EBV. Look hard enough and thou shall find

E

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis. Abrahamyan S, Eberspächer B, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Schroeder C, Grüter T, Tackenberg B, Paul F, Then-Bergh F, Kümpfel T, Weber F, Stangel M, Bayas A, Wildemann B, Heesen C, Zettl U, Warnke C, Antony G, Hessler N, Wiendl H, Bittner S, Hemmer B, Gold R, Salmen A, Ruprecht K; German Competence Network Multiple Sclerosis (KKNMS); Other members of the KKNMS that acted as collaborators in this study.J Neurol Neurosurg Psychiatry. 2020 May 5. pii: jnnp-2020-322941

OBJECTIVE:

To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

METHODS:

Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

RESULTS:

EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

CONCLUSION:

The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS

100% of MS cases are infected with EBV

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MouseDoctor

51 comments

  • What were the arguments in the past that EBV is NOT associated with either a triggering mechanism or the ‘etiological factor’ behind the genesis of MS ? Was it that some cases had NO evidence of Abs to either the capsid or nuclear Ag ?

    What percentage of the B cell follicles that drive MS, presumably are EBV positive ? Of course that may have to be a post-mortem type study but your study is intriguing. Prof G is also a strong advocate of the infectious mono and EBV theory and onset of MS earlier in girls (we are taking about the Western world now, not in Iran, for example or Japan, for instance !) because of kissing earlier than boys (by about 4 years) but perhaps there is more to the EBV trigger for MS ?

  • Can we say that the link between EBV and MS is like the link between smoking and lung cancer?

    Lung cancer is caused by mutations in certain genes

    Smoking greatly increases the rate and likelihood of those mutations, so we say that “Cigarette smoking causes cancer”

    Some non-smokers will get lung cancer because they got the same mutations because of other factors, or simply by chance, or by aging
    Some smokers will not get the mutations and will thus not get lung cancer

    EBV cannot be the immediate cause of MS – otherwise 90% of the population would have MS
    (90% or whatever percentage it is)

    What is the immediate cause?

    • Hi, genetic predisposition to autoimmune disease (U got choice in HLA catalog!) + EBV (+ HHV-6?) + IBS(?!) + crossed immunity = multi-factors.

      I got SPMS, EDSS6.5, sugar!!!

      Who cares for in-depth studies? Most immunotherapies are not enough targeted.

        • Hi Andrew,

          Yes, read it, (scarcely) tried it ; but it is hard to apply.
          Also read Paleo Solution: The Original Human Diet
          Robb Wolf, Loren Cordain Ph.D.”

          Took dietary supplements, useless. Melatonin (when needed) helps me sleep well.

          I avoid milk (cheese, etc), gluten, added salt, sugar (as possible).

          Maybe have a look at: “The Silent Saboteurs: Unmasking Our Own Oral Spirochetes as the Key to Saving Trillions in Health Care Cost” (may concern Alzheimer, Lyme, …).

          Cheers.

  • Thanks MD. It”s time to reclaim this site for MS news / research. Coronavirus is hopefully on the wane. I thought a lot of MS research papers were rubbish but some of the trash churned out by researchers relating to Coronavirus really scrapes the bottom of the barrel. We need Prof G to do a Bojo type announcement setting out a roadmap for Barts MS research following to recent focus on Coronavirus. We need the stalled trials to be started again, research papers published and a new drive relating to EBV. I see that interferon is being used in Coronavirus patients. Maybe some of the insights from tackling Coronavirus came be used in MS research. If a vaccine is developed for Coronavirus perhaps the technology / approach can be used for an EBV vaccine (saving hundred of thousands of lives from the vile disease which is MS and the various EBV cancers).

    • Coronavirus vaccine research is unlikely to yield any insights into the human herpes virus (EBV/HHV4) immunisations. Varicella Zoster and Cytomegalovirus are at least in the virus same virus family. I’ve seen that there are several groups working on an EBV vaccine, but while it might protect children from developing MS in the future, it’s unlikely to help us now.

  • Hi Mousedoctor

    How do we get tested for EBV Serology please. Of course when it is safe to do though.

  • This demonstrates the importance of understanding the sensitivity and specificity of a test. False negatives have misled most neurologists into thinking that EBV is not the root of all MS – which it is as confirmed by this study. Look out for false positives in CoVID-19 serology testing which will cause some people to think that they’re immune to the virus prior to exposure for the first time.

  • werent people looking into this 25/30 years ago?

    Why doesn’t someone just GET ON WITH IT and treat us for EBV ?

    • Exactly. Research isn’t done just for browny points from colleagues. Or to win investment from pharma to keep departments financed for.next 30 years. use this blog to raise the funds. Enough with talking show us the Road map to the cure and practical steps with timeliness.

    • There is nothing that can remove EBV from your body after you have caught it apart from wiping out your immune system and rebuilding it afresh. We cannot easily clear any herpes viruses once they are caught, although some drugs can slow replication. They are remarkably good at hiding. The chicken pox virus you had as a child remains hidden only to reactivate and give you shingles in later life.

        • You had chick pox, no one noticed. Shingles is the same virus moving up the nerves from the spine until it erupts at the skin.

          • never knew that!
            painful as heck it was, right near eyes, in ears etc.

            So was that me screwed from then on in with regards to MS then?

          • There have been cases of EBV being removed from people by cancer treatments where the immune system is rebuilt, but as the virus can always reinfect it is not permanent until there is a vaccine. I do not have MS but do have problems with EBV: Full blown mono/glandular fever twice, chronic fatigue for 5 years followed by Hodgkin’s Lymphoma. I used to get ill every autumn or winter recover late summer thus my interest in vitamin d. 10,000IU a day has stopped it for the last 13 years, except for the two times I allowed my levels to drop when both times I gained a number of new enlarged lymph nodes. When I raised my vitamin d level they stayed but stopped growing.

  • Yes ok. I believe in the black Swan. I accept ebv is the cause of ms. Its been more than 10 years since Bart has hypothesised this theory. So now what next ? Whats your road map to cure ms given all we know? Why keep hammering the idea if nothing is shifting in the therapeutic arena? Heres a idea why not give your barts ms patients antivirals that effect ebv? Too simplistic? If trial protocols can be ignored to cure covid 19 why not for ms? If cash is the only factor why not ask stop ms for money? If they say no ask them to justify their decision? Then publicise it to shame their links with pharma.

    • Valaciclovir has already been done and showed a trend but the study was only 2 years long and didn’t reach statistical significance. Pender M. et al genetically modified T-cells to target EBV infected B cells in MS in Australia and everybody, in whom the technique worked, improved clinically. A better question is, “Why this isn’t being repeated all over the world?” – Oh, wait, it can’t be copyrighted and pharma won’t make any money out of it and might lose income from the expensive drugs they’ve developed.

    • I know of no anti viral’s that affect herpes viruses when they are in their latent state (hiding). There are some that work when they are active, when you have mono/glandular fever/cold sores/chicken pox etc, but it is probably not the active virus that is causing MS. It is likely to be infected B cells sending out false messages the same way Reed–Sternberg cells disrupt the immune system in Hodgkin’s Lymphoma. Reed–Sternberg cells are B cells that EBV has made immortal and they pull other immune cells in around them, creating the lymphoma. They also cause all sorts of odd immune effects no where near the lymphoma.

      • We have developed a drug that inhibits EBNA1, the only protein expressed in EBV latent infection. The drug is now in Phase I clinical trials for patients with advanced nasopharyngeal carcinoma, a cancer that is almost 100% EBV positive.

        It would be interesting to take patients with CIS and treat them with the EBNA1 inhibitor or placebo to see how many of patients go on to develop MS.

        Stay tuned.

  • As I’ve had SPMS for the last 20 + years, preceded by 30+ years of benign MS, is any anti- EBV treatment EVER going to be on the horizon or offered to people like me? Or do I just have to accept progressive disability?

    • One of the reasons why the role of EBV in MS remains so speculative is that the serology, as carried out in this communication, indicates that > 95% of the control population has evidence of infection with EBV. It has been known and very well documented for many decades that pwMS have hyperreactive immune genes that significantly elevate antibody to a wide range of microbial antigens, and viruses in particular. The measles story is a good example, and we might well think about elevations to HHV6. So, are we NOT to expect that the XS 5% antibody to EBV in MS, demonstrated in this and other reports, can be accounted for in the same way? Simply put, raised antibody to EBV HAS to be elevated in MS.
      What is more problematic is the lack of a credible mechanism for the various manifestations of MS in the CNS. Also the lack of good evidence that the various trajectories of the disease are related to EBV activation.
      This is a VERY slippery fish!

      • It does not say there are raised antibodies to EBV, it says all the people in the trial had antibodies to EBV, so they had all been infected. If you don’t have antibodies you have avoided it. I managed to avoid it until I was 37.

  • Very interesting! I’m ina study with NIH, I got tested for EBV and have the antibodies for it. I do not really recall getting sick with mono like symptoms but I guess I was just lucky at that time.

  • Message to Prof G – get off your ass and identify treatments to target EBV. For the last few months you’ve gone Cornavirus mad – leave it to the specialists (virologists and epidemiologists). You’ve known (and said) for years that MS is caused by EBV (and we believe you). We now need a plan to get treatments to tackle the real MS not the immune response. We don’t need a 20 year study to test the hypothesis. You already have an army of lab rats (followers of this blog) happy to be part of a study to trial an EBV vaccine. Touch base with the Oxford bods who are working on the Covid 19 vaccine. They seem to know what they are doing and don’t beat about the bush like MS researchers. We now need action and speed rather than the constant dithering and navel gazing. You’ve got 4 years before your bus pass arrives. Time enough to have tackled EBV and put MS to bed.

    • At the moment that ass is in Scrubs and general medicine…Maybe the virus mania will rub off on EBV you will see hundreds of companies make vaccines in a few months.

      Bods in Oxford….Know what their doing and you complained at us about lining our pockets:-), but if you have the government ear it helps.

  • MD, your post today seems to provide more support for the iTeri study that was previously discussed on this blog.

    • It is whether sanofi can be enguaged to do it…otherwise you will have to clone ProfG to get more bandwidth

    • I dint know about CD10..i will need to read more, have you come across CD20 negative cells?
      I thouhgt CD21 was important for infection

    • Interesting presentation. I don’t agree with all the points, but after several years of research of scientific literature, publications and studies I came to the same basic conclusions.

      Based on Pender’s hypothesis and various studies implicating bacteria (or bacterial toxins) or fungi, I’d also argue, that antibiotics and antimycotics might help (in the short term), in removing an unknown culprit driving the B-cell response.

      However, it remains to be seen whether this is actually the case, as there are not enough studies on this. The fact is, however, that various infections have been repeatedly associated with MS for decades. EBV almost certainly plays a central role in this.

  • Surprise, Surprise.

    Why on earth is there still doubt about the causal link between EBV and MS? Sometimes it seems to me that a large part of the scientific community has been brainwashed. Theys seem to be indoctrinated with “The truth ONLY comes from double-blinded peer reviewed studies”. Sure, this is a useful method to verify new theories in a conclusive way.

    But it is a completely redundant approach and a pure waste of time if you already have a mountain of circumstantial evidence that paints a relatively clear picture. It’s as if people have forgotten how to think for themselves. It’s absolutely ridiculous.

    I find it hard to believe that anyone who is genuinely and critically examining this EBV-specific information can have any doubt about the important causal role of EBV and the need to tackle the virus in the body of people with MS.
    Often when I speak to people about this, I hear it’s important not to jump to conclusions. EBV has been implicated constantly for more than 40 years. Jumping to conclusions? Is this a joke?

    I also find the approach of “we can only be certain if it’s EBV, if we had a vaccine” highly problematic. No, that’s the only way to make sure it takes another 20 to 30 years for this whole thing to be solved. EBV can be treated with antivirals and T-Cell treatments, both already in place in oncology. How about starting trials on that, right now.

    https://df6sxcketz7bb.cloudfront.net/manuscripts/124000/124714/jci.insight.124714.v1.pdf
    https://www.msard-journal.com/article/S2211-0348(17)30118-9/pdf

    Excuse my cynicism, but I find the whole situation just absurd.

    • Hi,

      Thanks for both documents, but since they are dated 2018 & 2017, even if they provide information, thy’re not up-to-date, since much work has been published.

      It has been obvious since ages that EBV triggers MS, but other studies have provided much more facts.

      See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182248/ though my curiosity is not satisfied with it.

      Recent news: https://medicalxpress.com/news/2020-04-therapeutic-options-multiple-sclerosis-sight.html

      Brgds.

      • The contents of the papers I posted are 100% relevant today, as one of those actually describes the potential pathway leading to MS and the other shows how treating MS patients for EBV leading to a better clinical outcome. It doesn’t matter why or what EXACTLY casues MS, when there’s a smallest common denominator: EBV.

        MS is most likely the result of a chronic infection and looking at immune responses without trying to remove the cause is nonsensical.

        It’s like trying to figure out how to stay dry in the rain and start looking at how how the skin reacts to water and then start looking to various microscopic levels. First you look at skin cells, then you look at the cells below and then you look at how nerves react to the rain. Then you look at how the blood flow changes when the water hits the skin and check the immune system response etc. And finally when none of the 100,000 things you looked at provided a solutions for how to stay dry in the rain, you start looking at atoms for another 20 years.

        That’s how MS research presents itself.

        How about taking a step back and just use an umbrella (antivirals)?

        In terms of MS, the best way to move forward would be to actually start treating people in a systematic way with different antivirals or antiviral treatments (like the mentioned T-cell therapy). Let’s face it, everything else is a waste of time at this point.

        • Hi,
          Readinh this page again, I regret its focus is EBV ONLY, though I agree “there’s a smallest common denominator: EBV. “.

          I feel like you’re going around in circles talking about this one virus. Other factors seem completely excluded from your conversations. Is this a cultural problem? I’ve read so many articles about HLA (genetic susceptibility) genes that it’s clear to me that EBV potentially triggers several autoimmune diseases, including MS, but also Rheumatoid Arthritis for those who have its susceptibility genes, etc.

          I pay attention to my diet, especially milk (and its derivatives), to avoid a possible immune cross-reaction with the Myelin Basic Protein, which is attacked by the immune system. This could be based on a common pattern between the MbP and a milk protein, for example. The mechanism of the HLA system seems to me to be abused by the combination of amino acid sequences that “summarize” (imitate) the characteristics of an antigen. See https://en.wikipedia.org/wiki/Human_leukocyte_antigen . In computer science ( https://en.wikipedia.org/wiki/Hash_function ) some pairs of inputs may be mapped to the same hash value (“collision”). This is my hypothesis.

          Cheers.

          • You’re absolutely right, MS is a complex issue and there are dozens of factors relevant to the disease. It absolutely makes sense to look at those factors and also incomporate learnings into the life of MS patients.

            But I think it’s more important to start tackling the issue staring us in the face for so long. Herpes viruses seem to be at the center of it all in some way.

            Maybe it’s not EBV alone, maybe its other herpes viruses too. Maybe it’s not the viruses alone, but also bacteria and fungi.

            But those questions won’t be answered by looking at mice with EAE. And they won’t be ansered by taking an even into deeper look at immune responses.

            On the other hand, these questions can easily be answered by just treating people with easily accessible and cheap drugs, which usually also have a very good saftey profile. And once we do that, you can start looking for patterns, maybe even use machine learning and start clustering people with correlating MRI, blood works, symptoms, progressions and treatment responses etc.

            And then you start looking into those clusters and can finally start solving the mysteries instead of poking sticks randomly in the dark.

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