EBV and Other Diseases

EBV is Implicated in Multiple Sclerosis

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)."

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."

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.)

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.)

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."

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."

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."

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."

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.

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.)

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."

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."

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."

[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.

"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.)

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."

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."

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."

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."

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."

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."

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)."

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).

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)."

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.)

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."

Upregulation of Immunoglobulin-related Genes in Cortical Sections from Multiple Sclerosis Patients. O Torkildsen, C Stansberg, SM Angelskår, EJ Kooi, JJ Geurts, P van der Valk, KM Myhr, VM Steen, L Bø. 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."

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)."

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."

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.

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."

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 2011 Jul 21. doi: 10.1038/gene.2011.42 [Epub ahead of print]. "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."

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."

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.

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."

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)."

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-Cermeño. 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)."

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."

Strain differences

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."

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."

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."

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.)

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."

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.

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."

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 2011 Aug 8 [Epub ahead of print]. 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."

Hemophagocytic Lymphohistiocytosis

Hemophagocytic syndrome in Epstein-Barr virus-associated T-lymphoproliferative disorders: disease spectrum, pathogenesis, and management. IJ Su, CH Wang, AL Cheng, RL Chen. Leuk Lymphoma 1995 Nov;19(5-6):401-406. Review.

Polymerase chain reaction amplification of archival material for Epstein-Barr virus, cytomegalovirus, human herpesvirus6, and parvovirus B19 in children with bone marrow hemophagocytosis. MP Hoang, DB Dawson, ZR Rogers, RH Scheuermann, BB Rogers. Hum Pathol 1998 Oct;29(10):1074-1077.

Haematological associations of Epstein-Barr virus infection. M Okano. Baillieres Best Pract Res Clin Haematol 2000 Jun;13(2):199-214. Review.

Hemophagocytic syndromes and infection. DN Fisman. Emerging Infectious Diseases 2000 Nov-Dec;6(6):601-608. Review. In this disorder, macrophages engulf the other blood cell types. "HLH may be diagnosed in association with malignant, genetic, or autoimmune diseases but is also prominently linked with Epstein-Barr (EBV) virus infection."

Lytic infection of Epstein-Barr virus (EBV) in hemophagocytic syndrome associated with EBV-induced lymphoproliferative disorder. T Yamamoto, A Shirakawa, M Kawaguchi, A Masuda, T Nishikawa, M Kobayashi. Ann Hematol 2004 Feb;83(2):127-132. 3 females, aged 52 to 87.

Severe Epstein-Barr virus-associated hemophagocytic syndrome in six adult patients. AS Elazary, DG Wolf, G Amir, B Avni, D Rund, DB Yehuda, S Sviri. J Clin Virol 2007 Oct;40(2):156-159. There were six cases in three years in Israel. "EBV associated HPS may be more prevalent in non-Japanese adults than was previously considered."

Severe Mosquito Bite Reaction

Characterization of Epstein-Barr virus (EBV)-infected natural killer (NK) cell proliferation in patients with severe mosquito allergy; establishment of an IL-2-dependent NK-like cell line. I Tsuge, T Morishima, M Morita, H Kimura, K Kuzushima, H Matsuoka. Clin Exp Immunol 1999 Mar;115(3):385-392. There is a clonal expansion of EBV-infected NK cells in severe hypersensitivity to mosquito bites.

Hypersensitivity to mosquito bites is not an allergic disease, but an Epstein-Barr virus-associated lymphoproliferative disease. S Ishihara, R Yabuta, Y Tokura, K Ohshima, S Tagawa. Int J Hematol 2000 Aug;72(2):223-228. "Although the symptoms of HMB have been supposed to derive from Arthus phenomenon, it has become apparent that this unique disorder has the potential to develop into so-called malignant histiocytosis or related disorders."

Hypersensitivity to mosquito bites as the primary clinical manifestation of a juvenile type of Epstein-Barr virus-associated natural killer cell leukemia/lymphoma. Y Tokura, S Ishihara, S Tagawa, N Seo, K Ohshima, M Tajigawa. J Am Acad Dermatol 2001 Oct;45(4):569-578.

Is EBV involved in lupus?

An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. JA James, KM Kaufman, AD Farris, E Taylor-Albert, TJA Lehman, JB Harley. J Clin Invest 1997 Dec;100(12):3019-3026. "Virtually all (116 of 117, or 99%) of these young patients had seroconverted against Epstein-Barr virus, as compared with only 70% (107 of 153) of their controls (odds ratio 49.9, 95% confidence interval 9.3-1025, P<0.00000000001)... An assay for Epstein-Barr virus DNA in peripheral blood lymphocytes established Epstein-Barr infection in the peripheral blood of all 32 of the lupus patients tested, while only 23 of the 32 matched controls were infected (odds ratio >10, 95% confidence interval 2.53-[infinity], P<0.002)."

Editorial. The Epstein-Barr virus and systemic lupus erythematosus. JH Vaughan. J Clin Invest 1997 Dec;100(12):2939-2940. Re James et al: "As they note, this suggests either that EBV predisposes to the development of SLE or, conversely, that SLE predisposes to EBV. As there has been nothing during decades of intense clinical interest in SLE to suggest that SLE patients are hypersusceptible to EBV infection... the former interpretation is preferred."

Potential role of the Epstein-Barr virus in systemic lupus erythematosus autoimmunity. M Incaprera, L Rindi, A Bazzichi, C Garzelli. Clin Exp Rheumatol 1998 May-Jun;16(3):289-294. "50% of the patients with SLE and 100% of the patients in the acute phase of IM, but none of the seropositive normal individuals, produced IgG antibodies to the EBNA-2-derived synthetic peptide," which has a region resembling SmD1, a common target of autoantibodies. "We suggest the possibility that EBV may establish a persistent infection in at least a certain number of SLE patients."

Systemic lupus erythematosus in adults is associated with previous Epstein-Barr virus exposure. JA James, BR Neas, KL Moser, T Hall, GR Bruner, AL Sestak, JB Harley. Arthritis Rheum 2001 May;44(5):1122-1126. "Of the 196 lupus patients tested, all but 1 had been exposed to EBV, while 22 of the 392 controls did not have antibodies consistent with previous EBV exposure (OR 9.35, 95% CI 1.45-infinity, P=0.014)."

Epstein-barr virus-associated non-Hodgkin's lymphoma of B-cell origin, Hodgkin's disease, acute leukemia, and systemic lupus erythematosus: a serologic and molecular analysis. W Mitarnun, J Pradutkanchana, S Takao, V Saechan, S Suwiwat, T Ishida. J Med Assoc Thai. 2002 May;85(5):552-9. In 58 patients, "EBV internal repeat-1 region (IR-1) in peripheral blood CD3+ cells was detected in 10 of 14 patients (71.5%) with NHL-B, 3 of 8 patients (37.5%) with Hodgkin's disease, 1 of 6 patients (16.7%) with acute leukemia, 4 of 9 patients (44.5%) with SLE, and was not detected in any of the 21 patients with other diseases."

High prevalence of immunoglobulin A antibody against Epstein-Barr virus capsid antigen in adult patients with lupus with disease flare: case control studies. CJ Chen, KH Lin, SC Lin, WC Tsai, JH Yen, SJ Chang, SN Lu, HW Liu. J Rheumatol 2005 Jan;32(1):44-47. "In the first study, IgA antibody against EBV-VCA was the only marker with significantly higher prevalence in adults with SLE compared to healthy adults (36.1% vs 5.6%; p < 0.005). In the second study, we confirmed that the prevalence of IgA antibody against EBV-VCA was indeed higher in adults with SLE (38.9% vs 2.8%; p < 0.001)... SLE patients with flare showed much higher prevalence of IgA antibody against EBV-VCA compared to those without flare (81.3% vs 25.0%; p < 0.001)."

Elevated immunoglobulin G antibodies to the proline-rich amino-terminal region of Epstein-Barr virus nuclear antigen-2 in sera from patients with systemic connective tissue diseases and from a subgroup of Sjogren's syndrome patients with pulmonary involvements. M Yamazaki, R Kitamura, S Kusano, H Eda, S Sato, M Okawa-Takatsuji, S Aotsuka, K Yanagi. Clin Exp Immunol 2005 Mar;139(3):558-568. "The specific levels of IgG antibodies to the amino-terminal region of EBNA-2 were elevated in patients with SLE, primary SS or RA, as well as those with secondary SS complicated with SLE or RA."

Association of Epstein-Barr virus with systemic lupus erythematosus: effect modification by race, age, and cytotoxic T lymphocyte-associated antigen 4 genotype. CG Parks, GS Cooper, LL Hudson, MA Dooley, EL Treadwell, EW St Clair, GS Gilkeson, JP Pandey. Arthritis Rheum 2005 Apr;52(4):1148-1159. "In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0-10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6-10.4)."

Reactivation of Epstein-Barr virus in patients with systemic lupus erythematosus. ML Huggins, I Todd, RJ Powell. Rheumatol Int 2005 Apr;25(3):183-187. "Sera from SLE patients were tested for antibodies to several EBV antigens and had a significantly higher prevalence of immunoglobulin G antibodies against EBV early antigens than in normal or disease controls. This suggests that recent EBV infection or virus reactivation was occurring in these patients."

EBV and systemic lupus erythematosus: a new perspective. AJ Gross, D Hochberg, WM Rand, DA Thorley-Lawson. J Immunol 2005 Jun 1;174(11):6599-6607. Patients with SLE had abnormally high levels of EBV-infected cells in their blood.

Association of Epstein-Barr virus infection with systemic lupus erythematosus in Taiwan. JJ Lu, DY Chen, CW Hsieh, JL Lan, FJ Lin, SH Lin. Lupus 2007;16(3):168-175. 93 adult SLE patients and 370 matched controls. "Our results show that IgA anti-EBV EBNA1 antibodies were detectable in 31.2% SLE patients but only in 4.1% of controls (odds ratio [OR] = 10.72, 95% confidence interval [CI] = 5.19-22.35; P < 10(-7)), IgG anti-EBV DNase antibodies were detected in 53.8% SLE patients but only in 12.2% controls (OR = 8.40, 95% CI = 4.87-14.51; P < 10(-7)). EBV DNA was amplifiable from the sera of 41.9% SLE patients but from only 3.24% controls (P < 0.05). A significant association of IgG anti-EBV DNase antibodies with anti-Sm/RNP antibodies was observed (P < 0.005)."

Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. BD Poole, AK Templeton, JM Guthridge, EJ Brown, JB Harley, JA James. Autoimmun Rev 2009 Feb;8(4):337-342. "Expression levels of mRNA were significantly greater by Wilcoxen signed rank test in the ex vivo-infected SLE patient-derived cells for 4 of 8 EBV genes, including BLLF1, 3.2-fold (p<0.004); LMP-2, 1.7-fold (p<0.008); EBNA-1, 1.7-fold (p<0.01); and BcRF1, a proposed DNA binding protein, 1.7-fold (p<0.02). The frequency of LMP-1 gene expression was significantly greater by Chi square analysis in the peripheral blood from SLE patients than controls (44% of patients, 10% of controls p<0.05). PBMCs from SLE patients had greater expression of latent genes as well as increased expression of both latent and lytic genes after infection, suggesting that EBV may participate in SLE etiology through several mechanisms."

Exposure to Epstein-Barr virus infection is associated with mild systemic lupus erythematosus disease. G Zandman-Goddard, Y Berkun, O Barzilai, M Boaz, M Blank, M Ram, Y Sherer, JM Anaya, Y Shoenfeld. Ann N Y Acad Sci 2009 Sep;1173:658-663. In 120 SLE patients and 140 controls, "EAG titers were significantly elevated (P < 0.024) in patients with cutaneous symptoms and increased anti-Ro antibody titers (P < 0.005). VCA IgG titers were significantly elevated (P < 0.003) in patients with joint involvement. None of the titers differed by central nervous system or renal involvement or antiphospholipid syndrome."

Exhausted cytotoxic control of epstein-barr virus in human lupus. M Larsen, D Sauce, C Deback, L Arnaud, A Mathian, M Miyara, D Boutolleau, C Parizot, K Dorgham, L Papagno, V Appay, Z Amoura, G Gorochov. PLoS Pathog 2011 Oct;7(10):e1002328. "Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8(+) T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8(+) T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8(+) T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8(+) T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients."

HHV-6A can reactivate EBV infection

Isolation of human herpesvirus-6 (HHV-6) from patients with collagen-vascular diseases. GR Krueger, C Sander, A Hoffman, A Barth, B Koch, M Braun. In Vivo 1991 May-Jun;5(3):217-225. "Fifty-five percent of the SLE patients, 6.5% of the RA patients and both patients with Sharp's syndrome or with APL had antibody titers indicative of active HHV-6 infection."

Other studies suggesting EBV infection

CD4 positive peripheral T cells from patients with systemic lupus erythematosus (SLE) are clonally expanded. W Kolowos, US Gaipi, RE Voll, C Frank, JP Haas, TD Beyer, JR Kalden, M Herrmann. Lupus 2001;10(5):321-331.

Plasmacytoid dendritic cells (natural interferon- alpha/beta-producing cells) accumulate in cutaneous lupus erythematosus lesions. L Farkas, K Beiske, F Lund-Johansen, P Brandtzaeg, FL Jahnsen. Am J Pathol 2001 Jul;159(1):237-243.

An etiopathogenic role for the type I IFN system in SLE. L Ronnblom, GV Alm. Trends Immunol 2001 Aug;22(8):427-431.

EBV and Breast Cancer

Epstein-Barr virus in epithelial cell tumors: a breast cancer study. LG Labrecque, DM Barnes, IS Fentiman and BE Griffin. Cancer Research 1995; 55(1):39-45. 19 of 91 (21%) cases of breast carcinoma were positive for EBV DNA, versus none of 21 samples from benign breast tumors or normal breast tissue.

Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers. S Glaser, R Ambinder, J DiGiuseppe, P Horn-Ross, J Hsu. Int J Cancer 1998;75:555–558. No EBV was found by in situ hybridization for the EBER-1 transcript among 97 female and 28 male patients identified from a US population-based cancer registry.

Detection of Epstein-Barr Virus in Invasive Breast Cancers. M Bonnet, J-M Guinebretiere, E Kremmer, V Grunewald, E Benhamou, G Contesso, I Joab. Journal of the National Cancer Institute 1999 Aug 18;91(16):1376-1381. "We were able to detect the EBV genome by PCR in 51% of the tumors, whereas, in 90% of the cases studied, the virus was not detected in healthy tissue adjacent to the tumor (P<.001). The presence of the EBV genome in breast tumors was confirmed by Southern blot analysis."

Breast Cancer: a New Epstein-Barr Virus-Associated Disease? I Magrath, K Bhatia. Journal of the National Cancer Institute 1999 Aug;91(16):1349-1350. (Editorial.) "The possibility that there is variable or absent expression of EBER in EBV-positive breast cancer cells may explain, at least in part, the apparently conflicting results in the literature. Two of the groups that reported a lack of association of EBV with breast cancer of various histologies used only EBER ISH to detect EBV. A third, in which only three cases were studied, obtained positive results by PCR and negative results by EBER ISH. The remaining two, which used several techniques to detect EBV, examined only medullary carcinoma of the breast (8,9), a rare tumor (there was one in the series by Bonnet et al.) that is histologically similar to lymphoepithelioma-like carcinoma, a group of tumors that is often, but not always, EBV associated. Thus, although more data are needed, it seems likely at this time that EBV is frequently associated with multiple histologic types of breast cancer. The variable expression of EBER in neoplastic epithelial cells also leaves open the possibility that EBV may be associated with a broader range of tumors than previously thought, because many investigators in recent years have relied upon EBER ISH as a means of assessing EBV association. EBER ISH, if positive, is meaningful; however, if it is negative, it does not prove the absence of EBV, particularly in epithelial cells."

Hypothesis. Breast Cancer Risk and "Delayed" Primary Epstein-Barr Virus Infection. Y Yasui, JD Potter, JL Stanford, MA Rossing, MD Winget, M Bronner, J Daling. Cancer Epidemiology Biomarkers & Prevention 2001 Jan;10:9-16. Populations with higher incidence rates of breast cancer corresponded to those with higher likelihood of delayed primary EBV infection. "Age-adjusted odds ratios of breast cancer in women who reported a history of IM, relative to women who did not, increased monotonically from 0.55 [95% confidence interval (CI), 0.05–6.17] for women with 0–9 years of age at IM onset to 2.67 (CI, 1.04–6.89) for women with 25 years of age at IM onset (P = 0.016)."

Frequency and genome load of Epstein-Barr virus in 509 breast cancers from different geographical areas. F Fina, S Romain, L Ouafik, J Palmari, F Ben Ayed, S Benharkat, P Bonnier, F Spyratos, JA Foekens, C Rose, M Buisson, H Gerard, MO Reymond, JM Seigneurin, PM Martin PM. Br J Cancer 2001 Mar 23;84(6):783-790. 31.8% of 509 tumours contained the EBV genome.

No significant association of Epstein-Barr virus infection with invasive breast carcinoma. P Chu, K Chang, Y Chen, W Chen, L Weiss. Am J Pathol 2001;159:571–578. "Five of 48 cases (10%) of breast carcinoma showed focal EBER-positive tumor cells. Twelve cases (25%) were positive for EBNA-1 by immunohistochemistry, all but one different from the EBER-positive cases. None of the cases were positive for LMP-1 or ZEBRA protein by immunohistochemistry. PCR studies for EBNA-4 and LMP-1 were each positive in five cases (including three cases in common). However, Southern blot studies successfully performed in all but one of the PCR-positive cases were completely negative."

Demonstration of Epstein-Barr virus in carcinomas of various sites. S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo, VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "In 14 of 33 (42%) carcinomas, convincing nuclear reactions were noted involving a range of 5–30% of neoplastic cells; ductal and lobular variants of carcinoma were similarly involved; foci of in situ carcinoma also showed focal nuclear staining. Proliferative variants of fibrocystic disease with variable degrees of atypia, and occasionally a lack thereof, including ductal and lobular hyperplasia and papillomas, also showed focal nuclear immunoreactivity. These changes were found in cases with and without an associated carcinoma. In a cellular fibroadenoma (phyllodes tumor), EBV-reactive nuclei were found in some epithelial and stromal cells. Twenty-one normal breast, nonproliferative variants of fibrocystic changes and benign fibroadenomas were negative. CD21 showed no reaction in any epithelial component. Our demonstration of EBV in breast carcinomas confirm and broaden earlier reports including the relative incidence of positive cases. However, our findings on EBV in typical and atypical ductal and lobular proliferations and in situ carcinomas represent novel observations and may reflect a possible etiological role of EBV in breast carcinogenesis. Notably, these observations in the breast, with a different EBV pattern of expression (EBER-, LMP-1-, and EBNA-1+), parallel findings and hypothesis advocated by Pathmanathan et al. in nasopharyngeal carcinomas involving dysplasia or preinvasive carcinoma in situ (EBER+, LMP-1+), both representing evidence that EBV may be a primary etiological agent in a multistep process that leads to the development of a carcinoma."

Lack of expression of the Epstein-Barr Virus (EBV) gene products, EBERs, EBNA1, LMP1, and LMP2A, in breast cancer cells. C Deshpande, S Badve, N Kidwai, R Longnecker. Lab Invest 2002;82:1193–1199. No EBV was detected in 43 female breast cancer cases by in situ hybridization for EBV RNA (EBERs), or by immunohistochemistry, for EBV nuclear antigen 1 (EBNA1) and the latent membrane proteins (LMP1 and LMP2A.

Reactivity with A monoclonal antibody to Epstein-Barr virus (EBV) nuclear antigen 1 defines a subset of aggressive breast cancers in the absence of the EBV genome. PG Murray, D Lissauer, J Junying, G Davies, S Moore, A Bell, J Timms, D Rowlands, C McConkey, GM Reynolds, S Ghataura, D England, R Caroll, LS Young. Cancer Res 2003 May 1;63(9):2338-2343. EBV DNA was detected in 19 of 92 (21%) tumors.

Lack of evidence for an association of Epstein-Barr virus infection with breast carcinoma. K Herrmann, G Niedobitek. Breast Cancer Res 2003;5(1):R13-17. "EBV-encoded RNA-specific in situ hybridisation and EBV-encoded nuclear antigen 1 immunohistochemistry were negative in all cases. Using the PCR, EBV DNA was detected in four out of 59 cases. These cases were further studied by EBV DNA in situ hybridisation, showing an absence of viral DNA from the tumour cells."

Epstein-Barr virus gene expression in human breast cancer: protagonist or passenger? SA Xue, IA Lampert, JS Haldane, JE Bridger, BE Griffin. Br J Cancer 2003 Jul 7;89(1):113-119. EBV genes were found in 40% of 15 mastectomy-removed breast cancer samples, mostly of ductal origin.

Epstein-Barr virus in breast carcinoma in Argentina. MV Preciado, PA Chabay, EN De Matteo, P Gonzalez, S Grinstein, A Actis, HD Gass. Arch Pathol Lab Med 2005 Mar;129(3):377-381. EBV was found by immunohistochemical analysis in 24 (35%) of 69 samples and by PCR analysis in 12 (31%) of 39 samples; none was found in in any of the control breast biopsy specimens (17 biopsy specimens of fibroadenomas, 9 of benign epithelial proliferation [adenosis and sclerosing adenosis], 4 of atypical ductal hyperplasia, and 10 of usual ductal hyperplasia).

Real-time PCR measures Epstein-Barr Virus DNA in archival breast adenocarcinomas. LB Thorne, JL Ryan, SH Elmore, SL Glaser, ML Gulley. Diagn Mol Pathol 2005 Mar;14(1):29-33. "In four tumors (7%), low level EBV DNA was detected by at least one of the assays, with levels of up to 11 copies of EBV DNA per 100,000 cells. Immunohistochemisty for viral BMRF1 and BZLF1 and in situ hybridization for lytic gene transcripts showed no evidence of replicative EBV gene expression. Lymphocytes and malignant cells were also negative for latent infection by EBER in situ hybridization."

Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol). H Arbach, V Viglasky, F Lefeu, J-M Guinebretière, V Ramirez, N Bride, N Boualaga, T Bauchet, J-P Peyrat, M-C Mathieu, S Mourah, M-P Podgorniak, J-M Seignerin, K Takada, I Joab. J Virology 2006 Jan;80(2):845-853. "Our findings show that EBV genomes can be detected by Q-PCR in about half of tumor specimens, usually in low copy numbers. However, we also found that the viral load is highly variable from tumor to tumor. Moreover, EBV genomes are heterogeneously distributed in morphologically identical tumor cells, with some clusters of isolated tumor cells containing relatively high genome numbers while other tumor cells isolated from the same specimen may be negative for EBV DNA... Furthermore, we observed that in vitro EBV infection of breast carcinoma cells confers resistance to paclitaxel (taxol) and provokes overexpression of a multidrug resistance gene (MDR1). Consequently, even if a small number of breast cancer cells are EBV infected, the impact of EBV infection on the efficiency of anticancer treatment might be of importance."

[Detection of Epstein-Barr virus in breast cancers with lymphoid stroma]. A Trabelsi, S Rammeh, W Stita, M Mokni, A Mourou, S Korbi. Ann Biol Clin (Paris) 2008 Jan-Feb;66(1):59-62. 18 medullary carcinoma and 18 high grade invasive ductal carcinoma with lymphoid stroma, by immunohistochemistry with anti-LMP2 antibody and by hybridization in situ by oligonucleotides EBER1 and EBER1. "LMP1 as well as hybridization in situ were positive in 5 tumors (3 medullary carcinoma and 2 high grade invasive ductal carcinoma with lymphoid stroma). RESULTS: positivity was observed in tumor cells and neither in epithelial non tumoral ones nor in lymphoid cells."

Detection of Epstein-Barr virus in breast carcinoma in Egyptian women. S Fawzy, M Sallam, N Mohammad Awad. Clin Biochem 2008 May;41(7-8):486-92. 32 ductal and 8 lobular breast cancers, 20 controls with fibrocystic disease. "10/40 (25%) of the BC specimens stained positively for EBNA-1; EBNA-1 expression was restricted to a fraction 5%-60% of tumor epithelial cells. EBV-DNA was detected in 8/10 of BC specimens positive for EBNA-1. Control specimens were negative by both techniques."

Association of Epstein Barr virus infection (EBV) with breast cancer in rural Indian women. D Joshi, M Quadri, N Gangane, R Joshi, N Gangane. PLoS One 2009 Dec 4;4(12):e8180. 58 cases of malignant breast disease and 63 of benign breast disease (controls). "Mean antibody levels were significantly higher for cases (54.22 IU/ml) as compared to controls (18.68 IU/ml). IHC for EBNA-1 was positive in 28/51 cases (54.9%). No IHC positivity was noted in the tested 30 controls."

Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma. MA Lorenzetti, De Matteo, H Gass, P Martinez Vazquez, J Lara, P Gonzalez, MV Preciado, PA Chabay. PLoS One 2010 Oct 22;5(10):e13603. 71 biopsies of breast carcinoma and 48 non-neoplastic breast controls. "EBV genomic DNA and EBNA1 expression were detected in 31% (22/71) of patients specifically restricted to tumor epithelial cells in breast carcinoma while all breast control samples were negative for both viral DNA and EBNA1 protein. LMP2A was detected in 73% of EBNA1 positive cases, none of which expressed either LMP1 protein or EBERs transcripts."

Association between Epstein-Barr virus infection and risk for development of pregnancy-associated breast cancer: joint effect with vitamin D? CB Agborsangaya, T Lehtinen, AT Toriola, E Pukkala, HM Surcel, R Tedeschi, M Lehtinen. Eur J Cancer 2011 Jan;47(1):116-120. 108 cases, 208 controls. "EBV seropositivity was generally not associated with the risk of PABC. Among individuals with sufficient (≥75 nmol/l) levels of vitamin D, we, however, found similar increased risk estimates for PABC associated with serum immunoglobulin G (IgG) antibodies to EBV early antigens [odds ratio (OR)=7.7, 95% (confidence interval) CI 1.4-42.3] and the viral reactivator protein, ZEBRA (OR=7.8, 95% CI 1.1-61.2)."

Epstein-Barr virus as a marker of biological aggressiveness in breast cancer. C Mazouni, F Fina, S Romain, L Ouafik, P Bonnier, JM Brandone, PM Martin. Br J Cancer 2011 Jan 18;104(2):332-337. "EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P=0.05) and with high histological grade (P=0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P=0.007). The presence of EBV was weakly associated with HER2 gene amplification (P=0.08)."

Deliberate scientific fraud in the British Medical Journal, funded by the U.S. National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services. (Association of active and passive smoking with risk of breast cancer among postmenopausal women: a prospective cohort study. J Luo, KL Margolis, J Wactawski-Wende, K Horn, C Messina, ML Stefanick, HA Tindle, E Tong, TE Rohan. BMJ 2011 Mar 1;342:d1016. doi: 10.1136/bmj.d1016.) This study IS based on lifestyle questionnaires, which ignored the role of Epstein-Barr virus infection on order to falsely pretend to find a risk associated with smoking. It is supposed to be a basic principle of epidemiology that larger risks should be properly accounted for before making claims about smaller ones, but the authors and the editors of the BMJ have simply ignored this fundamental principle. The very design of this study makes its purposes clear. It is for lifestyle propaganda only, and not research on the real causes of disease. It epitomizes the agenda and methods of the ultra-politically-connected, unaccountable oligarchy of the Harvard School of Public Health, which secretly rules this country, its media and all the politicians. The fact that they commandeered the unprecedented sum of $625 million for this study, the Women's Health Initiative, is definitive proof of their power and influence. It proves that science is thoroughly corrupted by RELIGIOUS INTERESTS, who cynically disguise their theologiccal agenda under a flimsy veneer of pseudo-science in order to force it unwilling victims, in gross violation of our Constitutional rights to freedom of religion. These charlatans are so smugly confident that they will never be held accountable that they make no secret of their bias: "The addition of breast cancer to the list of diseases causally related to active or secondhand tobacco smoking would probably be a powerful argument for women to stop smoking or avoid taking it up." And they perform a cynical charade of pretending to consider the issue of confounding, without mentioning the word "virus." (Is breast cancer associated with tobacco smoking? P Boffetta, P Autier. BMJ 342:doi:10.1136/bmj.d1093.) It proves beyond a shadow of doubt that our so-called "science" is actually controlled by a theocracy!

Human papillomavirus and Epstein-Barr virus infections in breast cancer from chile. F Aguayo, N Khan, C Koriyama, C González, S Ampuero, O Padilla, L Solís, Y Eizuru, A Corvalán, S Akiba. Infect Agent Cancer 2011 Jun 23;6(1):7. "The amplification of a housekeeping gene showed that 46/55 samples (84%) had amplifiable DNA. HPV-16 was detected in 4/46 BCs (8.7%) and EBV [EBER-1] was detected in 3/46 (6.5%) BCs. The analysis of HPV-16 physical status showed that this virus was integrated in all of the tumors with a relatively low viral load (range: 0.14 to 33.8 copies/cell). E6 and E7 transcripts, however, were not detected in any HPV-16 positive specimens."

Localization of Epstein-Barr virus to infiltrating lymphocytes in breast carcinomas and not malignant cells. G Khan, PS Philip, M Al Ashari, Y Houcinat, S Daoud. Exp Mol Pathol 2011 Aug;91(1):466-470. 47.5% of 61 breast cancer cases were EBV positive, "but the virus was localized to occasional infiltrating lymphocytes and not in the malignant cells."

Epstein-Barr Virus and Breast Cancer: Lack of Evidence for an Association in Iranian Women. M Kadivar, A Monabati, A Joulaee, N Hosseini. Pathol Oncol Res 2011 Sep;17(3):489-492. 100 breast carcinoma and 42 control biopsies. EBNA-2 and LMP-1 were negative by IHC in all specimens, and no EBV DNA was found by PCR.

Investigation of Epstein-Barr virus in breast carcinomas in Tunisia. M Hachana, K Amara, S Ziadi, E Romdhane, RB Gacem, M Trimeche. Pathol Res Pract 2011 Nov 15;207(11):695-700. "Using specific PCR assays, EBV DNA was found in 33 (27%) out of 123 breast carcinoma cases. EBV-encoded small RNAs (EBERs) in situ hybridization was negative in the neoplastic cells, but stomal lymphocytes were positive in 4 cases. Immunohistochemistry for latent membrane protein 1 (LMP1) was negative in all cases. None of the normal breast tissues showed positive results for EBV using PCR, in situ hybridization, and immunohistochemistry. A correlation was found between EBV DNA presence and the negativity of estrogen receptor (P=0.008)."

EBV and Leukemia

Epstein-Barr virus in patients with chronic lymphocytic leukemia: a pilot study. AM Tsimberidou, MJ Keating, CE Bueso-Ramos, R Kurzrock. Leuk Lymphoma 2006 May;47(5):827-836. "EBERs were detected in the bone marrow of 12 of 32 (38%) CLL/SLL marrows vs 0 of 20 normal marrows (p = 0.002). EBERs were observed in sporadic granulocytes alone or in addition to its presence in lymphocytes in nine of the 12 EBV-positive patients. EBERs were detected less frequently in patients with Rai stage 0 - 1 disease (20%) compared with Rai stage 2 - 4 (66%; p = 0.008). EBER-positive patients tended to have higher lactate dehydrogenase levels (p = 0.053). The 10-year survival rate was 22% vs 58% for patients with and without discernible EBERs (log-rank, p = 0.08). Evidence of EBV infection was found in 38% of patients with CLL/SLL."

Epstein-Barr virus infection and risk of lymphoma: immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. S de Sanjosé, R Bosch, T Schouten, S Verkuijlen, A Nieters, L Foretova, M Maynadié, PL Cocco, A Staines, N Becker, P Brennan, Y Benavente, P Boffetta, CJ Meijer, JM Middeldorp. Int J Cancer 2007 Oct 15;121(8):1806-1812. "Ab_EBV positivity was a risk factor for all lymphomas combined (odds ratio [OR] = 1.42, 95% confidence interval [CI]=1.15-1.74), and specifically for chronic lymphocytic leukaemia (OR = 2.96, 95%CI = 2.22-3.95)."

Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. E Kostareli, A Hadzidimitriou, N Stavroyianni, N Darzentas, A Athanasiadou, M Gounari, V Bikos, A Agathagelidis, T Touloumenidou, I Zorbas, A Kouvatsi, N Laoutaris, A Fassas, A Anagnostopoulos, C Belessi, K Stamatopoulos. Leukemia 2009 May;23(5):919-924. 93 CLL cases with an intentional bias for the IGHV4-34 [immunoglobulin heavy-chain variable 4-34 (IGHV4-34)] gene. 9/25 cases positive for EBV but not CMV, and all nine double positives, utilized the IGHV4-34 gene. Seven of the latter expressed the stereotyped B-cell receptors.

Epstein-Barr virus latent membrane protein 1 mRNA is expressed in a significant proportion of patients with chronic lymphocytic leukemia. JJ Tarrand, MJ Keating, AM Tsimberidou, S O'Brien, RP LaSala, XY Han, CE Bueso-Ramos. Cancer 2010 Feb 15;116(4):880-887. "EBV LMP1 mRNA transcripts were found in 19 of 135 (14%) of the CLL cases, but only 1% of the healthy controls (P < .0001). In contrast, 23 solid tumor patients tested negative for EBV LMP1 transcripts. In a later cohort of patients after hematopoietic stem cell transplantation, 4 of 7 patients with Hodgkin lymphoma or Burkitt lymphoma had EBV LMP1 detected. In a preliminary analysis, outcome data were available for 88 of the 135 patients with CLL. EBV LMP1 mRNA positivity was associated with a significantly increased degree of histologically demonstrated bone marrow involvement by CLL (P = .003, Mann-Whitney U test)."

A prospective study of Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma. KA Bertrand, BM Birmann, ET Chang, D Spiegelman, JC Aster, SM Zhang, F Laden. Blood 2010 Nov 4;116(18):3547-3553. Case-control study nested in the Physicians' Health Study and Nurses' Health Study. "For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), suggestive associations were noted for elevated anti-EBNA-2 (RR: 1.74; 95% CI: 0.99, 3.05), anti-VCA (RR: 1.58; 95% CI: 0.79, 3.14), and EBNA-1:EBNA-2 ratio </= 1.0 (RR: 1.52; 95% CI: 0.91, 2.55)."

Epstein-Barr virus infection and chronic lymphocytic leukemia: a possible progression factor? R Dolcetti, A Carbone. Infect Agent Cancer 2010 Nov 22;5:22. REVIEW. "Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the United States and Western Europe...." Some patients also develop EBV-related lymphomas.

Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph. D Casabonne, O Reina, Y Benavente, N Becker, M Maynadié, L Foretová, P Cocco, A González-Neira, A Nieters, P Boffetta, JM Middeldorp, S de Sanjose. Haematologica 2011 Feb;96(2):323-237. 240 cases and 513 controls from five European centers. "In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed." "Overall, the odds ratio of chronic lymphocytic leukemia in all ab_EBV positive patients compared to all ab_EBV negative patients was 2.76 (95% CI=1.91 to 3.98)."

Infectious Mononucleosis

Epstein-Barr virus and infectious mononucleosis. National Center for Infectious Diseases, Centers for Disease Control and Prevention.

Infectious mononucleosis. Kirksville College of Osteopathic Medicine.

Epstein-barr virus and hodgkin lymphoma. RF Ambinder. Hematology Am Soc Hematol Educ Program 2007;2007:204-209. Review. "Recognition of the viral etiology of infectious mononucleosis followed the serendipitous observation that a technician working in a laboratory studying the serology of African children with BL became EBV seropositive as she recovered from the illness. Studies of college students followed that helped better define the syndrome. In a recent cohort study from the United Kingdom, more than 500 seronegative university students were followed for 3 years. Seroconversion occurred in 46%. Among seroconverters, infectious mononucleosis developed in 25%. But why some primary infection is associated with symptoms in some but not others remains a matter of speculation. Sexual activity, host age, host immune response polymorphisms, infection with particular strains of virus, and the size of the primary innoculum are all possible determinants. Recently, it has been recognized that infection with multiple viral strains is the rule rather than the exception. Viral copy number in whole blood correlates with severity and duration of symptoms. Whole-blood measurements do not distinguish between viremia (virions) or latently infected lymphocytes. Fine mapping of the evolution of the specific cellular immune response to viral antigens has progressed, as has an appreciation of the importance of innate immunity. Investigators have reported that EBV infectious mononucleosis is associated with a lifelong "immunologic scar." Individuals with a history of primary symptomatic disease differ from other healthy EBV seronegative and EBV seropositive individuals in that they lack CD8 T cells and natural killer (NK) cells expressing IL-15 receptor (recognized by flow cytometry for IL-15R). Assays of IL-15 responsiveness indicate that the absence of these cells have functional correlates in vitro. Whether they have clinical correlates is unknown. Remarkably, the change in lymphocyte cell populations is sustained over years and perhaps decades. No similar sustained change in the phenotype of lymphocytes accompanies the infectious mononucleosis-like syndrome associated with primary cytomegalovirus infection (or acute viral illnesses such as influenza). But what is the significance of the scar? Are there long-standing consequences with regard to health? As discussed below, EBV+ HL may be one of the consequences." A history of infectious mononucleosis was first linked to HL in reports in the 1950s.

X-Linked Lymphoproliferative Syndrome

Lymphoproliferative Syndrome, X-Linked, 1; XLP1; also known as XLP; EBV Susceptibility, etc. "X-linked lymphoproliferative syndrome is caused by mutation in the SHD2D1A gene encoding SLAM-associated protein (SAP)... X-linked lymphoproliferative syndrome, or Duncan disease, is characterized by extreme sensitivity to infection with Epstein-Barr virus, which results in a complex phenotype manifested by severe or fatal mononucleosis, acquired hypogammaglobulinema, and malignant lymphoma. Other features may include aplastic anemia, red cell aplasia, and lymphomatoid granulomatosis.... Coffey et al. (1998) noted that the average age of disease onset in XLP is 2.5 years, with 100% mortality by the age of 40 years. Following infection with EBV, patients mount a vigorous, uncontrolled polyclonal expansion of T and B cells. The primary cause of death is hepatic necrosis and bone marrow failure. The extensive tissue destruction of the liver and bone marrow appears to stem from the uncontrolled cytotoxic T-cell response."

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cast 01-04-12