You said “Could be a missing link into the trigger for MS”. Indeed there has been recent interest in the role of EBV as the cause of MS, and today the link is explained….or is it?
Someone else said “If EBV causes MS. Can it now be ruled out the MS isn’t an auto immune disease”
Here they looked at B cells in MS brain tissue and that some had been selected and expanded….presumably by disease. Then looked and many of the expanded B cells reacted with Epstein Barr Virus (EBV) and then they found a clone where the antibody reacted with a nerve protein and when animals were immunised against it disease got worse
It seems that an immune response to an EBV protein can cross-react with a brain protein to cause MS. This process is known as molecular mimicry where immunity to a pathogen cross-reacts with an protein to cause autoimmuniy. This study identifies glialcam as a cross-reactive target developing after EBV infection
If true then an idea that I put forward to explain autoimmunity after infection of B cells is incorrect.
However…let’s say hang on….. “molecular mimicry” is not a new idea and molecular micmicry between EBV and another brain protein anoctamin 2 (ANO2. On blood vessels?) was reported in 2019 and EBV and myelin basic protein in 1995 and now glialcam in 2022. What will be next?…..
Hopefully repetition because we have been here before, such as when MS was a result of antibodies to a potassium channel…It could not be replicated by others. So let’s see what happens and ask why didn’t they find reactivity to RASPRG2 another candidate last year or so. Maybe they did find it and just kept it quiet
What is Glialcam?
Glialcam is an adhesion molecule expressed by glial cells but the expression is high on astrocytes. So why MS and not Neuromyelitis Optica, which targets astrocytes. There is some expression on oligodendrocytes and furthermore, the gene name of glialcam is HEPACAM and was discovered as an adhesion molecule in…you guessed it…..hepatocytes…yep liver cells.
So why would you get a brain disease or would you expect the liver to be targeted in MS?
Lastly the question is is this the chicken or the egg? Is the immune response to Glialcam causing the damage or is it that damage caused by the cuase releases brain proteins that cause the glialcam response
If you want to read the paper search on the title and you will find a preprint. If you go to Nature look at the referees reports to get some insights.
Its not my idea, so we can let the authors of the work answer that one, indeed please come and send us a guest post on the work. Importantly, it will need to be repeated by other people, but a fantastic approach.
This manuscript suggets that EBV is a worthwhile target to control MS
Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM, Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.
If infected B cells are driving progression then anti EBV treatments will effect the course of MS. Much like treatments do now. However if the EBV kicks of the immune system early then taking out EBV while someone has MS and not before may not have a difference.
Clearly there’s a link and who knows eradicating EBV may cure/stop further progression. However surely there more in play than just EBV.
It’s of course more than “just” EBV.
But EBV seems to be the catalyst keeping the cycle running. Taking out the catalyst, will stop the progression.
I remember reading a blog entry here sometime ago, where it was suggested, that higher ocelizumab one-time-dosing should be investigated, to make sure it gets into tissues, that can’t be adequately reached with the regular dose and trapped lymphocytes can’t escape depletion.
I’d add an anti-EBV antiviral right after (and keep using it indefinitely) to keep EBV from (re)infecting B-cells and repeat the cycle until anti-EBV IgG levels start to drop and stay down. Then stop anti-CD20 therapy and just continue with the antiviral.
I’m glad we see so much movement related to EBV lately. I wouldn’t be surprised if long covid had some EBV relation too, which would of course be tragic, but still good new for MS patients. Because this means, EBV will be the next target after the current phase of the pandemic.
I know. Obviously there’s more at play then ‘just’ EBV. Some believe EBV is driving progression.
Your plan sound so great, and no one has ever though of this before I’m sure. So whats the name on these anti viral for EBV you talk about?
The one easiest accessible would be Valaciclovir/Aciclovir I guess. There’s conflicting data about the effectiveness for EBV treatment, but this paper suggests it’s somewhat effective in the long term: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772668/
Combining this modest effect with depleting B-cells first, might as well be enough to keep EBV in check.
But there are a few other antivirals, which seem to inhibit EBV replication. There are case reports about EBV being targeted by HIV anti-retrovirals, for example: https://pubmed.ncbi.nlm.nih.gov/29510325/
I think, as I said above – and that’s my personal opinion, which I can’t back up with any data unfortunately – the key to keep MS in remission permanently is to combine b-cell depletion with antivirals. Because antivirals alone will not get rid of “defective” b-cells (memory b-cells are possibly maintained the whole life) and b-cell depletion alone will not help with b-cell reinfection.
So only using one or the other might help some patients, but won’t stop progression completely in most patients.
It’s a shame that pretty much all the studies I’ve seen so far only focus on monotherapeutic interventions.
IMHO this is the best theory so far: https://www.msard-journal.com/article/S2211-0348(17)30118-9/fulltext
It explains many – possibly even all – observations of relapsing MS.
Maye profG can look at the data where he used Famciclovir and cladribine
If I was self-medicating I would probably try combivir based on this case study:
Cheap and easily accessible HIV medication.
They are reverse transcriptase inhibitors so they are good for RNA viruses like HIV…but DNA doesn’t need to be reverve transcribed from RNA to DNA…EBV is a DNA virus
Based on the assumption that EBV triggers an autoimmune response, why haven’t we found the antibody that’s doing the damage seeing there is an entire list on Wikipedia with all the known autoantibodies and what they attack.
They say that around 25% of MS cases are due to GlialCAM. Therefore it can still be true that ANO2 is the culprit in some other cases. It is quite likely that MS is heterogeneous.
It is also quite possible that this paper is a load of old b****cks 😉
If you have to work that hard to find an antigen, it’s probably telling you you’re barking up the wrong tree or maybe even the wrong forest.
GlialCAM is liver expressed and MS is a well known liver disease? 🙂