Potential viral causes
Objective: To investigate Epstein-Barr virus (EBV) oral shedding frequency and EBV genetic diversity in pediatric patients with multiple sclerosis (MS).
Methods: This was a prospective case-control study. We used PCR-based assays to detect viral DNA in the monthly mouth swabs of 22 pediatric patients with MS and 77 age- and sex-matched healthy controls. EBV-positive samples were further analyzed for sequence variation in the EBV BCRF1 (ebvIL-10) gene using direct DNA sequencing methods, and in the EBV LMP1 gene by mass spectrometry.
Results: Nineteen of the 22 (86.4%) children with MS were seropositive for remote EBV infection compared to 35 out of 77 (45.5%) healthy controls (p = 0.008). Baseline analysis of mouth swabs revealed a higher proportion of EBV-positive samples from EBV-seropositive patients with MS compared to EBV-seropositive healthy controls (52.6% vs 20%, p = 0.007). Longitudinal analysis of monthly swabs revealed average EBV detection rates of 50.6% in patients with MS and 20.4% in controls (p = 0.01). The oral shedding frequencies of Herpesviruses herpes simplex virus–1, cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 did not differ between groups. Changes in the predominant EBV genetic variants were detected more frequently in patients with MS; however, no specific EBV genetic variant was preferentially associated with MS.
Conclusion: Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV.
Carmen Yea, MSc, Raymond Tellier, MD, Patrick Chong, PhD, Garrett Westmacott, PhD, Ruth Ann Marrie, MD, PhD, Amit Bar-Or, MD, Brenda Banwell, MD; On behalf of the Canadian Pediatric Demyelinating Disease Network
Source: Neurology © 2013 American Academy of Neurology (30/10/13)
Assessing interactions between HLA-DRB1*15 and infectious mononucleosis on the risk of multiple sclerosis
Summary: This study from the UK looked at gene-environment interactions in MS.
The researchers looked at the interaction between HLA-DRB1*15 (DRB1-15) and history of infectious mononucleosis (IM). They found that individuals exposed to both factors were at an increased risk of disease. Both DRB1-15 and IM status were independent predictors of disease, while there interaction term was not, but interaction on an additive scale was evident.
Based on this, if the additive model is appropriate, the DRB1-15 and IM may be part of the causal process leading to MS. This study demonstrates the importance of reporting gene-environment interactions on both a multiplicative and additive scale.
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.
Authors: Disanto G, Hall C, Lucas R
Source: Mult Scler. 2013 Feb 14 & Pubmed PMID: 23413297 (20/02/13)
Although theories that multiple sclerosis arises from viral infections are alive and well, exposure to one virus -- cytomegalovirus (CMV) -- is associated with reduced risk for the disease, a researcher said here.
In a study of 669 MS patients and 786 controls who did not have MS, individuals testing positive for anti-CMV antibodies were about 30% less likely to have MS, reported Ingrid Kockum, PhD, of the Karolinska Institute in Stockholm.
The finding stayed significant and robust after adjustment for gender, body mass index, ethnic origin, and age at sampling and at disease onset, she told attendees at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
A number of earlier studies have implicated Epstein-Barr virus (EBV) as a possible cause of MS, largely on the basis of epidemiological associations, but also in research that found, for example, EBV genetic elements lurking in MS patients' brain lesions.
So-called endogenous retroviral elements in the human genome have also been linked to MS, according to Renaud Du Pasquier, MD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, who preceded Kockum at the ECTRIMS podium.
That link appears strong enough to prompt clinical trials with a monoclonal antibody targeting these elements, he noted.
CMV, as another common viral infection, has also been looked at previously for possible associations with MS, but there's been no consensus on its role. Kockum pointed to one study that found a dramatically lower risk of paediatric MS in children with prior CMV exposure, while another found a modest increase in risk of adult MS in CMV-seropositive individuals.
She and her colleagues analyzed data from two cohorts of patients and controls participating in a Swedish epidemiological study of MS called EIMS.
This study, begun in 2005, has recruited a total of about 2,000 patients and 3,000 controls, all of whom completed questionnaires and provided a blood or saliva sample for genetic analysis.
The data confirmed the positive association of EBV exposure with MS risk. More than two-thirds of the 669 patients in the EIMS cohorts had anti-EBV antibody titres higher than the median among controls.
But the presence of anti-CMV antibodies was significantly lower in patients than controls, Kockum reported.
After adjusting for gender imbalances, the odds ratio for MS among CMV-seropositive individuals in the first EIMS cohort was 0.69 (95% CI 0.52 to 0.90, P=0.007), and in the second cohort it was 0.65 (95% CI 0.52 to 0.82, P=0.0002).
CMV seropositivity was not evenly distributed among patients or controls. It was more common among women, individuals of lower socioeconomic status, those with higher body mass index values, and older participants.
But the association between CMV exposure and MS remained significant irrespective of gender, BMI, socioeconomic status, and age.
In a multivariate analysis that adjusted for these factors, the odds ratio for MS in CMV-seropositive participants in both cohorts combined was 0.73 (95% CI 0.57 to 0.91).
The association was also unaffected by participants' genotype, smoking status, or anti-EBV antibody titers, Kockum said.
But she cautioned that the study results did not prove that CMV infection is somehow protective against MS. How such an effect might work is unknown, she said, although the infection is known to leave a lasting imprint on immune cell distributions and activity.
The study was funded by the Wallenberg Foundation, the Swedish Research Council, the Swedish Council for Working Life and Social Research, and the Swedish Association of Persons with Neurological Disabilities.
Study authors reported relationships with Biogen Idec, Sanofi, Merck Serono, and Bayer Schering.
Du Pasquier reported serving on scientific advisory boards for Biogen Idec, Merck Serono, Teva, and Novartis and has received funding for travel, speaker honoraria, or support for research from Abbott, Bayer Schering Pharma, Biogen Idec, Merck Serono, Teva, and ViiV.
Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Sundqvist E, et al "Cytomegalovirus seropositivity is associated with lower multiple sclerosis risk" ECTRIMS 2012.
Source: MedPage Today © 2012 MedPage Today, LLC (12/10/12)
Objective: Vitamin D deficiency and Epstein-Barr virus (EBV) infection may be associated with the development of multiple sclerosis (MS).
We investigated serum 25-hydroxyvitamin D (25-OH-D) levels and anti-EBV immunoreactivity in 25 individuals before the first clinical manifestation of MS.
Patients and methods:
• 56 serum samples of 25 individuals who had donated blood prior to the first clinical MS manifestation (clinically isolated syndrome (CIS))
• Four male subjects, 21 female subjects,
• Mean age 31.5 years at time of pre-CIS blood sampling;
• Mean age at disease onset 33.4 years…
….were available, covering an interval of 7.3 years-2 months (mean 31.5 months) before CIS.
In 18 of 25 patients serum samples were also obtained after established diagnosis of MS.
Longitudinal age- and gender-matched healthy blood donors (four male subjects, 21 female subjects, 39 samples, mean age 32.5 years) served as controls.
Serum 25-OH-D was measured by isotope dilution-liquid chromatography-tandem mass spectrometry. 25-OH-D levels were deconvoluted using published seasonal coefficients from a German population.
Immunoglobulin G (IgG) against Epstein-Barr virus nuclear antigen-1 (EBNA1) were assessed using commercially available ELISA.
• Low 25-OH-D levels were observed during the 24-month pre-CIS interval (47.8 (32.5-77.2) nmol/l, median (IQR); healthy controls: 81.6 (57.7-98.5), p=0.004,
• However, still higher than after established diagnosis (24.5 (13.7-47.7), p
• IgG against EBNA1 during the 36-month pre-CIS interval was increased (185.9 (91.2–460.0) IU/ml, median (IQR); healthy controls 63.7 (29.5–121.6), p=0.002).
Conclusions: Low vitamin D and remote EBV infection may be associated with clinical MS breakthrough within 2–3 years.
By Brenard F Decard, Andrew Chan, et al
Source: Journal of Neurology, Neurosurgery and Psychiatry, Aug 11, 2012. PMID:22888143
Source: ProHealth Copyright © 2012 ProHealth, Inc (20/08/12)