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.

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 Feb 13 [Epub ahead of print]. "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."

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."

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 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)."

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 carcinoma in Egyptian women. S Fawzy, M Sallam, N Mohammad Awad. Clin Biochem 2008 Jan 3 [Epub ahead of print]. 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."

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."

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.

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 03-07-08