What should we do about it?
I gave the Charcot lecture earlier this year at the NIH. In the lecture, I made the point that the epidemiology and biology of MS are coming together around the B-cell and EBV and that it is looking increasingly likely that EBV is the cause of MS.
Although my slides tell the story it is important to stress that proving causation is a complex process and the only way to prove that EBV is the cause of MS is to prevent EBV infection and see what happens to the incidence and prevalence of MS over time. This hypothesis is based on many epidemiological studies, but the most compelling piece of data is the observation that people who are EBV negative are protected from getting MS. Yes, protected from getting MS.
One hurdle we have at the moment is that we don’t yet have a good sterilising vaccine to prevent EBV infection. The latter is a technological challenge and there are very good vaccinologists working on bivalent and trivalent vaccines as we speak. Let’s hope they are safe and effective.
Some of you may know that I now wear two hats. My new hat is that I am a co-director of the Preventive Neurology Unit within the Wolfson Institute of Preventive Medicine and one of the diseases we are focusing on is MS. This is one of the main reasons I left Queen Square to move to Barts and The London; I wanted to work on EBV and MS.
In October 2016 we held a task force meeting on EBV as a cause of MS (see PDF below). The conclusions of the meeting was a unanimous yes; we need to go ahead and design and perform EBV vaccination trials to try and prevent MS. The latter is easier said than done, but that is our direction of travel, with ‘many miles to go before we sleep’.
There will be a lot of naysayers along the way but to quote Arthur Schopenhauer, ‘All truth passes through three stages; first, it is ridiculed, then it is violently opposed and finally, it is accepted as self-evident’.
Thanks Prof. G. Great article and gives All MS people. However in order to design a trial that vacinate against MS. You first need to indentitfy subpoulation at risk of MS. Given MS is still relatively rare and and affecting 1 in 600. Wouldn't you be better. At finding a subpoulation on the world that isn't infected with ebv and 1 case of MS disapproves your theory? If such sub opulation still exist.
Ps should Ms patients be taking spironolactone to stop MS?
Imagine if they would leave HIV patients to die and wait for a preventive vaccine to supposedly save the future patients. There must be a way to control the latent form of EBV with drugs and test the worth of this theory now and not in 25 years. Atara Bio is trying to do it in another way but even if it works there is still room for alternative interpretations.I also believe that the HERV theory or the interaction between the two is something to search.
"EBV is known to activate HERV-W/MSRV in vitro and in vivo (in IM patients and in healthy humans with high anti-EBNA1 IgG titers). This suggests that EBV could be an initial trigger, and that HERV-W/MSRV is a direct neuropathogenic contributor, before and during MS, in addition to its known contribution to promoting autoreactive T cells, immunoinflammation, and remyelination blockade." Arp '18https://www.sciencedirect.com/science/article/pii/S1471491418300315You can wait till ProfG gets his payment from this EBV vaccine or just target HERV now.
Prof G,The EBV causes MS theory has been around for decades. Here is the conclusion of a study which was published on this blog on 24/1/10 (almost 9 years ago):"This study is very important with regard to pinning down whether or not EBV causes MS."9 years later and we don't seem to have moved very far forward. Why do things take so long? Are MSologists involving immunologists and virologists in the research or are they doing it on their own (which may explain the lack of progress)? I'm 100% believer that EBV causes MS, but am 100% frustrated that we don't seem to make any progress in proving it.Two other things: Happy Christmas and thanks for all your work. Did you attend the European Charcot meeting and , if so, was there anything worthwhile to report?
EBV is linked to number of other conditions. That pharma are making Hugh bucks for treating. Like other research clinics, barts rely on pharma money. Forget 9 more years. Well still be discussing black Swan in 25 years. No point blaming barts. Blame lies with governments and their protection of pharma monoplies.
It's Time for gov to bring in a law all pharma spend 30% profits on cure related trials. Not just Treatments.
Are you talking to Michael Pender the Australian researcher whose interest appears to be MS and EBV. His work has been reported on this blog http://multiple-sclerosis-research.blogspot.com/2018/11/ebv-immunotherapy-works-in-ms.html#more
yes
"people who are EBV negative are protected from getting MS"Considering the prevalence of MS and EBV seropositivity, one has to ask why most EBV positive people DON'T have MS. The following study says that there are EBV negative children with MS:https://www.ncbi.nlm.nih.gov/pubmed/15100207Therefore, the question should be why people with MS seem to usually get EBV positive.
All the studies that use the gold standard for detecting EBV (immunofluorescence) show a 100% positivity. The paediatric studies used screening serology only.
Paediatric MS is hard to diagnose. In adult MS we get the diagnosis wrong in 1 in 20 patients, i.e. ~5% of people who have been told they have MS don't have MS. In paediatric MS this figure is going to higher. I would like to know by how much; wouldn't you?
What i would like to know is the exact way EBV leads to lesion formation, according to you.You say EBV acts from infected B cells that enter CNS through CSF circulation, right?1.What does it mean that EBV comes to life within an infected cell? 2.Does this happen spontaneously in a single infected B cell and then by molecular signals to all neighboring cells?3.How many of the infected cells wake up that way? Why not all? Does this happen to infected B cells of the periphery? Why not?4.Since CSF is everywhere around CNS and within the ventricles, why isn't there a uniform lesion distribution on the outer surface of the grey matter and along the coast of ventricles in the brain, and upon white matter of the spinal cord?5.How does EBV cause deep white matter lesions?6.How do you explain recurrent lesions?7.What is the nature of the damaging factor secreted by EBV infected B cells?8.Have you ever found a single candidate for that factor? Have you tested it?9.Do infected cells enter through BBB also? How and why?10.Why most MS lesions have a distinct vein almost at the center of them? (another MS specific feature, totally underestimated) If lesions are caused by EBV infected cells residing in the CNS, why do they constantly affect tissue around veins with such geometric consistency? If those MS lesions are caused by infiltrating cells, how do they pass BBB, against what are they sensitized and why there is no documentation of any single lesion being populated by infiltrating immune cells in absence of local CNS damage?
Re: "What i would like to know is the exact way EBV leads to lesion formation.."Me too. However, you don't need to know this to do vaccination trials. We still don't know exactly how HPV causes cervical cancer, but the community did the vaccine trials anyway. The rationale for he trials were based mainly on epidemiological data.
Re: "You say EBV acts from infected B cells that enter CNS through CSF circulation, right?"Wrong. I have no idea how EBV causes MS and where and how it is acting. It may simply be a trigger. I may drive disease in the periphery and or CNS or simply be a cofactor in term of B-cell autoimmunity.It is the epidemiology that is so compelling, which is why we need to do the vaccine trials sooner than later.
It seems to me you know very little to support your view on epidemiology alone. Instead of waiting a generation to create, test, affirm the use of anti EBV vaccine, you (plural) could simply try to disprove this idea against known and distinctive features of MS. At least, you could do that in parallel.What is more, all epidemiology data depend upon the truth/fallacy of a single claim: that EBV infection precedes MS onset. If you prove that MS is right there from the beginning, your idea falls apart. You could try identifying the very very early MS signs, but this is not feasible without identifying the exact pathology.So, this whole EBV idea is nothing but a rope that ties your hands. My view is that the anatomical malformations that are necessary (but not always enough) for MS to develop are largely congenital, but are operationally manifested during periods of great bodily changes, like puberty and pregnancy, or in case of trauma.
"one has to ask why most EBV positive people DON'T have MS.". The same reason why most people who are EBV positive don't get mixed cellularity Hodgkin's Lymphoma, but some do. It will depend on the specific damage done by the virus to specific cells.
The pathogenetic contribution of EBV to HL "remains poorly defined", just like MS. Also, the main reason for implicating EBV in HL is the epidemiology data, just like MS. So, you can't really extrapolate the HL example to MS as all this could be just a fluke.
Vasilis Vasilopoulos. I was not extrapolating HL to MS, you were. I was pointing out that your argument does not hold water. I could change "The same reason why most people who are EBV positive don't get mixed cellularity Hodgkin's Lymphoma, but some do." to "The same reason why most people who are EBV positive don't get Burkitts lymphoma, but some do." or "Most people who get EBV don't get Glandular Fever but some do." My point is unchanged. You cannot imply from 'most people who get EBV don't get MS' that one does not cause the other, because it is true of things where we know EBV causes them but only in a very small subset of the population.
"You cannot imply from 'most people who get EBV don't get MS' that one does not cause the other"Adopting the statement that all people are more alike than different, i can imply that the cause of a clear functional difference (MS) must be similarly clear and uniquely identified in people with MS. There is nothing unique in being EBV positive as there is nothing unique in drinking more than 1lt water a day, getting exposed to more than half an hour of sunshine, etc.
It does not have to be unique to be causal. Causal simply mean that if the first thing does not happen then the second will not. Asbestosis is caused by asbestos. If you do not get asbestos in your lungs you don't get asbestosis. However, not everyone who breaths in asbestos into there lungs gets asbestosis. It is still causal.
Let me put it another way. In chaos theory (say a hurricane model) you can start a process from as close to the the same place each time as is possible and still the outcomes are wildly different after a number of days have passed. If we assume the infection with EBV is necessary for MS (it may not be). Then the point of infection is the starting point (all the same). The end point is the effects of the bodies interaction with that virus over many years and this will be widely different. The starting point is the same for all, the end point is unique. The starting event is still causal as without it the rest would not occur.
Baker et al"However, definitive evidence for EBV exhibitinga causal link in multiple sclerosis is lacking (Burnard et al.,2017).""Thus, the aetiological involvement of EBV inmultiple sclerosis, and above ideas, must remain as speculationuntil disease activity can be shown to respond toviral inhibition."Learning from other autoimmunities tounderstand targeting of B cells to controlmultiple sclerosisBRAIN 2018: 0; 1–14 | 1:)
How do you generate the definitive evidence that EBV causes MS? You should ask Zur Hausen, the Nobel Laureate and virologist, who proposed HPV was the cause of cervical cancer.
"above ideas, must remain as speculation"Baker et al
HPV was proven to be the cause of MS after successful vaccination studies. Zur Hausen was ridiculed and when the link between HPV and cervical cancer became self-evident, he was awarded the Nobel Prize for medicine. Interesting?
Fair enoughVincent Racaniello virologist professor and researcher inin Colúmbia university Says "vírus dont cause câncer they lead up to cancer"There are HPV positive persons that dont have cancerhttps://youtu.be/RaHw7sESL8QIf you apply the same principle Ebv positivity dont cause MS but sould lead (risk factor) to MS And sure there are MS positive persons that dont have MS "If you only remember One thing vírus themselves dont cause câncer they lead up to cancer"Vincent RacanielloObrigado
So cigarettes do not cause cancer the lead up to cancer. I think the lawyers for the Tobacco Industry may be phoning you to see if they can borrow that idea.
"B-cell hypothesis"Yes, I am eating my hat. I predicted that unless a BTKi was depleting it would not work in MS. Why?"This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards."This puts T-cells back on the agenda, possibly downstream of B cellshttp://multiple-sclerosis-research.blogspot.com/2018/03/is-it-b-cell-or-t-cell-prof-g-eats-his.html
Unfortunately, the evobrutinib (BTKi) results were at best modest. B-cell depletion seems the best option. However, a BTKi may be a good maintenance agent.
This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards.http://multiple-sclerosis-research.blogspot.com/2018/03/is-it-b-cell-or-t-cell-prof-g-eats-his.html"the response to therapy indicates that depletion of B cellsconsistently inhibits disease activity."Learning from other autoimmunities tounderstand targeting of B cells to controlmultiple sclerosisBaker et alCum caneco??????
Re: "This is telling us that you don't need to deplete B cells to get a therapeutic effect and that B-cell antigen signalling and presentation are back on the cards."YEs., I said that, but the results of the BTKi are modest and not highly-effective. We may still need depletion or BTKi may need CNS penetration and or to be given after a round of depletion. At the moment I have difficulty identifying a place for Evobrutinib when anti-CD20 are destined to become the most prescribed class of DMTs in the MS space.
Unfortunately, the evobrutinib (BTKi) results were at best modest. B-cell depletion seems the best option. However, a BTKi may be a good maintenance agent.
Dr. Giovanni- a likely better avenue would be to test more anti retroviral drugs that target ebv and herv, such as combivir, as add on therapies by hitting their dna replication cycle. The link between hiv and lower incidence of Ms is already established.Since ectrims didn't work, are people abandoning other anti retrovirals? Also, you won't be able to do a proper ebv vaccination study as a preventative because so many people become lifelong infected in daycare. An ebv vaccine as therapeutic may work if part of the reason is the latent vs lytic t cell response like atarra suggests.Really, we need a combivir study yesterday.
Any link between HSV2 and MS? Given it causes alzimers and parkinsons.
If you think the EBV is the causes. Why dont you think that the recent T-cell therapy against the EBV is the cure? https://insight.jci.org/articles/view/124714
The ddata does support it
Or, smoking doesn't cause cancer, many who smoke, get cancer.There are still those who smoke that do not get cancer.But it clearly sets up an environment conducive to the development of it.Over 30 years ago, I had glandular fever and remember being told then that: it could lead to 'other things' way down the line if I don't call back for another injection (I don't remember what of), and I didn't call back.But EBV is a virus and there were no antivirals. Or were there?And I've often thought, has that made all the difference?
The only anti-viral licensed for EBV is rituximab and anti-CD20 B-cell depleting antibody.
how well does rituximab treat EBV? if ritux works, presumably ocrevus would too?
Is there a way to test if you have had EBV is the past? I have no recollection of having the disease.
Yes, it is a simple serological test to see if you have anti-EBV antibodies.