Research: EBV infection: a smoking gun for MS?

Sundqvist et al. Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis. Neurology 2012 Aug 29.

BACKGROUND: Epstein-Barr virus infection, smoking, HLA-A*02, and DRB1*15 have all been proposed as risk factors for MS. In 2010, Simon et al. from Boston USA, described an interaction on the multiplicative scale between EBNA1 immunoglobulin G (IgG) and smoking regarding risk of MS, a finding that we attempted to replicate.

METHODS: This Swedish case-control study consisted of MSers with newly diagnosed MS and matched controls. Using logistic regression, they analyzed association to MS risk and interactions between EBNA1 IgG and smoking, HLA-DRB1*15, and A*02, respectively, on the multiplicative scale. In addition, they analyzed interactions on the additive scale using attributable proportion due to interaction (AP).

RESULTS: They did not observe any interaction on the multiplicative scale between EBNA1 IgG and any of the 3 risk factors, smoking, DRB1*15, or absence of A*02, although in a conditional analysis the interaction with absence of A*02 became significant. However, they observed interactions on the additive scale between EBNA1 IgG and DRB1*15 (AP = 0.34, 95% confidence interval 0.11-0.57, p =  0.005 and between EBNA1 IgG and absence of A*02 (AP = 0.36, 0.13-0.59, p = 0.02) but not between smoking and DRB1*15 and EBNA1 IgG. The interaction between EBNA1 IgG and DRB1*15 was not significant in the conditional analysis.

CONCLUSION: They did not observe any interaction between EBNA1 IgG and smoking, regardless of scale used, and thus did not replicate the observations from Simon et al.

“Evidence of past infection with EBV, in particular infectious mononucleosis or glandular fever, and smoking are well-known risk factors for  the development of MS. These two exposures are risk factors for several cancers, including nasopharyngeal carcinoma and Hodgkin’s lymphoma. For these diseases, EBV and smoking may be independent risk factors, associated with different histologic types that have different prognoses. Yet other research suggests a biological interaction between EBV infection and smoking for Hodgkin’s Lymphoma. Smoking may itself influence EBV infection. For example, EBV DNA (as a marker of EBV replication) was more likely to be detected in oral epithelial cells of HIV-infected individuals who smoke than in non-smokers, and in a Danish (non-MS) population sample, smoking was associated with increased anti-EBV viral capsid antigen titers with a dose-response relationship for number of smoking pack-years, and a stronger effect in women.  There was a study from Boston that suggested that if you have certain MHC genes and smoke you have more of a risk of developing MS.”
“What this study tells us is that these known MS risk factors may not necessarily interact. We have published data that EBV does not interact with the know HLA genes associated with MS. This study suggests that EBV may not interact with smoking either. This is important as we then have to work out how these agents work biologically as risk factors and then target those pathways as part of prevention or treatment strategies.”

“Smoking and EBV are another two grand challenges in MS.”

The number of the posts on this blog concerning EBV tells you how important it is and what a hot topic it is. I am already convinced that it is the cause of MS, hence the launch of The Charcot Project.”

Other posts on EBV on this blog:

17 Aug 2012
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 methods56 serum samples of 25 individuals who had 
11 Jul 2012
This includes the observation that nearly all MSers show serological (blood) markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity 
01 Jul 2012
BACKGROUND: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06.
25 May 2012
EBV causes IM I think (the kissing disease) in adolescents and most people would remember having it then, but I don’t think it causes such symptoms in children. Do you know whether anyone who had IM in their teens goes 
25 May 2012
The cause of MS is still unknown but epidemiological and immunological studies have implicated Epstein-Barr virus (EBV), which infects B cells, as a possible aetiological agent involved in disease. Of particular interest is EBV 
04 Apr 2012
To examine the CD8(+) T cell response in greater detail, we analyzed the HLA-A2-, HLA-B7-, and HLA-B8-restricted EBV- and Cytomegalovirus (CMV)-specific CD8(+) T cell responses in MSers and control subjects.
10 Mar 2012
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 
15 Jul 2012
The current evidence base supports a strong association between EBV and MS, but potential causality remains strongly debated. Available data on seroprevalence of EBV in MSers has been conflicting and thus used to both 
11 Jul 2012
Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected 
03 Feb 2012
Objectives: To identify Epstein-Barr virus (EBV) genotypes and strains in samples from individuals with and without a first diagnosis of central nervous system (CNS) demyelinating disease (a possible precursor to multiple 
01 Feb 2012
Mycobacterium avium subsp. paratuberculosis (MAP; a bacteria or microbe that is related to TB) and Epstein Barr virus DNA were detected in 27.5% and 17.3%, respectively, of the MS patients, compared to 6.3% and 4.5% in 
24 Jul 2011
Results: Higher anti-EBV antibody levels and a history of infectious mononucleosis (IM) were associated with increased CIS risk and there was an additive interaction with the main MS susceptibility gene HLA-DRB1*1501.
10 Jan 2012
strangely enough we found many cars parked next to the path and even more strangely we found several white vans (EBV infected white blood (B) cells) – more than you would usually see on a motorway (blood system).
24 Dec 2011
OBJECTIVE: To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple 
21 Aug 2011
Recent epidemiological and immunological studies provide evidence for an association between Epstein-Barr virus (EBV) infection and multiple sclerosis, suggesting a role of EBV infection in disease induction and disease 
07 Dec 2011
Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate 
19 Jul 2011
They are contrary to what we know about the immune system; if you get infected with one EBV strain your immune system learns and should prevent you getting infected with a second strain. In other words the first EBV strain 
23 Jul 2011
Subjects with raised antibodies in the blood to the EBV protein EBNA1 IgG had a 1.74x higher risk of developing MS. Subjects with antibodies that reacted with the 385-420 fragment of EBNA1 had 3.60x higher risk of 
11 Jul 2011
There is some evidence that EBV reactivation within the body may be triggering MS relapses and disease activity on MRI. Therefore if we can treat MS’ers with a drug that targets EBV we may be able to suppress MS disease 
29 Apr 2011
RESULTS: Children diagnosed with MS were more likely than those with monophasic ADS, i.e. non-MS, to be seropositive for remote EBV infection (37/49 vs 82/185, p<0.001) but not for CMV (7/33 vs 37/97, p=0.09), HSV 
11 Jul 2011
“This study provides a hint that vitamin D supplementation that results in higher blood vitamin D levels many suppress EBV within the body. Interesting? We think very interesting and trying to work out how EBV and vitamin D 
17 Apr 2011
PwMS rarely have antibodies against EBV that are produced within the brain and spinal cord. Some antibodies are produced but are part of the general immune response that occurs in MS. Only rarely are anti-EBV antibodies 
24 Jan 2010
Even if EBV was proven to be a cause / one of the causes of MS, what would this mean in terms of treatment? Vaccination of children against EBV (when a vaccine is available)? This might erradicate MS for future generations.
02 Aug 2011
In this study the researchers have shown that a particular immune cell, called the CD8 T cell, is deficient in MS’ers and contributes to the decreased immune response to EBV-infected B cells. Importantly, this worsens with age 
07 Jul 2011
Sunlight, Vitamin D and EBV …. More on EBV and MS · Survey results on the issue of woman with MS havin… Article of interest (7) – Infusion reactions to na… Prof DB has a life outside of MS · Symptoms in MS: tremors, 
04 Mar 2010
A new study looking into the immune response to EBV in people with MS has shown that a group of white blood cells responsible for killing EBV, the so called CD8+ cytotoxic lymphocytes or CTLs, are increased in theblood of 
17 Jun 2011
Latest PML risk estimate on natalizumab · My MS Manager · Results of the EBV survey · Genetic Testing: Can We Predict Multiple Sclerosis… Yellow Fever Vaccination and Increased Relapse Rat… Smoking and two human 
15 Feb 2012
Here it is proposed that this CD8+ (virus-killing) T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that 
02 Jul 2012
Re education about EBV – lots needs to be done to counteract prejudice. In the wider world, it seems to me, this idea is perceived either as outdated or not that credible. Some researchers are not immune to that either.
26 May 2012
Research: viral infection and evidence is with EBV. Zaadstra et al. Selective association of multiple sclerosis with infectious mononucleosis. Mult Scler. 2008;14(3):307-13. Previous studies have suggested an 
01 May 2011
OBJECTIVE: To evaluate the effect of interferon-beta and neutralizing anti-interferon-beta antibodies (NAbs) on markers of EBV infection and activity in subjects with MS. RESULTS: 100% of MS subjects in this study were 
01 Jun 2011
“Is there sufficient data to support EBV as being the cause of MS? Clearly, further research is required to disprove the hypothesis. Is it premature and irresponsible to make claims of causation? People with MS feel that the 

6 thoughts on “Research: EBV infection: a smoking gun for MS?”

  1. My daughter is 12 years old. I am now trying to assess her risk of contracting MS and am keeping a close eye on her VitD levels.Is there a blood test or else to test for EBV infection?

    1. Yes, a simple serological test! Most 12 years old in the developed world are EBV-ve; they get their infection horizontally when the start kissing and often get infectious mono. Unlike the developing world where most 12 year olds are EBV+ve; they get their infection in childhood, vertically from their mothers or grandmothers, and usually have asymptomatic infections. These typical patterns of infection are not absolute and may be changing.

    2. Thanks a lot!just thinking now that EBV can come at any time in the girl's life.As such, testing for it today does not mean much in terms of decision taking

    3. Testing would do if we have a vaccine! There is one available that prevents infectious mono, but not wild-type infections. It is my dream in the future to do a trial of this vaccine. But we are not ready for that yet.

    4. We don't know which is why we need to do a clinical trial. The vaccine is not available; it was developed to prevent cancers and failed.

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