History Of Infectious Mononucleosis Research Articles

Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein.

A history of infectious mononucleosis (IM), symptomatic primary infection with the Epstein Barr virus, is associated with the development of autoimmune diseases and increases the risk to develop multiple sclerosis. Here, we hypothesized that immune activation during IM triggers autoreactive immune responses. Antibody responses towards cellular antigens using a HEp-2 based indirect immunofluorescence assay and native myelin oligodendrocyte glycoprotein (MOG) using a flow cytometry-based assay were determined in 35 patients with IM and in 23 control subjects. We detected frequent immunoglobulin M (IgM) reactivity to vimentin, a major constituent of the intermediate filament family of proteins, in IM patients (27/35; 77%) but rarely in control subjects (2/23; 9%). IgG autoantibodies binding to HEp-2 cells were absent in both groups. In contrast, IgG responses to native MOG, present in up to 40% of children with inflammatory demyelinating diseases of the central nervous system (CNS), were detectable in 7/35 (20%) patients with IM but not in control subjects. Normalization of anti-vimentin IgM levels to increased total IgM concentrations during IM resulted in loss of significant differences for anti-vimentin IgM titers. Anti-MOG specific IgG responses were still detectable in a subset of three out of 35 patients with IM (9%), even after normalization to increased total IgG levels. Vimentin-specific IgM and MOG-specific IgG responses decreased following clinical resolution of acute IM symptoms. We conclude from our data that MOG-specific memory B cells are activated in subset of patients with IM.

Does low socioeconomic status in early life protect against multiple sclerosis? A multinational, case–control study

The findings from existing research on the association between socioeconomic status (SES) and multiple sclerosis (MS) are inconsistent. Most previous studies are limited to one country and do not adequately adjust for other risk factors for the disease. The association between SES and MS was examined using data from the multinational Environmental Risk Factors in Multiple Sclerosis (EnvIMS) case-control study, comprising 2144 cases and 3859 controls from Norway, Canada and Italy. Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between early life SES, measured by parental educational level, and MS. Analyses were adjusted for age, sex, sunlight exposure, history of infectious mononucleosis, smoking, obesity and family size. Relative to those whose parents had primary school education or below, the adjusted odds ratio (95% confidence interval) for MS amongst individuals with university-educated parents, and the P value for trend across education levels, were 1.45 (1.03-2.05) in Canada (P for trend 0.030), 1.09 (0.85-1.39) in Norway (P for trend 0.395) and 0.65 (0.39-1.07) in Italy (P for trend 0.158). There is no consistent association between parental SES and MS risk in Norway, Canada and Italy, with a protective effect of low SES only found in Canada.

Immune response induced by Epstein–Barr virus and Mycobacterium avium subsp. paratuberculosis peptides in current and past infectious mononucleosis: a risk for multiple sclerosis?

Infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) has been associated with increased risk of multiple sclerosis (MS). However, the mechanism linking these pathologies is unclear. Different reports indicate the association of EBV, and recently Mycobacterium avium subsp. paratuberculosis (MAP), with MS. For a better understanding of the role of these pathogens, the host response induced by selected antigenic peptides in subjects with a history of IM that significantly increases the risk of MS was investigated. Both humoral and cell-mediated response against peptides able to induce a specific immune activation in MS patients deriving from lytic and latent EBV antigens BOLF1(305-320), EBNA1(400-413), from MAP MAP_4027(18-32), MAP_0106c(121-132) and from human proteins IRF5(424-434) and MBP(85-98) in subjects with current and past IM were examined. EBNA1 and MAP_0106c peptides were able to induce a humoral immune response in subjects with a history of clinical IM in an independent manner. Moreover, these peptides were capable of inducing pro-inflammatory cytokine interferon γ by CD4+ and CD8+ T lymphocytes and interleukin 6 and tumour necrosis factor α by CD14+ monocyte cells. Our results highlight that EBV and MAP may be involved independently in the same causal process leading to MS in subjects with a history of IM.

Common Immune-Related Exposures/Conditions and Risk of Non-Hodgkin Lymphoma: A Case-Control Study of Disease-Discordant Twin Pairs

We evaluated the association between common immune system-altering experiences and non-Hodgkin lymphoma (NHL) risk using a case-control study of 162 like-sex twin pairs discordant for NHL, identified from the International Twin Study. Information on medical history and evidence of childhood exposure to microbes was obtained by questionnaire from 1998 to 2002. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. Intra-twin-pair agreement between twins on individual exposures was high (76%-97%). A negative association between NHL and seasonal hay fever (odds ratio (OR) = 0.28, 95% confidence interval (CI): 0.10, 0.75) and certain allergies (OR = 0.29, 95% CI: 0.13, 0.68) was observed. The number of atopic diseases was negatively associated with NHL (P for trend = 0.0003). A history of infectious mononucleosis was negatively associated with NHL risk (OR = 0.35, 95% CI: 0.14, 0.90). NHL risk was associated with more frequent childhood exposure to microbes during early life (P for trend = 0.04). No differences in association by NHL subtype were observed, although statistical power for these comparisons was low. These observations support the hypothesis that immune-related exposures, especially atopy, are associated with decreased NHL risk. Use of the within-twin-pair study design mitigates confounding by genome, family structure, and unmeasured characteristics of early childhood factors.

No association between rs6897932 in the gene encoding interleukin-7 receptor α and low-grade inflammation or self-reported health - results from the Danish Blood Donor Study.

The T-allele in the single nucleotide polymorphism rs6897932 in the gene encoding the IL-7 receptor α (IL7RA) is associated with reduced risk of autoimmune diseases including multiple sclerosis and also affects the course of HIV infection. Low-grade inflammation (LGI) and self-reported, health-related quality of life (HRQL) are often associated with chronic diseases and widely used in assessing and monitoring health status. The aim of the present study was to evaluate whether the T-allele in rs6897932 is associated with reduced risk of LGI (hsCRP 3-10mg/L), history of infectious mononucleosis (IM), and HRQL in healthy individuals. A total of 17, 293 healthy Danish individuals from the Danish Blood Donor Study were included in the analyses. We tested rs6897932 as a predictor of LGI, self-reported IM, and HRQL in univariable and multivariable models stratified by sex. No associations between rs6897932 and LGI, self-reported IM or HRQL were found in men or women. This suggests that rs6897932 is not associated with general inflammation, and the reported associations between the T-allele in rs6897932 with several autoimmune diseases may be mediated through effects on a restricted part of the immune system.

Epstein–Barr virus candidate genes and multiple sclerosis

BackgroundPrevious infection with Epstein–Barr virus (EBV) and a history of infectious mononucleosis (IM) have been previously associated with an increased risk of multiple sclerosis (MS). Whether there are common genetic factors that may partially explain these associations has not been thoroughly explored. ObjectiveTo investigate whether select polymorphisms in genes associated with IM susceptibility are related to MS risk—a self-reported history of IM or antibody titer against Epstein–Barr virus nuclear antigen 1 (anti-EBNA1). MethodsA case-control study including 1213 MS cases and 454 controls enrolled in the Accelerated Cure Project for MS (ACP) Repository. Select polymorphisms in HLA-A, SH2D1A and IL15RA and anti-EBNA1 Ab titers were measured using stored blood samples provided by participants. Generalized linear models were used to assess the associations between select polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titers. ResultsNo significant associations were observed between the selected polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titer. ConclusionIt is unlikely that any of the studied polymorphisms contribute to the explaining the association between anti-EBNA1 Ab titer or history of IM and MS.

Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis

Background: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). Objective: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA-DR15 are associated with NMO or TM. Methods: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. Results: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. Conclusions: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently.

Editorial Commentary: Genetics and Infectious Mononucleosis

(See the Major Article by Rostgaard et al on pages 1684–9.) The epidemiology of primary Epstein-Barr virus (EBV) infection is not completely understood. We know that kissing is the major route of transmission of primary EBV infection among teenagers and young adults [1], but we do not know the mechanism(s) of transmission among preadolescent children. In addition, we do not know why the majority of primary EBV infections in young children go unrecognized [2], whereas those in adolescents and young adults usually result in infectious mononucleosis (IM) [1]. We also do not know whether it is better to get infected by EBV early in life or later on. Evidently, much remains to be learned about the enigmatic epidemiology of EBV, but we now have some compelling information that genes are involved. In this issue of Clinical Infectious Diseases, Rostgaard and colleagues tracked familial clustering of hospitalized cases of IM [3]. Using very large Danish national databases, these investigators reported that same-sex twins had a rate ratio of 9.3 for mono, compared with 2.3 for first-degree relatives (opposite-sex twins, siblings, and parents), 1.4 for second-degree relatives (half-siblings, grandparents, uncles, and aunts), and 1.0 for third-degree relatives (first cousins). The 95% confidence intervals for those 4 classes of relationships did not overlap, supporting the conclusion that degree of relatedness increased the likelihood of contracting mono. Hwang et al, utilizing the California Twin Program registry, reported that concordance for IM in monozygotic twins was twice that of dizygotic twins [4]. They interpreted their results as consistent with a genetic contribution to susceptibility to mono. Twins certainly share the same environment and likely have similar behavior, which cannot be ruled out as risk factors. However, the significantly greater number of cases in monozygotic or same-sex twins vs dizygotic or opposite-sex twins in both the California and the Danish studies is compelling evidence that susceptibility to IM has a genetic component. A strength of both studies was the large size of the cohort investigated. A limitation of the Danish study was that only relatively severe IM was captured (85% of the cases were inpatient admissions), and therefore the results may not be applicable to typical outpatient cases of mono. Shortcomings of both studies include the lack of laboratory confirmation of EBV infection, and few data on racial groups other than whites. Rostgaard and colleagues suggest that genome-wide association studies might uncover EBV susceptibility loci that not only confer a risk for IM but also for development of EBV-associated cancer or autoimmune disease. Including diverse racial/ethnic groups in such investigations could broaden our ability to discover important genetic variants associated with acquisition, severity, and sequelae of EBV infection. In support of this, 2 separate cross-sectional surveys of US children found that early acquisition of EBV infection, as evidenced by having antibodies against EBV viral capsid antigen, was a racial disparity that could not be satisfactorily explained by socioeconomic factors alone [5, 6]. The enormous difference in overall age- and sex-adjusted EBV antibody prevalence between non-Hispanic white (32%) and non-Hispanic black children (62%) in the study by Condon et al [6] is consistent with a genetic basis for the racial clustering of EBV infection in younger children. A history of IM predisposes to Hodgkin lymphoma [7] and multiple sclerosis [8]. Why? A plausible explanation is that more severe primary EBV infection reflects dysregulated immune control of the virus (probably due to the host's genetic makeup), which persists during viral latency, eventually leading to EBV-associated malignancy or autoimmune disease. Rostgaard and colleagues have told us that susceptibility to symptomatic EBV infection is genetically influenced. Our challenge now is to find a candidate genetic marker that identifies individuals in jeopardy for serious EBV disease so that we can recognize them and potentially intervene before they get sick. These individuals would greatly benefit from a prophylactic EBV vaccine, and such vaccines are now in development [9].

Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors

Background: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence. Objective: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada. Methods: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases. Results: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 – 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019). Conclusion: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.

Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis

Gene–environment interactions may shed light on the mechanisms underlying multiple sclerosis (MS). We pooled data from two case-control studies on incident demyelination and used different methods to assess interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). Individuals exposed to both factors were at substantially increased risk of disease (OR=7.32, 95% CI=4.92–10.90). In logistic regression models, DRB1-15 and IM status were independent predictors of disease while their interaction term was not (DRB1-15*IM: OR=1.35, 95% CI=0.79–2.23). However, interaction on an additive scale was evident (Synergy index=2.09, 95% CI=1.59–2.59; excess risk due to interaction=3.30, 95%CI=0.47–6.12; attributable proportion due to interaction=45%, 95% CI=22–68%). This suggests, if the additive model is appropriate, the DRB1-15 and IM may be involved in the same causal process leading to MS and highlights the benefit of reporting gene–environment interactions on both a multiplicative and additive scale.

Pulmonary Carcinosarcoma

We present a case of pulmonary carcinosarcoma. The patient is a 31-year-old man with a history of infectious mononucleosis in whom a right lung mass was found. His age is lower than the mean age at which pulmonary carcinosarcoma is usually reported. Chest CT scan showed a lobulated 29-mm mass in the right upper lung and multiple hypervascular liver nodules. FDG PET/CT showed increased FDG uptake in the right upper lung nodule (SUVmax, 4.1). However, the hepatic radiouptake showed only background activity. The liver nodules were stable at the 1-year follow-up period and were suggestive of hemangiomas.

Infectious mononucleosis and risk of breast cancer in a prospective study of women.

The association between infectious mononucleosis (IM) and risk of breast cancer is unclear; no prospective studies have examined this relationship. We examined self-reported history and age at IM in relation to risk of invasive breast cancer. Self-reported history and age at IM were examined in relation to risk of invasive breast cancer in a large cohort of women, the Nurses' Health Study II (81,807 women followed from 1989 to 2007). Through questionnaires, women were asked whether they ever had IM and if so, at what age. During follow-up, 2,349 cases of invasive breast cancer were documented. Cox proportional hazards regression was used to estimate relative risks (RR) and 95 % confidence intervals (CI) for the association of IM with breast cancer. The multivariable-adjusted RR for history of IM and risk of invasive breast cancer was 1.00 (95 % CI: 0.90-1.11). Similar null results were obtained when estrogen receptor/progesterone receptor positive and negative tumors were considered separately. There were no clear patterns of association between age at IM and risk of breast cancer: compared to women with no history of IM, those who were ≤15 years old when they had IM were at lower risk (RR: 0.77; 95 % CI: 0.60, 0.97), but there was no association for women who had IM at ages 16-19, 20-24, or 30+. However, an increased RR (1.45; 95 % CI: 1.02-2.04) was observed for women who had IM at ages 25-29. Results of this large prospective study do not support a clear association between history of clinical IM and risk of invasive breast cancer.

Heart disease, overweight, and cigarette smoking are associated with increased prevalence of extra-cranial venous abnormalities

Objectives: Most of the extra-cranial venous abnormalities have been previously described as truncular venous malformations. In this hypothesis-driven study, we evaluated possible association of risk/protective factors with the presence of truncular and functional venous abnormalities in internal jugular veins (IJVs) in a large cohort of volunteers without known central nervous system (CNS) pathology.Methods: The study included 240 controls who underwent physical and Doppler sonography (DS) examinations for the presence of intra- and extra-luminal structural and functional abnormalities of the IJVs, and were assessed with a physical examination and structured environmental questionnaire for demographic characteristics, presence of autoimmune and other concomitant diseases, vascular risk factors, environmental factors, and habits. Logistic regression analysis was used to test which risk/protective factors were associated with the presence and number of extra-cranial venous abnormalities.Results: Subjects with heart disease (P<0·001), overweight (P = 0·005), and smoking (P = 0·016) had a significantly increased number of intra-luminal structural venous abnormalities. Presence of heart disease increased the risk of a malformed valve 12·9 times (95% CI: 5·4–31·3, P<0·001), while smoking increased it 2·21 times (95% CI: 1–4·9, P = 0·033). Being overweight (P = 0·003), a history of mononucleosis (P = 0·012) and smoking (P = 0·042) increased risk for presence of a flap. No association was found between the investigated risk factors and extra-luminal or functional venous abnormalities. However, use of dietary and herbal supplements had a protective role for the presence of functional venous abnormalities.Conclusions: There is a close association between intra-luminal, structural, extra-cranial, venous system pathology and the presence of heart disease, overweight, and smoking.

Epstein–Barr virus cause of multiple sclerosis

The cause of multiple sclerosis (MS) has eluded medical science for over a century. Pierre Marie speculated that MS is an infectious disease and this paradigm has had a prominent place in the discussion. A number of candidate pathogens have been proposed, but most have not survived scrutiny. In this review, we summarize the evidence that MS is caused by Epstein-Barr virus (EBV), which has been a prominent candidate for several decades. Although there is much suggestive evidence that EBV is involved in the pathogenesis of MS, the precise effect of EBV is still unclear. EBV is more common in MS patients than in controls. A history of infectious mononucleosis, and high baseline EBV antibody titers are risk factors for MS. More controversial are findings of changes in the reactivity of the T-cell repertoire, presence of EBV antibodies in the cerebrospinal fluid, and presence of EBV in meningeal lymphoid follicles and perivenular infiltrates in the white matter. The contribution of EBV to the cause of MS is not yet established, but a relationship is clearly present.

Risk Factors for Chronic Cerebrospinal Venous Insufficiency (CCSVI) (P05.127)

Objective: To investigate the association between presence of a newly proposed vascular condition called chronic cerebrospinal venous insufficiency (CCSVI) and environmental factors in a large volunteer control group without a known central nervous system pathology. Background The role of intra- and extra-cranial venous system impairment in the pathogenesis of various vascular, inflammatory and neurodegenerative neurological disorders, as well as in aging, has not been studied in detail. Design/Methods: The data were collected in a prospective study from 252 subjects who were screened for medical history as part of the entry criteria and participated in the case-control study of CCSVI prevalence in multiple sclerosis (MS) patients and were analyzed post hoc. All participants underwent physical and Doppler sonography examinations, and were assessed with a structured environmental questionnaire. Fullfilment of ≥ 2 positive venous hemodynamic (VH) criteria on Doppler sonography was considered indicative of CCSVI diagnosis. Risk and protective factors associated with CCSVI were analyzed using logistic regression analysis. Results: Seventy (27.8%) subjects presented with CCSVI diagnosis and 153 (60.7%) presented with one or more VH criteria. The presence of heart disease (p=.001), especially heart murmurs (p=.007), a history of infectious mononucleosis (p=.002), and irritable bowel syndrome (p=.005) were associated with more frequent CCSVI diagnosis. Current or previous smoking (p=.029) showed a trend for association with more frequent CCSVI diagnosis, while use of dietary supplements (p=.018) showed a trend for association with less frequent CCSVI diagnosis. Conclusions: Risk factors for CCSVI differ from established risk factors for peripheral venous diseases. Vascular, infectious and inflammatory factors were associated with higher CCSVI frequency. Supported by: Funded with internal resources of the Buffalo Neuroimaging Analysis Center and Baird MS Center, the Jacobs Neurological Institute, University of Buffalo. In addition, we received support from the Direct MS Foundation and the Jacquemin Foundation. Disclosure: Dr. Dolic has nothing to disclose. Dr. Weinstock-Guttman has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Serono, Inc., Novartis, Pfizer Inc, Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weinstock-Guttman has received research support from Acorda Therapeutics, Biogen Idec, Serono Inc., Novartis, Pfizer Inc, Teva Neuroscience, National Multiple Sclerosis Society, the National Institutes of Health, ITN, Teva Neuroscience, Aspreva-Roche, Acorda Therapeutics and Shire Pharmaceuticals. Dr. Marr has nothing to disclose. Dr. Valnarov has nothing to disclose. Dr. Carl has nothing to disclose. Dr. Hagemeier has nothing to disclose. Dr. Brooks has nothing to disclose. Dr. Kilanowski has nothing to disclose. Dr. Ramanathan has received personal compensation for activities with EMD Serono, Biogen Idec, Allergan, Netezza, Pfizer, Novartis, The National Multiple Sclerosis Society, The Department of Defense, Jog for the Jake Foundation, and The National Institutes of H as a consultant.Dr. Ramanathan has received personal compensation in an editorial capacity for The American Association of Pharmaceutical Scientists.Dr. Ramanathan has received research support from EMD Serono, Biogen Idec, Allergan, Netezza, Pfizer, Novartis, The National Multiple Sclerosis Society, The Department of Defense, Jog for the Jake Foundation, and The National Institutes of H. Dr. Zivadinov has received personal compensation for activities with Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals as a speaker and/or consultant. Dr. Zivadinov has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corporation, Bracco, Questcor Pharmaceuticals and EMD Serono.

Epstein-Barr virus in multiple sclerosis

Genetic and environmental factors determine the susceptibility to develop multiple sclerosis (MS). Improved epidemiologic study designs helped identify environmental risk associations for MS, such as a history of infectious mononucleosis (IM), a symptomatic primary infection with the human γ-herpesvirus Epstein-Barr virus (EBV). EBV preferentially infects B lymphocytes and persists lifelong in a transcriptionally quiescent state in circulating latently infected memory B cells (0.5 to 50 per million). Lytic EBV infection can occur from the memory B-cell pool, presumably after an encounter with the cognate B-cell receptor antigen. The immune control of EBV infection centers around strong memory CD4+ and CD8+ T-cell responses, whereby the CD4+ T cells maintain EBV-specific immunity, and both CD4+ and CD8+ T cells can target EBV-infected cells directly. Patients with MS are nearly universally seropositive for EBV (i.e., close to 100% in adults and >90% in children) compared with seropositivity rates of 90%–95% in adults and less than 80% in age-matched pediatric cohorts and show deregulated T-cell and antibody responses to EBV-encoded antigens. These changes are initiated early in disease development, since increased EBV-specific antibody titers are detectable as early as 5 or more years before the clinical onset of MS.1 In patients with clinically isolated syndromes and …

Risk Factors for Chronic Cerebrospinal Venous Insufficiency (CCSVI) in a Large Cohort of Volunteers

BackgroundThe role of intra- and extra-cranial venous system impairment in the pathogenesis of various vascular, inflammatory and neurodegenerative neurological disorders, as well as in aging, has not been studied in detail. Nor have risk factors been determined for increased susceptibility of venous pathology in the intra-cranial and extra-cranial veins. The aim of this study was to investigate the association between presence of a newly proposed vascular condition called chronic cerebrospinal venous insufficiency (CCSVI) and environmental factors in a large volunteer control group without known central nervous system pathology.Methods and FindingsThe data were collected in a prospective study from 252 subjects who were screened for medical history as part of the entry criteria and participated in the case-control study of CCSVI prevalence in multiple sclerosis (MS) patients, and then were analyzed post-hoc. All participants underwent physical and Doppler sonography examinations, and were assessed with a structured environmental questionnaire. Fullfilment of ≥2 positive venous hemodynamic (VH) criteria on Doppler sonography was considered indicative of CCSVI diagnosis. Risk and protective factors associated with CCSVI were analyzed using logistic regression analysis. Seventy (27.8%) subjects presented with CCSVI diagnosis and 153 (60.7%) presented with one or more VH criteria. The presence of heart disease (p = .001), especially heart murmurs (p = .007), a history of infectious mononucleosis (p = .002), and irritable bowel syndrome (p = .005) were associated with more frequent CCSVI diagnosis. Current or previous smoking (p = .029) showed a trend for association with more frequent CCSVI diagnosis, while use of dietary supplements (p = .018) showed a trend for association with less frequent CCSVI diagnosis.ConclusionsRisk factors for CCSVI differ from established risk factors for peripheral venous diseases. Vascular, infectious and inflammatory factors were associated with higher CCSVI frequency.

Antibody titers against EBNA1 and EBNA2 in relation to Hodgkin lymphoma and history of infectious mononucleosis

A role for Epstein Barr virus (EBV) in Hodgkin lymphoma (HL) pathogenesis is supported by the detection of EBV genome in about one-third of HL cases, but is not well defined. We previously reported that an elevated prediagnosis antibody titer against EBV nuclear antigens (EBNA) was the strongest serologic predictor of subsequent HL. For the present analysis, we measured antibody levels against EBNA components EBNA1 and EBNA2 and computed their titer ratio (anti-EBNA1:2) in serum samples from HL cases and healthy siblings. We undertook this analysis to examine whether titer patterns atypical of well-resolved EBV infection, such as an anti-EBNA1:2 ratio ≤ 1.0, simply reflect history of infectious mononucleosis (IM), an HL risk factor, or independently predict HL risk. Participants were selected from a previous population-based case-control study according to their history of IM. We identified 55 EBV-seropositive persons with a history of IM (IM+; 33 HL cases, 22 siblings) and frequency-matched a comparison series of 173 IM history-negative, EBV-seropositive subjects on HL status, gender, age and year of blood draw (IM-; 105 cases, 58 siblings). In multivariate logistic regression models, an anti-EBNA1:2 ratio ≤ 1.0 was significantly more prevalent in HL cases than siblings (odds ratio, 95% confidence interval = 2.43, 1.05-5.65); similar associations were apparent within the IM+ and IM- groups. EBNA antibodies were not significantly associated with IM history in HL cases or siblings. These associations suggest that chronic or more severe EBV infection is a risk factor for HL, independent of IM history.

Epstein-Barr virus and multiple sclerosis: interaction with HLA

Epstein-Barr virus (EBV) infection, history of infectious mononucleosis (IM) and HLA-A and DRB1 have all been proposed as risk factors for multiple sclerosis (MS). Our aim was to analyse possible interactions between antibodies against Epstein-Barr virus nuclear antigen 1 (EBNA1) or EBNA1 fragments, presence of DRB1*15 and absence of A*02. The study population includes newly diagnosed cases and matched controls. Interaction on the additive scale was calculated using attributable proportion due to interaction (AP), which is the proportion of the incidence among individuals exposed to two interacting factors that is attributable to the interaction per se. 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

To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors. This was a multicenter incident case-control study. FCD cases (n = 282) aged 18-59 years and controls (n = 558, matched on age, sex, and region) were recruited from 4 Australian centers between November 1, 2003, and December 31, 2006. A nested study (n = 215 cases, n = 216 controls) included measurement of whole blood quantitative EBV DNA load and serum EBV-specific antibodies. Conditional logistic regression was used to analyze case-control differences. 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. We found additional interactions between high anti-EBNA IgG titer and SNPs in HLA-A (adjusted odds ratios [AOR] = 19.84 [95% confidence interval (CI) 5.95 to 66.21] for both factors compared to neither) and CTLA-4 genes (AOR = 0.31 [95% CI 0.13 to 0.76] for neither factor compared to both). EBV DNA load was lower at higher serum 25-hydroxyvitamin D concentrations in controls (r = -0.17, p = 0.01). An adverse effect of higher EBV DNA load on FCD risk was increased with higher 25-hydroxyvitamin D concentration (p[interaction] = 0.02). Past infection with EBV, but not current EBV DNA load in whole blood, is significantly associated with increased FCD risk. These associations appear to be modified by immune-related gene variants.