Friday, 21 November 2014

Antibodies to EBV in MS

How does EBV cause MS? #MSBlog #MSResearch

"This study confirms several previous studies and demonstrates that the majority of MSers do not have synthesis of EBV specific antibodies in the spinal fluid. This is an important finding and indicates that direct EBV infection of the brain spinal cord is unlikely to be the cause of MS. Why do I say this? In infections of the CNS (central nervous system) with known viruses, for example measles, mumps, rubella and herpes, almost all the immunoglobulin (antibody) bands react against components of the infecting virus and they tend to do so with high affinity; high affinity simply means the antibodies bind the relevant virus very strongly. The high affinity indicates that the virus is responsible for driving the immune response. If we discover a viral cause of MS the oligoclonal bands will almost certainly bind with high affinity to the causative virus. This raises the question how EBV is involved in the causal pathway of MS? I wish I knew. I suspect the EBV is interacting with another virus to cause MS. We call this this dual viral hypothesis. For example, EBV may be transactivating an endogenous retrovirus and it is the latter virus that is important. Despite this finding I still think we need to test antiviral drugs that target EBV in MS."

"Ideas on how EBV causes MS are welcome!"



Background: The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in MS and controls.

Methods: Cerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other non-inflammatory neurological disorders (NIND).

Results: Levels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed.

Conclusions: Our findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.

17 comments:

  1. Prof G,

    I think it's tiem to give up the ghost with this one (take up golf?). 30 years ago a friend had to visit a neuro with a nerve problem in her face. The neuro asked wha illnesses she had had. She said a bad case of mono a few years before. I remember the neuro saying that mono was linked to MS. That was 30 years ago and we havent got much further. We can land a craft on a comet traveling at XX,XXX miles per hour, but can't find out what starts a disease in the brain! I coming to the conclusion that finding cause isn't so important. The anti-inflammatories will get better and safer, diagnosis will be given much earlier, treatments to repair some of the damage will come. In ten years time a newly diaagnosed RRMSer will go to Dr Coles for some Alemtuzumab Plus (it won't casue secondaray auto-immunity), then pop across the corridor to Prof Franklin to get an injection of Myelin Made Good, a bit of physio, an injection of Vit D and the relevant homone (depending on sex). The patient will be almost back to pre-MS days. The will be no need to identify the cause. If an anti-EB vacinne comes along - all the better. This will put Mouse Doctors out of work - not a bad thing. Team G will be able to focus on another neurological disease.

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    Replies
    1. Re "finding cause isn't so important"
      I'm afraid I completely disagree with this statement - it may be fine and dandy to have ways of treating any illness, but this is shutting the stable door after the horse has bolted. Far better if the cause/s can be found and if possible a form of prevention able to be used. Much cheaper too - expensive clinical trials and hugely expensive medication (to recoup the trial costs) may then not be needed, not to mention the costs involved in (eventually) getting a diagnosis (MRIs, EVPs, LPs, etc etc). Better for economies too - prevent MS and people can keep working and contributing to society and the tax coffers. And the money that has to be spent on symptom management meds, and services such as nursing, home help, physio, etc can be spent on dealing with diseases or conditions which can't be prevented.

      Call me a pessimist if you want - but I don't see another ten years providing safe drugs with no or minimal side effects. From what I can see the newer drugs being tested or recently approved just have even more side effects and risks that those that have been around from some years. And yet again - what about those who are not RRMS - look like the above poster seems to have forgotten about them.

      Oh - and just a minor detail - if people can be prevented from getting MS in the first place, there's the disappearance of all that suffering that comes from facing and dealing with a life of increasing disability, and the impacts from that which then affect families and friends of MSers.

      Continuing the efforts to find a cause/s is essential - it's a no brainer for me!

      Delete
  2. "Ideas on how EBV causes MS are welcome!"

    Amino acid sequence motif, RRPFF.
    It is known for 30 years and no one ever traced it down or did some deeper research. It is simple, plausible and explains the "autoimmune" part.

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  3. Prof G,

    I had a ON one year ago following a really severe cough that lasted over a month.
    My mother-in-law is an ophthalmologist and since I have 2 cases of MS in family she reacted very quickly when I told her about my vision loss.
    She took me to the hospital she's working at and arranged all tests imagineable. Within 36 hours I got my MRI and CT and saw so many different doctors from ENT to oral surgeons etc. She also had my blood checked for everything(!) available at the lab.

    MRI results: 2 lesions
    CT: severe Sinusitis maxillaris on one side (same as ON)
    Blood: Nothing really special besides a high EBV load and low HHV6 load

    There must be a connection between sinusitis, EBV and ON.
    The sinus maxillaris is so close to the eye cavity! Maybe it served as some kind of EBV reservoir that somehow spread to the eye?

    And for the lesions: Could it be an EBV infection of the endothelial cells that form the BBB?


    Greetings from Vienna!







    ReplyDelete
    Replies
    1. I regularly repeat the following but no one is in the least interested.

      Gay D et al Multiple Sclerosis associated with Sinusitis: A case controlled study in general practice. Lancet 1986: 1:815-9
      Gay F. Bacterial toxins and Multiple Sclerosis. J Neuro Science 2007;262:105-12
      Gay F Nose to brain. Is the trigeminal nerve a conduit for CNS disease. MS and Related Disorders. 2012;4:154-5
      Gay F. Staphylococcal immune complexes and Myelinolytic toxin in early acute MS. MS and Related diseases 2013; 2:213-232.

      Delete
    2. I wonder why :-)

      It is up to the Gays to present the case that convinces people, it is not our job to give people soap boxes:-)

      Delete
    3. "There must be a connection between sinusitis, EBV and ON".
      Hmm, it can't be in every case because I have never had sinusitis. Really nothing even close to this and I've had my fair share of colds and flu, even pneumonia and none triggered sinusitis. And yes, many attacks of ON over the years.

      Delete
    4. "Gay F Nose to brain. Is the trigeminal nerve a conduit for CNS disease. MS and Related Disorders. 2012;4:154-5"

      This is very very interesting. Since the ON I mentioned above I lost sensitivity in the area under my eye up to the temple. This is exactely where the nervus infraorbitalis is located, which is apparently connected to the sinus maxillaris.

      Any opinion on this from a pro?

      Delete
  4. No, it does not work like that. Every case of viral rhinitis causes a degree paranasal sinusitis, but the clinical effects are variable.This in medicine is known as 'sub-clinical' and has to be taken into account. To give another example that is topical. 'I have never been infected with EBV, and have not had glandular fever, therefore MS cannont be a cause of MS since I have MS. No. We all have been infected or have met the EBV but only a small number had symptoms or signs that clinically showed up. CT scanning and MRI show significant sinusitis in a very high proportion of URTIs. You will have had multiple attacks of sinusitis, but they will have been clinically inapparent. That is the way it works in the real world!

    ReplyDelete
  5. EBV infects B cells. The virus makes these infected cells immortal. The virus goes into hibernation but the infected B cells still cause an immune response, because of the mutations caused by the virus. A few of these cells get into the brain and trigger the immune response. Mixed Cellularity Hogkin's Lymphoma is caused by the infection of B cells by EBV. The lymphoma in the lymph nodes contain very few cancer cells. They mainly contain other normal immune cells responding to the signalling from the few mutated B cells. The effects on the local and distant immune system are stunning even though there are very few cancer cells (things like severe itching at unrelated sites). If the mutations do not allow the cells to divide to form a cancer they are going to be very hard to spot.

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  6. "Ideas on how EBV causes MS are welcome!"

    Perhaps by increased antigen presentation in the CNS. B cells go through 2 rounds of activation and clonal expansion in MS, one in the periphery and one in the CNS. EBV is latent within a subset of memory B cells. EBV infected B cells (latent) do not express all the EBV but do express latent membrane protein 2A (LMP2A). Expression of this protein is associated with increased B cell survival in the absence of BCR signalling and also increases the expansion and differentiation of B cells that are stimulated through the BCR. Bottom line is that there are increased numbers of B cells capable of presenting antigen within the CNS


    couple of abstracts:
    http://www.ncbi.nlm.nih.gov/pubmed/11913951
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354779/

    ReplyDelete
  7. Could there be a different strain of EBV not tested?
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295168/

    Reactivation of another virus or HERV by another pathogen as suggested by Prof. G
    http://www.medicalnewstoday.com/articles/278890.php

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0076359

    ReplyDelete
  8. Intrathecal oligoclonal IgG synthesis in multiple sclerosis.?
    http://www.ncbi.nlm.nih.gov/pubmed/23890808

    ReplyDelete
  9. Prof. Pender is doing a trial about EBV suppression in MS, furthermore we have Inspire Trial.
    So, let's wait and see what happens.....
    Casually a couple of month before my CIS, I have done complete blood tests.
    Was all ok, only EBV level was very, very high...

    ReplyDelete
  10. I wonder what Prof. response would be?
    Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy
    Michael P Pender and Scott R Burrows
    Citation: Clinical & Translational Immunology (2014) 3, e27; doi:10.1038/cti.2014.25
    Published online 31 October 2014
    http://www.nature.com/cti/journal/v3/n10/full/cti201425a.html

    Of course this could also be caused by a reverse placebo effect targetting the neurologists!!
    The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial.
    Noseworthy JH1, Ebers GC, Vandervoort MK, Farquhar RE, Yetisir E, Roberts R.

    Neurology. 1994 Jan;44(1):16-20.

    Author information

    Abstract

    In the randomized, placebo-controlled, physician-blinded Canadian cooperative trial of cyclophosphamide and plasma exchange, neither active treatment regimens (group I: i.v. cyclophosphamide and prednisone; group II: weekly plasma exchange, oral cyclophosphamide, and prednisone) were superior to placebo (group III: sham plasma exchange and placebo medications) using the blinded, evaluating neurologists' assessments of disease course (primary analysis).

    All patients were examined by both a blinded and an unblinded neurologist at each assessment in this trial.

    We compared the blinded and unblinded neurologists' judgment of treatment response and analyzed the clinical behavior of patients who correctly guessed their treatment.

    The unblinded (but not the blinded) neurologists' scores demonstrated an apparent treatment benefit at 6, 12, and 24 months for the group II patients (not group I or placebo; p < 0.05, two-tailed).

    There were no significant differences in the time to treatment failure or in the proportions of patients improved, stable, or worse between the group II and group III patients who correctly guessed their treatment assignments and those who did not.

    Physician blinding prevented an erroneous conclusion about treatment efficacy (false positive, type 1 error).

    ReplyDelete
  11. "This study confirms several previous studies..." says it all really.

    ReplyDelete
  12. https://www.jpt.com/fileadmin/user_upload/2014_Peptide_Microarrays.pdf
    Humoral Immune Responses towars Epstein-Barr Virus in Multiple Sclerosis using Peptide Microarrays.
    "Results confirm predominat role of EBNA-1 in altered antibody response in MS"
    So, who is right?

    ReplyDelete

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