared to 82 % of controls (p = 0.0006). A strong, significant association of MS with EBV infection was documented, similar to studies in first world populations."

Karampoor - Acta Neurol Belg 2016 abstract / PubMed

Strain Differences and Mechanisms

Identification of Epstein-Barr Virus Strain Variants in Hairy Leukoplakia and Peripheral Blood by Use of a Heteroduplex Tracking Assay. D Sitki-Green, RH Edwards, J Webster-Cyriaque, N Raab-Traub. J Virol 2002 Oct 1;76(19):9645-9656. "These analyses reveal that the nature of EBV infection can be very dynamic, with changes in relative strain abundance over time as well as the appearance of new strains."

Sitki-Green - J Virol 2002 Full Article / PubMed Central
Sitki-Green - J Virol 2002 Full Article

Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency of infection. B Neuhierl, R Feederle, W Hammerschmidt, HJ Delecluse. Proc Natl Acad Sci USA 2002 Nov 12;99(23):15036-15041. "We show here that the EBV BALF4 gene product, the glycoprotein gp110, dramatically enhances the ability to infect human cells... Analysis of several virus isolates showed that the amount of BALF4 present within mature virions markedly differed among these strains... gp110 constitutes an important virulence factor that determines infection of non-B cells by EBV."

Neuhierl - PNAS 2002 Full Article / PubMed Central
Neuhierl - PNAS 2002 Full Article

Epstein-Barr virus genotypes in multiple sclerosis. JW Lindsey, S Patel, J Zou. Acta Neurol Scand 2008 Feb;117(2):141-144. "We found a variety of LMP-1 sequences in both MS and controls, with no significant differences between the groups."

Lindsey - Acta Neurol Scand 2008 abstract / PubMed

Japanese macaque encephalomyelitis: A spontaneous multiple sclerosis-like disease in a nonhuman primate. MK Axthelm, DN Bourdette, GH Marracci, W Su, ET Mullaney, M Manoharan, SG Kohama, J Pollaro, E Witkowski, P Wang, WD Rooney, LS Sherman, SW Wong. Ann Neurol 2011 Sep;70(3):362-373. In a colony of Japanese macaques established in 1956, "Since 1986, 57 JMs spontaneously developed a disease characterized clinically by paresis of 1 or more limbs, ataxia, or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed, and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of 8 cases of JME revealed multiple gadolinium-enhancing T(1) -weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum, and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1% to 3% of the ONPRC colony per year." (Also: MS-Like Disease Found in Monkeys. By John Gever. Medpage Today, Jul. 1, 2011.)

Axthelm - Ann Neurol 2011 abstract / PubMed
MS-Like Disease Found in Monkeys / Medpage Today

Epstein-Barr Virus Genotypes and Strains in Central Nervous System Demyelinating Disease and Epstein-Barr Virus-Related Illnesses in Australia. ML Lay, RM Lucas, C Toi, M Ratnamohan, AL Ponsonby, DE Dwyer. Intervirology 2012;55(5):372-379. 55 subjects, including 17 with and 21 without CNS demyelination, and 17 with EBV-related diseases. "Both EBV genotypes, A and B, were detected (genotype A, 54/55, 98.2%; genotype B, 1/55, 1.8%). Within genotype A, GD1 was the most commonly detected strain (42/54, 77.7%), followed by B95-8 (9/54, 16.7%) and M-ABA (3/54, 5.6%). Genotype B, strain AG876, was found in one individual with CNS demyelinating disease." No disease-specific genotypes or strains were found.

Lay - Intervirology 2012 abstract / PubMed

Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis. C Casiraghi, I Shanina, S Cho, ML Freeman, MA Blackman, MS Horwitz. PLoS Pathog 2012;8(5): e1002715. "Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases."

Casiraghi / PLoS Pathog 2012 full article

CD8 T cell deficiency impairs control of Epstein-Barr virus and worsens with age in multiple sclerosis. MP Pender, PA Csurhes, CM Pfluger, SR Burrows. J Neurol Neurosurg Psychiatry 2012 Mar;83(3):353-354. 64 MS patients and 68 age- and sex-matched healthy subjects. "The mean percentage±SE of CD8 T cells was significantly decreased in MS patients (19.4±0.7) compared with healthy subjects (22.7±0.8, p<0.01, Mann–Whitney). The decrease in CD8 T cells was more pronounced in SPMS (18.8±1.0) and PPMS (16.9±1.7) than in RRMS (21.7±1.1). Strikingly, the proportion of CD8 T cells declined markedly with age in MS patients compared with healthy subjects."

Pender / J Neurol Neurosurg Psychiatry 2012 full article

EBV-specific immune responses in patients with multiple sclerosis responding to IFNβ therapy. M Comabella, K Kakalacheva, J Río, C Münz, X Montalban, JD Lünemann. Mult Scler 2012 May;18(5):605-609. 28 responsive patients over 2 years. "Clinically effective IFNβ-therapy was associated with a downregulation of proliferative T cell responses to the latent EBV nuclear antigen-1 (EBNA1). EBNA1-specific IgG responses as well as cellular and humoral immune responses to MHC class I restricted EBV antigens expressed during lytic replication and viral B cell transformation were similar before and after IFNβ therapy. Although HCMV-specific IgG levels slightly decreased, proliferative T-cell responses towards HCMV antigens remained unchanged during IFNβ therapy."

Comabella - Mult Scler 2012 abstract / PubMed

B-cell enrichment and epstein-barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. R Magliozzi, B Serafini, B Rosicarelli, G Chiappetta, C Veroni, R Reynolds, F Aloisi. J Neuropathol Exp Neurol 2013 Jan;72(1):29-41. Postmortem brain samples from 44 cases of secondary progressive MS. "Cells expressing EBV-encoded small RNA and plasma cells expressing EBV early lytic proteins (BZLF1, BFRF1) were present in all and most of the intracortical perivascular cuffs examined, respectively. Immunohistochemistry for CD8-positive cells, granzyme B, perforin, and CD107a indicated cytotoxic activity toward EBV-infected plasma cells that was consistently observed in infiltrated cortical lesions, suggesting active immune surveillance."

Magliozzi - J Neuropathol Exp Neurol 2013 abstract / PubMed

Structural and Dynamical Insights on HLA-DR2 Complexes That Confer Susceptibility to Multiple Sclerosis in Sardinia: A Molecular Dynamics Simulation Study. A Kumar, E Cocco, L Atzori, MG Marrosu, E Pieroni. PLoS One 2013;8(3):e59711. With the predisposing allele (DRB1*1501) there is "a higher degree of functional and molecular mimicry between the self [myelin basic protein] and the non-self [EBNA-1] peptide, thus leading to a higher possibility of T cell cross-reactivity, with potential autoimmune consequences... Moreover, we observe MBP and EBNA-1 distributions for the predisposing allele having an almost perfect overlap in region D3 at ~17.5 Ĺ, and a weaker overlap in region D2 at ~14.5 Ĺ," while the protective allele discriminates between the two peptides.

Kumar / PLoS One 2013 full article

Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis. Angelini DF, Serafini B, Piras E, Severa M, Coccia EM, PLoS Pathog 2013;9(4):e1003220. 113 MS patients, 43 healthy donors. "Using HLA class I pentamers, lytic antigen-specific CD8+ T cell responses were detected in fewer untreated inactive MS patients than in active MS patients and HD while the frequency of CD8+ T cells specific for EBV lytic and latent antigens was higher in active and inactive MS patients, respectively. In contrast, the CD8+ T cell response to cytomegalovirus did not differ between HD and MS patients, irrespective of the disease phase. Marked differences in the prevalence of EBV-specific CD8+ T cell responses were observed in patients treated with interferon-β and natalizumab, two licensed drugs for relapsing-remitting MS. Longitudinal studies revealed expansion of CD8+ T cells specific for EBV lytic antigens during active disease in untreated MS patients but not in relapse-free, natalizumab-treated patients. Analysis of post-mortem MS brain samples showed expression of the EBV lytic protein BZLF-1 and interactions between cytotoxic CD8+ T cells and EBV lytically infected plasma cells in inflammatory white matter lesions and meninges. We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse."

Angelini / PLoS Pathog 2013 full article

Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis. G Disanto, C Hall, R Lucas, AL Ponsonby, AJ Berlanga-Taylor, G Giovannoni, SV Ramagopalan; the Ausimmune Investigator Group. Mult Scler 2013 Sep;19(10):1355-1358. Individuals with HLA-DRB1*15 and a history of infectious mononucleosis "were at substantially increased risk of disease (OR=7.32, 95% CI=4.92-10.90)."

Disanto - Mult Scler 2013 abstract / PubMed

Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. L Querol, PL Clark, MA Bailey, C Cotsapas, AH Cross, DA Hafler, SH Kleinstein, JY Lee, G Yaari, SN Willis, KC O'Connor. Neurology 2013 Sep 10;81(11):956-963. "[W]e found a higher prevalence of autoantibodies against RBPJ in the CSF of patients with MS (12.5%) compared with the CSF of patients with other neurologic diseases (1.6%; p = 0.02) by ELISA. This difference in reactivity was restricted to the CSF as serum reactivity against RBPJ did not differ between patients and controls." RBPJ is "a ubiquitous protein of the Notch signaling pathway that plays an important role in Epstein-Barr virus infection."

Querol - Neurology 2013 abstract / PubMed

Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis peptides are cross recognized by anti-myelin basic protein antibodies in multiple sclerosis patients. G Mameli, D Cossu, E Cocco, S Masala, J Frau, MG Marrosu, LA Sechi. J Neuroimmunol 2014 May 15;270(1-2):51-55. "Competitive assay demonstrated that antibodies recognizing EBNA1400-413 and MAP121-132 cross-react with MBP85-98, possibly through a molecular mimicry mechanism." These antibodies are more prevalent among patients than among controls.

Mameli - J Neuroimmunol 2014 abstract / PubMed

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. K Ruprecht, B Wunderlich, R Gieß, P Meyer, M Loebel, K Lenz, J Hofmann, B Rosche, O Wengert, F Paul, U Reimer, C Scheibenbogen. J Neuroimmunol 2014 Jul 15;272(1-2):56-61. "Using a peptide microarray containing 1465 peptides representing 8 full-length EBV proteins, we identified higher (p<0.001) antibody reactivities to 39 EBV-peptides in MS patients (n=29) compared to healthy controls (n=22). Seventeen of the 39 peptides were from EBNA-1 and 13 located within the glycine-alanine repeat of EBNA-1. Further reactivities were directed against EBNA-3, EBNA-4, EBNA-6, VP26, and LMP1. Thus, antibodies against EBV in MS patients primarily target, but are not confined to, the glycine-alanine repeat of EBNA-1."

Ruprecht - J Neuroimmunol 2014 abstract / PubMed

A complex role of herpes viruses in the disease process of multiple sclerosis. SC Wuest, I Mexhitaj, NR Chai, E Romm, J Scheffel, B Xu, K Lane, T Wu, B Bielekova. PLoS One 2014 Aug 22;9(8):e105434. 62 untreated MS patients, compared to 19 patients with other inflammatory neurological diseases and 19 long-term treated patients. In CD4+ and CD8+ T cells of patients with relapsing-remitting and progressive MS compared to subjects with other inflammatory neurological diseases. "We observed comparably low T cell responses to complex auto-Ag's including human myelin, brain homogenate, and cell lysates of apoptotically modified oligodendroglial and neuronal cells in all cohorts and both compartments. Conversely, we detected a strong intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific (but not cytomegalovirus-specific) reactivities of the Th1-phenotype throughout all patients. Qualitatively, the intrathecal enrichment of herpes virus reactivities was more pronounced in MS patients. This enrichment was completely reversed by long-term treatment with the IL-2 modulating antibody daclizumab, which strongly inhibits MS disease activity. Finally, we observed a striking discrepancy between diminished intrathecal T cell proliferation and enhanced cytokine production of herpes virus-specific T cells among progressive MS patients, consistent with the phenotype of terminally differentiated cells."

Wuest - PLoS One 2014 full article / PubMed Central
Wuest / PLoS One 2014 full article

Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy. MP Pender, SR Burrows. Clin Transl Immunology 2014 Oct 31;3(10):e27. Review.

Pender & Burrows - Clin Transl Immunology 2014 / PubMed Central

High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. A Lossius, JN Johansen, F Vartdal, H Robins, JS Benth, T Holmřy, J Olweus. Eur J Immunol 2014 Nov;44(11):3439-3452. "TCRβ sequences of EBV-reactive CD8+ T cells, including several public EBV-specific sequences, were intrathecally enriched in MS patients only, whereas those of EBV-reactive CD4+ T cells were also enriched in CSF of controls."

Lossius - Eur J Immunol 2014 abstract / PubMed

Epstein-Barr virus genetic variants are associated with multiple sclerosis. R Mechelli, C Manzari, C Policano, A Annese, E Picardi, R Umeton, A Fornasiero, AM D'Erchia, MC Buscarinu, C Agliardi, V Annibali, B Serafini, B Rosicarelli, S Romano, DF Angelini, VA Ricigliano, F Buttari, L Battistini, D Centonze, FR Guerini, S D'Alfonso, G Pesole, M Salvetti, G Ristori. Neurology 2015 2015 Mar 31;84(13):1362-1368. 53 patients and 38 controls. "MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123)... EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features."

Mechelli - Neurology 2015 abstract / PubMed

Identifying Patient-Specific Epstein-Barr Nuclear Antigen-1 Genetic Variation and Potential Autoreactive Targets Relevant to Multiple Sclerosis Pathogenesis. M Tschochner, S Leary, D Cooper, K Strautins, A Chopra, H Clark, L Choo, D Dunn, I James, WM Carroll, AG Kermode, D Nolan. PLoS One 2016 Feb 5;11(2):e0147567. 73 cases. "EBNA-1 sequence variation was limited, with no evidence of multiple viral strains and only low levels of variation identified by FLX technology (8.3% nucleotide positions at a 1% cut-off). In silico epitope mapping revealed two known HLA-DRB1*1501-restricted epitopes ('AEG': aa 481-496 and 'MVF': aa 562-577), and two putative epitopes between positions 502-543. We identified potential cross-reactive targets involving a number of major myelin antigens including experimentally confirmed HLA-DRB1*15-restricted epitopes as well as novel candidate antigens within myelin and paranodal assembly proteins that may be relevant to MS pathogenesis."

Tschochner / PLoS One 2016 full article

Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis. F Rizzo, E Giacomini, R Mechelli, MC Buscarinu, M Salvetti, M Severa, EM Coccia. Immunol Cell Biol 2016 Oct;94(9):886-894. "Epstein-Barr virus (EBV), associated with MS etiopathogenesis, harbors in this cell type and an IFN-β-induced reduction of the memory B-cell compartment, in turn, resulted in a decreased expression of the EBV gene latent membrane protein 2A in treated patients."

Rizzo - Immunol Cell Biol 2016 abstract / PubMed

EBV and Vitamin D

Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes. SP Yenamandra, U Hellman, B Kempkes, SD Darekar, S Petermann, T Sculley, G Klein, E Kashuba. Cell Mol Life Sci 2010 Dec;67(24):4249-4256. "We found that EBNA3 blocks the activation of VDR-dependent genes and protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis."

Yenamandra - Cell Mol Life Sci 2010 abstract / PubMed

Epstein-Barr and other viral mimicry of autoantigens, myelin and vitamin D-related proteins and of EIF2B, the cause of vanishing white matter disease: massive mimicry of multiple sclerosis relevant proteins by the Synechococcus phage. CJ Carter. Immunopharmacol Immunotoxicol 2011 Feb;34(1):21-35. Review.

Carter - Immunopharmacol Immunotoxicol 2011 abstract / PubMed

Relationship of UV exposure to prevalence of multiple sclerosis in England. SV Ramagopalan, AE Handel, G Giovannoni, S Rutherford Siegel, GC Ebers, G Chaplin. Neurology 2011 Apr 19;76(16):1410-1414. "UVB exposure and IM together can explain a substantial proportion of the variance of MS. The effect of UVB on generating vitamin D seems the most likely candidate for explaining its relationship with MS."

Ramagopalan - Neurology 2011 full article / PubMed Central

Vitamin D: a link between Epstein-Barr virus and multiple sclerosis development? G Disanto, U Meier, G Giovannoni, SV Ramagopalan. Expert Rev Neurother 2011 Sep;11(9):1221-1224. Review. MS peaks in the late teens and early 20s while low levels of vitamin D affect all ages. Also, the EBV protein EBNA-3 stops the expression of the vitamin D-regulated genes C-FOS, CYCLIN C, CYP24A1, GADD45A and P21.

Disanto / Expert Rev Neurother 2011 full article

Low vitamin D and elevated immunoreactivity against Epstein-Barr virus before first clinical manifestation of multiple sclerosis. BF Décard, N von Ahsen, T Grunwald, F Streit, A Stroet, P Niggemeier, V Schottstedt, J Riggert, R Gold, A Chan. J Neurol Neurosurg Psychiatry 2012 Dec;83(12):1170-1173. 25 MS cases, 25 controls. "Low 25-OH-D levels were observed during the 24-month pre-CIS interval (47.8 (32.5-77.2) nmol/l, median (IQR); healthy controls: 81.6 (57.7-98.5), p=0.004, however, still higher than after established diagnosis (24.5 (13.7-47.7), p<0.0001 compared with controls). IgG against EBNA1 during the 36-month pre-CIS interval was increased (185.9 (91.2-460.0) IU/ml, median (IQR); healthy controls 63.7 (29.5-121.6), p=0.002). Conclusions Low vitamin D and remote EBV infection may be associated with clinical MS breakthrough within 2-3 years."

Décard - J Neurol Neurosurg Psychiatry 2012 abstract / PubMed

Vitamin D supplementation and antibodies against the Epstein-Barr virus in multiple sclerosis patients. G Disanto, AE Handel, J Damoiseaux, R Hupperts, G Giovannoni, J Smolders, SV Ramagopalan. Mult Scler 2013 Oct;19(12):1679-1680. Report on 15 relapsing–remitting MS patients.

Disanto / Mult Scler 2013 extract

Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS Study. A Lossius, T Riise, M Pugliatti, K Bjřrnevik, I Casetta, J Drulovic, E Granieri, MT Kampman, AM Landtblom, K Lauer, S Magalhaes, KM Myhr, T Pekmezovic, K Wesnes, C Wolfson, T Holmřy. Mult Scler 2014 May;20(6):669-674. 1660 MS patients and 3050 controls from Norway and Italy. "IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66). IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir."

Lossius - Mult Scler 2014 abstract / PubMed

EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy. VA Ricigliano, AE Handel, GK Sandve, V Annibali, G Ristori, R Mechelli, MZ Cader, M Salvetti. PLoS One 2015 Apr 8;10(4):e0119605. "We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS."

Ricigliano / PLoS One 2015 full article

EBV and vitamin D status in relapsing-remitting multiple sclerosis patients with a unique cytokine signature. A Nejati, Z Shoja, S Shahmahmoodi, A Tafakhori, Y Mollaei-Kandelous, F Rezaei, KM Hamid, A Mirshafiey, R Doosti, MA Sahraian, M Mahmoudi, F Shokri, V Emery, SM Marashi. Med Microbiol Immunol 2016 Apr;205(2):143-154. 83 patients with relapsing-remitting multiple sclerosis and 62 healthy controls. "In total, 98.8 % of MS patients showed a history of EBV exposure compared to 88.6 % in the healthy group (p = 0.005). EBV DNA load was significantly higher in MS patients than healthy subjects (p < 0.0001). Using a panel of biomarkers, we found a distinct transcriptional signature in MS patients compared to the healthy group with mRNA levels of CD73, IL-6, IL-23, IFN-γ, TNF-α, IL-15, IL-28, and IL-17 significantly elevated in MS patients (p < 0.0001). In contrast, the mRNA levels for TGF-β, IDO, S1PR1, IL-10, and CCL-3 were significantly lower in MS patients compared to healthy controls (p < 0.0001). No significant differences were found with the mRNA levels of IL-13, CCL-5, and FOXP3. Interestingly, in MS patients we found an inverse correlation between vitamin D concentration and EBV load, but not EBNA-1 IgG antibody levels."

Nejati - Med Microbiol Immunol 2015 abstract / PubMed

Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients. S Wergeland, KM Myhr, KI Lřken-Amsrud, AG Beiske, KS Bjerve, H Hovdal, R Midgard, SS Kvistad, T Holmřy, T Riise,Ř Torkildsen. Eur J Neurol 2016 Jun;23(6):1064-1070. 90 patients. "There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]."

Wergeland - Eur J Neurol 2016 abstract / PubMed


Comparison of two commercial ELISA systems for evaluating anti-EBNA1 IgG titers. R Dobson, J Topping, G Giovannoni. J Med Virol 2013 Jan;85(1):128-131. "The positive predictive value of the VirionSerion ELISA was 99.1% when compared to the DiaSorin ELISA, however, the negative predictive value was 64.3%. Sensitivity and specificity were acceptable at 95.5% and 90.0%, respectively. There was poor correlation between absolute results, R(2)  = 0.49; and the kappa coefficient for rank quintiles was low at 0.23. Although sensitivity and specificity appear adequate, the poor negative predictive value and kappa coefficient are of major concern. Care must be taken when selecting assays for experimental use."

Dobson - J Med Virol 2013 abstract / PubMed

Epidemiology of MS

The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions. AE Handel, L Jarvis, R McLaughlin, A Fries, GC Ebers, SV Ramagopalan. PLoS One 2011 Jan 27;6(1):e14606. Fig. 2. "There was a nominally significant inverse correlation with smoking but this was lost in the weighted regression."

Handel / PLoS One 2011 full article

U.S. Government Funds Scientific Fraud

Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. A Langer-Gould, SM Brara, BE Beaber, C Koebnick. Neurology 2013 Feb 5;80(6):548-552. [Epstein-Barr virus infection is now believed to be involved in all or nearly all cases of MS, but this study didn't consider its role. That means that they're exploiting confounding by the fact that children of lower socioeconomic status are both more likely to be obese and to have been infected by EBV. And our tax dollars have been misused to manufacture propaganda based on junk science, due to its funding by the National Institute of Diabetes and Digestive and Kidney Disorders. Furthermore, this kind of trash is systematically compiled and used to justify public policy, while the quality science is ignored. -cast]

Langer-Gould / Neurology 2013 abstract

Co-author Corinna Koebnick in 2010 and 2011 received $384,203 for "Complications of Severe Childhood Obesity."

Corinna Koebnick - NIH Reporter (via Tinyurl)

Co-author Annette Langer-Gould at the Kaiser Foundation Research Institute in 2011-2012 received $1,234,826 from NINDS for "Vitamin D, Race/Ethnicity, Genotype, and Multiple Sclerosis."

Annette Langer-Gould / NIH Reporter (via Tinyurl)

See Also:

HLA-DRB1*1501 is at highest frequency in northwestern Europe, including Norway, Sweden, Denmark, and Great Britain, with another peak around Moscow, Russia. (Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies. OD Solberg, SJ Mack, AK Lancaster, RM Single, Y Tsai, A Sanchez-Mazas, G Thomson. Hum Immunol 2008 Jul;69(7):443-464.)

Frequency Map - HLA-DRB1*1501 / Pypop.org
Population Data for HLA-DRB1*1501 / Pypop.org

Epstein-Barr Virus Causes Nasopharyngeal Cancer
Epstein-Barr Virus Causes Lymphomas
EBV Causes Interstitial Lung Disease
Epstein-Barr Virus Causes Gastric Carcinoma
EBV Causes Lymphoepithelioma-like Lung Cancer
EBV Causes Mental Impairment in Children
EBV & Socioeconomic Status
EBV Causes Lupus
Epstein-Barr Virus Causes Sjogren’s Syndrome
EBV and Other Diseases


cast 10-19-16