Bar-Or A, Banwell B, Berger JR, Lieberman PM. Guilty by association: Epstein-Barr virus in multiple sclerosis. Nat Med. 2022 . doi: 10.1038/s41591-022-01823-1.
ProfG has been banging on about EBV and MS as long as I have known him, but when two papers come together (one showing that you get infected before you get MS and the other one suggesting a mechanism of how T cells are activated in (i) below) and peoples ears prick up.
Whilst there is no discussion of the work being questioned as to its importance, they provide alternative explanations
So here is a pretty picture of the different ways that EBV may be involved in development of MS
(i & vii)) Cross reactive antibodies and mimicry. So immune response to one element that cross reacts with a nervously-expressed element occurs. This have been suggested before in associated with myelin basic protein and other poteins long before GlialCam was suggested. This puts the problem at the level of the antibody…However, the original description of molecular mimicry was firmly at the T cell level. The anti-EBV T cell response makes an anti-CNS T cell-mediated immune response.
(ii) EBV infection leads to HSP heat shock protein on B cells this activated heat shock specific T cells and target HSP expressing brain cells possibly after EBV infection
(iii) EBV reactive or CNS reactive (v, vi) T cells are generated and and enter the CNS and produce toxic molecules that damage the CNS (x). Therefore you may not need to a specific antigen to drive this and why would measles virus, cytomegalo virus etc. be associated with MS is a same way as EBV is?
(iv, v) EBV-reactive T cells may kill (viii)EBV infected cells in CNS, but why would it be so hard to find EBV in brains and MS lesions.
(vi) EBV infected B cells enter CNS and are targets for T cells or activate T cells
Maybe another one, EBV infected B cells enter the CNS and cause bystander damage (x) without bothering T cells (Yep heresy) or the other reasons we have suggested previously.
So how we disprove these ideas and if we can then it is not a major mechanism. With regard to finding antibodies in MS we have to wait for the Lanz et al idea to be repeated as we have been here before with Kir 4.1 (potassium channel specific antibodies). Essentially, no-one could repeat the work. Finding EBV in the brain has been another one where people have struggled to find it in the brain.
Molecular mimicry
I know and you know
You dont like this bit
🙂
Nice post
Thanks
Maybe EBV isn’t the target, it just helps to trigger the MS process along the way.
There are people with out EBV exposure who have MS. Some children who have no evidence of EBV can get MS.
It clearly increases damage in the brain. If it drives MS. Then could MS with evidence of EBV anti bodies and MS without evidence be 2 different diseases of EBV is the cause.
Or could they both be MS non EBV positive is an auto immune disorder and EBV positive is purely mimicry of some sort to an EBV protein.
Is EBV the CNS first target, and does it target other organs long before it enters the CNS if is in the CNS.
So many questions, hopefully it will unravel. It’s clear no an anti viral trial is needed, if big pharma don’t fancy it then charity’s should get together on this, on a well designed phase 3 trial.
More work is needed on the sequence of events during Glandular Fever. I was in a weakened state when my immune system had gotten EBV under control and then I started getting cramp like pain in my knees. This was Reactive Arthritis that had begun to develop, and I wonder if MS was kicked off at the same time with symptoms only emerging much later.
an open label anti viral trial with 15 people with RRMS, SPMS and PPMS. See where it goes from there on
Looks like they’ve created 20 years more work for MS researchers. The only hope is that an EBV vaccine shows a positive effect and can be quickly trialled on MSers or that the Atara trial is positive. Until a therapy can stop the neurodegenerative processes we are still stuck in the dark ages. A recent piece by Prof G (sorry to mention his name) said that even those on Natalizumab after a long time still go on to SPMS. I suspect that this will be the same for the other highly effective therapies which are just dealing with the response of the peripheral immune system not the root cause of the disease (on going damage within the CNS).
Sid is that you? I wish the regulars would start posting again.
Unfortunately very little breakthrough MS research seems to be being published (apart from the ebv paper earlier in the year). Plus, still too much covid stuff. At least Prof G put forward some suggestions / hypotheses (smouldering MS etc.) that led to a good discussion. I follow his Twitter account, but it’s a bit repetitive. This whole field needs a kick up the backside. Many are waiting for the results of the BTK Inhibitor trials ir the Atara trial. We are always in no-man’s land and are usually let down (numerous remyelination trials).
Which BTK trial the progression ones
Yes. The highly effective DMTs now address relapses, but the big issue remaining is progression. BTK inhibitor trials for progressive MS, Chariot trial, Sizomus trial, Atara trial, Cambridge remyelination trial. Time for therapies to slow / stop smouldering MS / neurodegeneration.
Imho it doesn’t matter how EBV is involved in the progression of MS. Sure, knowing can help in treating the illness. But that’s only true if there weren’t any other options available.
Just treat the EBV infection and worry about the rest later. Starting studies with different anti-herpes antivirals should be the next step. There are promising antivirals out there which seem to inhibit EBV replication.
At the moment, it reminds me of firemen standing in front of a burning house and arguing what caused the fire and how exactly it spread, instead of just putting it out, because knowing the cause would make the job easier, regardless of having all tools readily available to just get the job done even without knowing the exact cause.
You’re spot on. How can we sloop while are CNS is burning? (Sorry about that Midnight Oil fans)
In relation to EBV and the cause of MS, has the virus been fully sequenced, and does this help explain why it could be a cause of MS? Using the Covid-19 virus as a comparison, the EBV must have mutated many times over the last century or more, so one would expect the effect on causing MS to have changed over the years, both positively and negatively. Is there any evidence for this? It would also suggest there maybe be different variants of EBV currently circulating in the general population.
My maternal grandmother died of MS in 1920, aged 29, and my brother died of MS in 1979, aged 26, which would suggest no change in the ability of the EBS to cause MS.
Not all viruses mutate as rapidly as flu or even Covid. The vaccines for measles, German measles and chicken pox (And others) which are live attenuated vaccines are still as effective as they were 20-40 years ago.