Tuesday, 15 April 2014

Does EBV have nothing to do with MS?

What is the difference between a belief and a hypothesis? #MSBlog #MSResearch

Does EBV cause MS? Join the debate. #MSBlog #MSResearch

"The study below found no differences in EBV viral loads in the spinal fluid and peripheral between MSers and controls. Does this mean EBV has nothing to do with MS? No it doesn't. The link between MS and EBV is based on epidemiological and not mechanistic studies. I note from discussion We have no idea how EBV causes, or is causally linked to MS. All we have is a series of hypotheses that need testing." 

  1. EBV triggers autoimmunity in the periphery by upregulating alpha-B crystallin in B cells (van Noort hypothesis).
  2. EBV immortalises central antigen-presenting B cells and when this is coupled with poor cytotoxic CD8+ T cell response drives CNS autoimmunity (Pender hypothesis).
  3. EBV infected B-cells in the CNS triggers a cytotoxic CD8+ T-cell response that damages oligodendrocytes and axons (Aloisi hypothesis).
  4. EBV triggers CD4+ T-cell autoimmunity via molecular mimicry (Wucherpfennig-L√ľnemann-Martin hypothesis).
  5. EBV transactivates human endogenous retroviruses that cause MS (Perron hypothesis).
  6. EBV is one of many viruses that provides the secondary danger signal that stimulates autoimmune reactions within the CNS (Meier hypothesis).
  7. EBV results in dysregulated T-cell function (Mainstream hypothesis).
  8. A mutant EBV strain infects glial cells and neurones and triggers an anti-viral response (Trillo-Pazos hypothesis).
  9. Etc. 
"The Trillo-Pazos hypothesis was suggested by a virologist I was working with 10 years ago; unfortunately she never quite got her methods to work well enough to disprove her hypothesis. However, her hypothesis is the closest hypothesis to my field hypothesis. The field hypothesis doesn't necessarily depend on the virus being EBV; it could be HERVs or another virus that is deficient and requires co-infection with EBV to be pathogenic. I like the field hypothesis as it would explain the Prineas early MS lesion (oligodendrocyte apoptosis) and is congruent with the Japanese macaque encephalomyelitis model, which is the closest spontaneous animal model we have to human MS. I agree that any hypothesis that involves EBV needs to be congruent with current knowledge and explain all our epidemiological observations. The fact that natalizumab works, or at least it does in the short-term, does not exclude the field hypothesis. The latter may require a robust immune response to cause disease; there are well established precedents for this in virology. Some viruses are only pathogenic in the presence of an immune response."

"Enough said; the bottom line is I have no idea how EBV causes MS. All we have is a long-list of hypotheses that need testing. The good news is that several are being currently tested. The ones I would like to test are:
  1. Would targeting EBV lytic infection with an anti-viral reduce MS disease activity? 
  2. Would treating infectious mononucleosis to prevent an aberrant immune response to EBV reduce your risk of getting MS? 
  3. Would vaccinating young children to prevent them getting EBV reduce their risk of getting MS?
  4. Would infecting young children with wild-type EBV, without them getting infectious mononucleosis, reduce their risk of getting MS?"


"What is the difference between a belief and a hypothesis? You can disprove a hypothesis but not a belief. Fortunately, I am not a believer, which according to Popper makes me a scientist."

Karl Popper


Aims: What has EBV got to do with MS?

Methods: The presence of Epstein-Barr Virus (EBV) DNA in cerebrospinal fluid (CSF) and peripheral blood (PB) samples collected from 55 patients with clinical and radiologically-active relapsing-remitting MS (RRMS) and 51 subjects with other neurological diseases was determined using standardized commercially available kits for viral nucleic acid extraction and quantitative EBV DNA detection. Both cell-free and cell-associated CSF and PB fractions were analyzed, to distinguish latent from lytic EBV infection. 

Results: EBV DNA was detected in 5.5% and 18.2% of cell-free and cell-associated CSF fractions of patients with RRMS as compared to 7.8% and 7.8% of controls; plasma and peripheral blood mononuclear cells (PBMC) positivity rates were 7.3% and 47.3% versus 5.8% and 31.4%, respectively. No significant difference in median EBV viral loads of positive samples was found between RRMS and control patients in all tested samples. 

Conclusions: Absence of statistically significant differences in EBV positivity rates between RRMS and control patients, despite the use of highly sensitive standardized methods, points to the lack of association between EBV and MS disease activity.

25 comments:

  1. ETTO KEEP SHOESHINE HAPPY.Epitope spread from viral attack to autoimmunity (Tuohy/Miller)

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    1. OK cat tongue. I think EBV causes your jugular veins to be restricted which causes ms. If only we could eradicate EBV from humans we could cure MS. I guess Zamboni was right in his hypothesis. After all we have no clue how EBV is involved in MS. We just frail around and throw darts at a board that has a list of suggested mechanisms of action, test it and see the outcome. No need to understand. If the trial fails we throw another dart, and so on and so on and.......time to retire.

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    2. Cat Tongue, of all of those things you listed in items 1 through 9 can you tell me which one supports your theory that EBV is directly attacking the CNS and causing MS. If not, just admit that this is probably not the case and stop bashing all of the other theories about what is causeing MS.

      I guess if you have a hypothesis, it should first be vetted to see if it is even plausible, at least this should be the case. I would rather you just state that you have no idea what causes MS, but we need to test every drug known to man to see if we can find one that has an effect on the disease in a two year trial. No need to find the cause.

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    3. Dear shoeshine or anon
      The jungular vein hypothesis without ebv haa been found wanting and you have come up with EBV linking to jugulat vein.
      But aa the jugular vien hypthesis has been questioned. This on

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    4. You have to read to open your world view

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    5. You're wasting your time MD. Just ignore him/her

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    6. I agree wasting your time; you need to develop a thick teflon skin. What has happened to your trollometer?

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    7. I agree whilst the cat was away (ProfG Birthday) the mice could play but agree time for spam against the troll.

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  2. Prof G I am a believer; my MS came on 18 months after I had IM.

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  3. Why so many people gone mad on Zamboni?
    I can believe that all of us do want a cure, but why CCSVI, why not HSCT for instance? There is so much data on HSCT out there and nothing on CCSVI

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    1. I agree. HSCT is the best bet for highly active disease and it may be an option down the road for people who fail first line drugs. Dr. Burt is currently running a phase 3 trial for this at Northwestern University. The problem is that there are too many pharmaceutical industry bootlickers working on other drug based treatments. Giavoni could spend multiple lifetimes testing existing drugs for their impact in a two year trial, but he will be no closer to understanding the cause which is required to develop a cure. Also, the pharmaceutical bootlickers will tell you that HSCT is dangerous. Much more dangerous than Tysabri. But they will never provide any data to backup their claims.

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    2. > but he will be no closer to understanding the cause which is required to develop a cure.
      They can find a treatment and only then find out how it works, usual situation for MS drugs i think. I believe if the cure will be ever found, probably it would be that way

      > But they will never provide any data to backup their claims.
      But there is data, it is fatal in 1-5% cases. Still it works at least for the remitting phase at least in small studies, which has not been shown for ccsvi, and yet so many CCSVI fanatics everywhere on the interwebz

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    3. The fatality rates of 5% are based on studies that were using total body irradiation. Reduced intensity conditioning is the norm now and it would be hard to proclaim of 5% mortality rate with this method:

      http://www.ncbi.nlm.nih.gov/pubmed/22771495

      Fortunately, there are good people working on this. The sad part is that it probably won't be available for a long time. This would seriously cut into the MS drug gravy train.

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    4. Thats why I said 1 to 5%, and who knows what mortality rate is in clinic you referred to.

      > http://www.ncbi.nlm.nih.gov/pubmed/22771495
      Btw, seen one of those guys, they are performing HSCT in Russia, it is available here, at least if you can pay for it and ready to take risks. I was not convinced in safety by him though, so I choose alemtuzumab (thanks to this blog) over them. May be I have been mistaken, who knows.

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    5. I had a son who had leukaemia and had a bone marrow transplant following a total myloablative protocol. It is a dangerous procedure and needs to be carried out in a specialist unit with isolation units as you are so vulnerable to infection from all sides- bacterial, viral, fungal. Some people get very sick indeed from it- Stella did a blog a couple of years ago about her HSCT for aggressive MS on a UK MS site. I think she lost some toes and has hearing problems following it. Saying that, my son sailed through the transplant, but it takes months to get back to normal. I don't know if MSers are getting a total or partial myloablative regime. My other son has MS and has had alemtuzumab. It is a far easier treatment to have, takes a lot less time to get over, and has less of a mortality rate. I don't think doctors are suggesting alemtuzumab over HSCT because of the drug gravy train; it's just a lot less risky.

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    6. I agree it can be risky if you have it performed by untrained personnel. The difference between the procedure for cancer patients and ms patients is that ms patients receive their own stems cells while cancer patients receive stem cells from another person. In the later case you have the risk if graft vs. host day disease which has a mortality rate near 30%.

      But for MS trials are being conducted for non-meyoblative HSCT in a phase 3 study. We will see if this becomes an accepted option:

      http://www.stemcell-immunotherapy.com/pub_pub.html#mul

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    7. The guys from the study mentioned beyond use standard BEAM+ATG conditioning, very much the same as used in leukaemia, I think this is typical regime for the HSCT in MS. Also, talked with some of their patients who where treated there (they have a small closed community, more like a sect hehe). The typical answer is that it is not so bad and scary as you can read on the Internet. But, the guys I saw did well, and of course I can't talk to those who are unwell or even dead after that procedure, so this tells nothing.

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    8. Vasy,

      when did you get the alemtuzumab? Any obvious effects from it, good or bad?

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    9. I got my first dose just a month ago, so it's early to say about the effects. Got some sensory improvements and my Lhermitte nearly disappear, but this may be due to a metilprednisone (they give you corticosteroids and antihistamines before the alem every time to ease the infusion complications). Doc said this possibly could be attributed equally to both steroids and alem, but usually people do get temporarily worse during the first 1-2 months, and then gradually improve or stabilise. But who knows

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  4. It looks like fingolomod makes people more susceptible to viral infections.

    http://www.msdiscovery.org/news/new_findings/10559-explaining-fingolimod%E2%80%99s-fatal-flaw

    So, here is another drug that has an impact on MS but does not fall in line with the Giovannoni Theory of EBV as the direct cause of MS.

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    1. I am not sure if Prof G has ever said that EBV is the direct cause of MS; I think he outlined a large number of hypotheses yesterday most of which implicate EBV indirectly.

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    2. The Epstein Barr virus does not exist on its own, it infects cells. If those infected cells are killed preferentially by Fingolimod, then this is not inconsistent with EBV causing MS even though it raises the risks from other viruses. We know very little about EBV in the body. I have never even seen a reasonable explanation of how it converts normal B cells into Reed–Sternberg cells in Hodgkin's Lymphoma.

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    3. The immune system deals with viral infections. Remove part of your immune repetoire and you are liable to get infections some of these are life threatening others not so

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  5. I can see how you may have that impression since he seems to change his views every other day. But this is the basis for the Charcot Project. This is his hypothesis, and the Charcot Project is being conducted to test this hypothesis.

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  6. Increased CD8+ T Cell Response to Epstein-Barr Virus Lytic Antigens in the Active Phase of Multiple Sclerosis


    http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003220

    "We therefore propose that inability to control EBV infection during inactive MS could set the stage for intracerebral viral reactivation and disease relapse."

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