Potential viral causes
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)
Multiple sclerosis (MS) is a disease with multiple etiologies. The most recent theory of the vascular etiology of MS, Chronic Cerebrospinal Venous Insufficiency (CCSVI), suggests that cerebral venous obstruction could lead to cerebral venous reflux, promoting local inflammatory processes.
This review article offers strong evidence that the route of the observed narrowing of cerebral veins arises from autonomic nervous system dysfunction, particularly cardiovascular autonomic dysfunction.
The dysfunction of this system has two major effects: 1) the reduction of mean arterial blood pressure, which has the potential to reduce the cerebral perfusion pressure and the transmural pressure, and 2) the failure of cerebral autoregulation to maintain constant cerebral blood flow in the face of fluctuations in cerebral perfusion pressure. Alterations in cerebral autoregulation could in turn raise the critical closure pressure, indicated to be the cerebral perfusion pressure at which the transmural pressure will be sub-sufficient to overcome the active tension imparted by the smooth muscle layer of the vessel. These two effects of autonomic nervous system dysfunction (reduction in arterial blood pressure and alterations in cerebral autoregulation), when combined with inflammation-induced high levels of nitric oxide in the brain, will lower transmural pressure sufficiently to the point where the threshold for critical closure pressure is reached, leading to venous closure.
In addition, cerebral vessels fail to overcome the closure as a result of low central venous pressure, which is also regulated by autonomic nervous system function. Furthermore, through their neuroregulatory effects, infectious agents such as the Epstein-Barr virus and vitamin D3 are able to alter the functions of the autonomic nervous system, influencing the rate of CCSVI occurrence.
The absence of CCSVI specificity for MS, observed in recent clinical studies, may stem from a high prevalence of autonomic nervous system dysfunction in control groups which were recruited to these studies. Future studies should investigate CCSVI in relation to cardiovascular autonomic function.
Abbreviations ANS, autonomic nervous system; BBB, blood brain barrier; BP, blood pressure; CCSVI, chronic cerebrospinal venous insufficiency; CIS, clinically isolated syndrome; CP, chronic progressive; CrCP, critical closure pressure; EBV, Epstein-Barr virus; EDSS, expanded disability status scale; HR, heart rate; IJV, internal jugular vein; MBP, myelin basic protein; PTA, percutaneous transluminal angioplasty; RR, relapsing remitting; SLE, systemic lupus erythematosus; Vit D, 1,25-dihydroxyvitamin D
Zohara Sternberg, Department of Neurology, Baird MS center, Jacobs Neurological Institute, 100 High St. Buffalo, NY 14203, USA
Source: Autoimmunity Reviews Copyright © 2012 Published by Elsevier B.V. (08/05/12)
Might some forms of neurological illness, such as multiple sclerosis and schizophrenia, be caused at least partly by bacteria, viruses or other parasites? A largely Danish team has recently published evidence of a strong association between multiple sclerosis and a retrovirus, together with hints that a gene called TRIM5, which is used by cells to fight viruses, is especially active in people with MS.
Other illnesses have unexpectedly turned out to be caused by parasites. In the 1980s, Barry Marshall of the University of Western Australia ran into a brick wall of official disbelief for suggesting that a bacterium caused stomach ulcers. Only by deliberately infecting and then curing himself did he finally get the medical establishment's attention (and eventually the Nobel Prize).
The virus implicated in multiple sclerosis is called HERV-Fc1, a bizarre beast called an "endogenous" retrovirus. What this means is that its genes are part of the human genome. For millions of years, they have been integrated into our own DNA and passed on by normal heredity. It was one of the shocks of genomic science to find that the human genome contains more retroviral than "human" genes: some 5% to 8% of the entire genome.
Normally, the genes of endogenous retroviruses remain dormant, but—a bit like a computer virus that springs into action on a trigger—something wakes them up sometimes, and actual viruses are made from them, which then infect other cells in the body. The Danish scientists suggest that this is what happens in multiple sclerosis. Bjørn Nexø of Aarhus University writes that "retroviral infections often develop into running battles between the immune system and virus, with the virus mutating repeatedly to avoid the immune system, and the immune system repeatedly catching up. One can see the episodic nature of multiple sclerosis as such a running battle."
The possibility that you can inherit the genes of a virus blurs the distinction between a genetic and an infectious disease. The HERV-Fc1 genes lie on the X chromosome. Since women have twice as many X chromosomes as men, this might explain why some forms of MS are more common in women. Dr. Nexø concludes hopefully: "The finding that a disease is caused by an infectious agent is an encouraging one. These are the diseases which we know best how to treat."
Source: The Wall Street Journal Copyright ©2012 Dow Jones & Company (12/03/12)
Summary: This very interesting article from Germany investigates a potential interplay between two viruses previously implicated in MS pathogenesis; The torque teno virus (TTV) and Epstein-Barr virus (EBV). The authors report that viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain was significantly higher in EBV-positive cell lines than a EBV-negative Burkitt's lymphoma cell line. The authors suggest that possible interaction of EBV and TTV may exist in the aetiology and progression of multiple sclerosis.
Viral infections have been implicated in the pathogenesis of multiple sclerosis. Epstein-Barr virus (EBV) has frequently been investigated as a possible candidate and torque teno virus (TTV) has also been discussed in this context. Nevertheless, mechanistic aspects remain unresolved.
We report viral replication, as measured by genome amplification, as well as quantitative PCR of two TTV-HD14 isolates isolated from multiple sclerosis brain in a series of EBV-positive and -negative lymphoblastoid and Burkitt's lymphoma cell lines.
Our results demonstrate the replication of both transfected TTV genomes up to day 21 post transfection in all the evaluated cell lines.
Quantitative amplification indicates statistically significant enhanced TTV replication in the EBV-positive cell lines, including the EBV-converted BJAB line, in comparison to the EBV-negative Burkitt's lymphoma cell line BJAB. This suggests a helper effect of EBV infections in the replication of TTV.
The present study provides information on a possible interaction of EBV and TTV in the etiology and progression of multiple sclerosis.
Borkosky SS, Whitley C, Kopp-Schneider A, Zur Hausen H, Devilliers EM.
Source@ PLoS One. 2012;7(2):e32160. Epub 2012 Feb 22. & Pubmed PMID: 22384166 (07/03/12)