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Epstein-Barr virus genetic variants are associated with multiple sclerosis

Discussion in 'Other Health News and Research' started by Ecoclimber, Mar 9, 2015.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Permission to repost from: Prof. G
    This could also open the door to further research of genetic variants with ME/CFS.


    Mechelli et al. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology. 2015 Mar 4.

    OBJECTIVE:
    We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in MSers and control subjects to verify whether virus genetic variants are involved in disease development.

    METHODS:
    A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 MSers and 17 HDs). MSers underwent gadolinium-enhanced MRI and human leucocyte antigen typing.

    RESULTS:
    MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006).

    We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and MSers (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features.

    CONCLUSIONS:
    Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development.

    Commentary from Gavin Giovannoni

    Is there a specific variant of EBV associated with MS?


    It is time the MS community takes the EBV hypothesis seriously?

    "I am jealous; this is a study we were meant to do several years ago. With new deep sequencing technologies you get low frequency DNA sequencing reads from viruses present in peripheral blood including EBV. These viral sequences are typically filtered out and ignored with geneticists analyse genomic DNA data.

    We had a collaboration with colleagues in the UK to analyse EBV sequence data from MSers, disease controls and healthy people. Unfortunately, the person leading on this left our group and the project was never completed."

    "The study below suggests that a specific genetic variation in one of the genes from EBV is associated with MS. Could a specific subtype of EBV be causing MS?

    This is not such way-off or out-of-field hypothesis. Most viruses that cause systemic infections and rarely cause a disease of the central nervous system, as a delayed or complication of infection, have a variant or variants that evolve to infect the brain.

    Examples of this are are the JC virus (PML), measles (subacute sclerosing panencephalitis or SSPE), rubella (panencephalitis) and herpes simplex virus (encephalitis). Why would EBV be any different?

    What we haven't be able to establish with any confidence is whether or not the EBV we find in the brains of MSers is there by accident or driving the MS disease process.

    You need to remember that EBV infects B-cells and lives in B-cells; therefore any disease that involves B-cells will have a small number of EBV-infected B cells in the target organ that is found there by chance. MS maybe no different.

    The EBV hypothesis of MS, i.e. that EBV is the cause of MS, is not driven by biological or experimental data, but by epidemiological studies.

    For example, if you are not infected with EBV the chances of you getting MS are close to zero. In comparison if you have been infected with EBV, in particular if you have symptomatic EBV infection or infectious mononucleosis or glandular fever, the chances of you getting MS soar. Unfortunately, the epidemiological data are not good enough to prove, or disprove, causation. This is why this study's findings are so tantalising and need to be confirmed."

    "What next? I suggest the International MS genetics consortium (IMSGC) take on the task of trying to replicate this study's findings. Why the IMSGC?

    The IMSGC have the necessary samples in the freezer and have in depth data on the MSers and their family members to analyse associations and new hypotheses in detail. For example, they can address vertical transmission (mother-to-child) and horizontal transmission (person-to-person) patterns and associate them with age of onset, latitude, country of birth and residence, etc.

    It is very likely that if EBV causes MS it will interact with some human genes to trigger the disease. The IMSCG have acquired large amount of genomic data already to fast-track analyses of this nature. Finally, if the IMSCG take up the challenge of replicating this study it will be much cheaper that starting from scratch. The other thing is speed; the IMSGC have time and resources on their side."

    "I have one reservation about this study that could potentially be addressed by a pathological study. The peripheral blood compartment may not be the best compartment to look for MS-specific EBV variants. The best place to look is in the brain of MSers. Therefore in parallel to the proposed IMSGC replication studies I would urge funders to put out a specific call for MS investigators to tackle the CNS vs peripheral compartment EBV hypothesis."
    [​IMG]
    "I often use the virus HTLV-1 as an analogy when discussing the viral hypothesis of MS. It is an interesting virus as it can be transmitted vertically and horizontally and rarely causes a disease in infected subjects that is not too dissimilar to PPMS, called tropical spastic paraparesis or HTLV-1 associated myelopathy (HAM). I discuss this here to illustrate the transmission patterns."


    Comments:

    1. AnonymousSunday, March 08, 2015 9:51:00 am
      Prof G, could rituximab and ocrelizumab be working via killing EBV infected B cells?

      MouseDoctorSunday, March 08, 2015 10:23:00 am
      Thats what ProfG thinks


      Sunday, March 08, 2015 10:35:00 am
      Hi
      Not sure if you guys saw my previous post regarding a chap who contracted hiv after Ms and once treated with HAART had no issues with MS as far as I'm aware
      He even stopped beta interferon for awhile with no issues
      This was on another forum, supports your hypothesis even more

      Sunday, March 08, 2015 6:43:00 pm
      stopped beta interferon for a while?

      did he have to go back on it?

      Matt PerrySunday, March 08, 2015 1:35:00 pm
      Hey Team G.

      I know it's relative guess work until the trials are done, but in terms of your best guess/hypothesis, is your working assumption that eradicating EBV/suprressing HERVs would "cure" MS for those that already have it. Or do you see it more as a preventative measure (i.e. vaccinate kids to stop MS from ever developing)?

      Thanks!
     
    Last edited: Mar 9, 2015
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  2. anciendaze

    anciendaze Senior Member

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    Anyone feel like disputing the claim that there are multiple strains of EBV, including genetic variants not previously recognized? What does this do to the argument that "everyone has it"? Anyone want to argue that EBV is not transmissible? I believe the role of EBV in etiology of ME is back on the table.
     
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  3. Bob

    Bob

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    EBV, being a herpes virus, inhibits mitochondrial replication/function...

    In case anyone is interested, we had a new discussion thread yesterday, discussing how herpes viruses interfere with mitochondria:
    http://forums.phoenixrising.me/inde...s-the-antiviral-innate-immune-response.36073/
     
    Last edited: Mar 9, 2015
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  4. Bob

    Bob

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    We all know that the problem with researching EBV is that it's a very common virus, so how do we prove that EBV contributes to ME, or causes ME only in a certain subset of the population? If there are different strains of EBV, of which a specific subset causes ME, then that would be a nice neat answer for us. I can't help feeling that it's more complex than that though. i.e. an interplay of various environmental, pathogenic and genetic factors.
     
    melamine likes this.
  5. Daffodil

    Daffodil Senior Member

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    great article!

    as far as I am concerned, EBV as a cause of CFS has never been off the table. so many of us have had the disease start right after mono, it simply cannot be off the table.

    but why do some people with MS and CFS respond to antibiotics?
     
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  6. Daffodil

    Daffodil Senior Member

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    it was always my suspicion that rich celebrities with CFS got intermittent adoptive immunotherapy for CFS. here, they gave anti-EBV immunotherapy it to a man with MS and he got better:

    http://www.ncbi.nlm.nih.gov/pubmed/24493474
     
  7. anciendaze

    anciendaze Senior Member

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    We are talking about a disease which affects about 1% of the general population. Even in cluster outbreaks we generally see much less than 100% of those exposed affected. This is not exactly a unique situation. Over 95% of those infected with poliomyelitis virus are either completely asymptomatic or have such mild symptoms that they never consult a doctor. This can be the result of genetic factors caused by thousands of years of selection in urban populations. It can also be the result of which enteroviruses a patient was exposed to prior to exposure to poliomyelitis virus, leading to acquired immunity.
     
    SOC likes this.
  8. Gamboa

    Gamboa Senior Member

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    Does anyone know, offhand, how many of us have active ( or reactivated) EBV?

    My meager testing in this area shows I have "possible reactivation" due to testing positive or reactive to VCA IgG, EA IgG and EBNA IgG. I was not referred to an infectious disease doctor since this was considered "normal" to have these results. Supposedly 20% of the population has this result. I'm now wondering if the 20% happen to all have things like ME/CFS , MS etc.

    It will be fascinating to see where this all leads as well as potentially very helpful to us.
     
    SOC likes this.
  9. SOC

    SOC Senior Member

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    Possibly because the impact of the virus on the immune system may inhibit its ability to handle all kinds of infections. Some of us might develop secondary infections which are treatable by by abx. Just a thought, not a sound hypothesis. :)

    We need to be careful about how with think about symptoms, pathogens, and causation. Some of us clearly have Lyme and other tick-borne illnesses, for example, but that doesn't mean those pathogens are clearly the cause of ME/CFS/SEID. It's also possible that the reason they have chronic Lyme, etc, while others clear it is because of the damage done to the immune system (or other systems) by whatever is actually the cause of ME/CFS/SEID. There are any number of possible paths to where we are now. We don't have enough research to say much at all about causation.
     
    alex3619 likes this.
  10. Daffodil

    Daffodil Senior Member

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    my specialist thinks the EBV is actually a reactivation and that almost everyone is exposed early on.... something causing weakness in immune system (I guess he thinks it is bacteria) makes it reactivate when you are exposed to it again? or something
     
  11. Mij

    Mij Senior Member

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    When I relapsed on immune modulators my test results showed high reactivation of HHV6 and EBV.

    I don't know my initial viral onset was though. I don't think I was tested for any in particular.
     
  12. wastwater

    wastwater Senior Member

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    I seem to have a problem with EBV and was perhaps looking too far out at leukemia viruses when EBV is the original leukemia virus.
     

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