Thursday, 4 February 2016

ResearchSpeak: genetic link to antibody response to EBV proteins

Could the link between EBV and MS be an association and not causal? #ResearchSpeak #MSBlog #MSResearch

"We have know for sometime known that elevated antibodies to the EBV protein EBNA-1 increase your risk of getting MS. This particular EBV protein is part of the complex that keeps EBV in its latent, or sleeping, phase. Why an immune response to this particular EBV protein is linked to EBV risk is unknown. The study below suggests that there is a particular genetic locus, or area, in the  genome that increases your antibody response to EBNA-1. Interestingly, this locus also increases your chances of getting MS. This is a novel finding and opens up new ways of looking at genetic risk."

"How we bring all this together in a simple causal pathway is difficult; I am finding it perplexing. Could the antibody response to EBNA-1 simply be an association and not part of the causal pathway? In other words what increases your risk of getting MS increases your antibody response to EBNA-1. The latter however can't explain the other observations around the timing of EBV infection and onset of MS and the observation that if you are EBV negative your chances of getting MS are close to zero."


"I remain convinced that EBV is the cause of MS and we need to pursue our aims of targeting the virus with a vaccination strategy, antiviral drugs and drugs that deplete B cells and plasma cells. This is why we launched the Charcot Project."

Epub: Zhou et al. Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Mult Scler. 2016 Jan 27. pii: 1352458515626598.

BACKGROUND: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).

OBJECTIVE: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.

METHODS: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231).

RESULTS: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8).

CONCLUSIONS: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

20 comments:

  1. I agree that EBV is an important factor that needs further research, but I don't understand why you exclude other Herpes viruses from your theory.
    Varicella Zoster Virus for example: Almost everyone had the chickenpox when they were young and the virus is known to stay in neurons for lifetime after infection.

    My impression is everyone supporting a viral/infectious hypothesis is looking for "the one" infectious agent responsible while in reality there may be more that share a common mechanism/pathway.

    ReplyDelete
    Replies
    1. Very true. I got chicken pox two days after completing my last A level exam when I was 17-years-old. Ten years later the first symptoms of PPMS materialised.

      We need more research in this area.

      Delete
  2. Yes, my MS first occurred after I had had a severe case of pox at the age of 24.

    ReplyDelete
    Replies
    1. We have to be carefulwe don't fall into perception bias.

      Why do birds
      Suddenly appear
      Every time you are near?
      Most likely
      It is simply
      Perception bias.
      Aaaaah ah ah ah ah ah ah aah Perception bias

      Apologies to Burt Bacharach and the Carpenters ;-)

      Delete
    2. Yes, with n=1 you'll always have the problem of perception bias.
      On the other hand, focusing narrow-mindedly on "the one" infectious agent might produce 10 negative studies on 10 viruses while in the end it's one underlying mechanism shared by several pathogens.

      Delete
    3. Och! Mouse Doctor #2, I now have that tune stuck in my head! It's not one I like.

      Anon 11:47 - Perhaps some / any viral infection can steer up the immune system, leading to flares which bring previously unnoticed MS to the fore? (The flu jab gave me flares, I believe.) But it doesn't mean that this viral infection caused the MS. I don't know.

      From what I understand, EBV is the most likely virus, for a whole host of reasons?

      "...we need to pursue our aims of targeting the virus with a vaccination strategy, antiviral drugs and drugs that deplete B cells and plasma cells."

      I'd rather just take an antiviral. What a dream - not to have to consider all these drugs that essentially just knacker your immune system in various ways. I'm sure they will seem primitive one day in the future.

      Delete
    4. Aw, come on Karen Carpenter had a great voice, in the same vein the guitar solo in Goodbye to Love is one of the alltime greats.
      I think any infection could cause flares as proinflammatory chemicals released by the immune system can upregulate the activity of microglia (not in a good way) which I'm sure are a fundamental part of the disease process in MS including PPMS. You see the same thing apparently in Alzheimer patients with infections and again microglia are increasingly implicated in the pathology.
      Which gets me back to aspirin...................

      Delete
    5. Yes, very nice voice, it's true. And 'Top of the World' was kinda groovy!

      Aspirin... Ibuprofen too?

      Delete
    6. MD2 - what do you mean by 'gets me back to aspirin'? Plz explain.

      Delete
    7. I'm thinking of epidemiological data suggesting long-term use of NSAIDs (such as low dose aspirin after heart bypass surgery or NSAIDs for arthritis) are protective against the development of Alzheimers.
      http://scholar.google.co.uk/scholar_url?url=http://www.psy.ohio-state.edu/bruno/documents/wenk2.pdf&hl=en&sa=X&scisig=AAGBfm1uPmia2WciMbE0f7OGb0McX5P77A&nossl=1&oi=scholarr&ved=0ahUKEwisqtf4w97KAhXGpR4KHW0OAZ8QgAMIIigBMAA

      Delete
    8. Modulating the inflammatory properties of activated microglia with Docosahexaenoic acid and Aspirin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663775/

      Delete
    9. Why do neurons fall out of my mind?
      Everytime MS drops by...
      Just like me it longs to be too close to you.

      Delete
  3. MD2 may be right...

    But already I I'll agree with Prof. G, most people I talk to and who had infectious processes predecessors at the first symptoms of MS had infectious mononucleosis...
    I know some who say they have had infectious episodes caused by other viruses of the herpes family...
    So it may be that several pathogens, viruses specifically, would the action to unleash the ultimate pro inflammatory events of MS...
    I can speak for myself. I never had anything in life related to MS, no symptoms at all. In December 2010, at age 25, I made a trip to Santos, in Brazil, a city with a high rate of MS compared to other cities. There developed a strong throat infection it took to pass, I was quite ill and days later I find out it was mono. In 2013 I had the Mono relapse in two episodes during the year, and about six months after I presented the first symptoms of MS. I always thought it had something to do, whatever the trigger for the disease. Every time I had a relapse of Mono thought I would die! It was pretty bad even. And look at that as a child I had mumps, chickenpox and dengue 2x as a teenager (in Brazil dengue is a curse), and when I recovered from all these other infections very well. Now the Mononucleosis I can no longer say that. But perhaps MS may have as to trigger aberrant response of various immune system infections, especially viral ...
    Late last year reported that certain genetic variations to combat certain viruses. It may also be the key to understanding aberrant responses to them, included Epstein Barr Virus...


    http://www.eurekalert.org/pub_releases/2015-10/epfd-gvi100715.php

    ReplyDelete
  4. What about those people with MS who never had mono? What virus triggered MS in them?

    ReplyDelete
    Replies
    1. Just because you haven't had full blown diagnosed mononucleosis doesn't mean that you haven't been infected with EBV. Many get infected as children when the effects of infection aren't as severe as getting it in puberty or adulthood. I'm EBV positive but didn't get full blown mono so must have got it when I was a child and it was "just another fever".
      As far as I know pretty much every pwMS has antibodies against EBV, indicating they've been infected with the virus at some point in their life.

      Delete
  5. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108384#pone.0108384-Wojkowska1
    The regulation of EBV may be under control of intrinsic SNPs in lymphoblastoid cell lines (B cells which are transformed by EBV).Increased CXCL16 expression is associated with EBV replication and this chemokine is prominent in active MS.

    ReplyDelete
    Replies
    1. Steve S this study is very interesting, I had read last year ... It will not surprise me if EBV cause all these disorders as their own MS, because here in Brazil and the Zika virus Chycungunia are demonstrating potential action on the nervous system and Immune system. The numbers of cases of Guillain-Barré syndrome quadrupled this week on people who either had contracted Zika or Chycungunia.

      I don't know who put it here on the Blog link is a study of HERV expression and the presence of placenta in women.
      It may even be that in this regard the positive expression HERV during pregnancy can suppress EBV activity...
      I'm just not finding the link of the study ...

      Delete
    2. I don't know that you mean this paper I asked about, but it does have placenta and HERV bits in it!

      http://rsx.sagepub.com/content/16/11/1023.abstract

      Delete
    3. Sterntaucher it was one of the studies I read about it. Thanks for posting the link. o//

      Delete
  6. Trimesta + Copaxone failed in the phase 2 study to evaluate them as a treatment for MS.

    Do the hormones have nothing to do with Multiple Sclerosis, either during pregnancy, where women have virtually no outbreaks?

    Perhaps the study Sterntaucher posted here on the blog demonstrating the HERV regulation of the Placenta but make sense and explain better the state of remission during pregnancy, and when it ceases pregnancy probability of relapse is 50% ....

    http://rsx.sagepub.com/content/16/11/1023.abstract

    http://multiplesclerosisnewstoday.com/2016/02/08/experimental-rrms-therapy-trimesta-fails-demonstrate-efficacy-review-clinical-trial/

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.