Why I think MS is a Virus

[Ecoclimber]

Permission to repost Prof. G

Canada: why I think MS is caused by a virus

I now want to get the next phase of the Charcot Project off the ground ASAP
"As promised my presentation that I gave at the grand round in London, Ontario. I got a lot of verbal support from attendees at the lecture for the Charcot Project. Their support makes me want to get our IM, EBV and HAART trials off the ground ASAP. As always we need funding."

Xenforo plugin would not allow slideshare.net code so those who are interested click on the link below

http://www.slideshare.net/gavingiovannoni/why-i-think-ms-is-an-infectious-disease-for-the-blog

Also

J Neuroimmunol. 2014 May 15;270(1-2):51-5. doi: 10.1016/j.jneuroim.2014.02.013. Epub 2014 Mar 6.
Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis peptides are cross recognized by anti-myelin basic protein antibodies in multiple sclerosis patients.
Mameli G1, Cossu D1, Cocco E2, Masala S1, Frau J2, Marrosu MG2, Sechi LA3.
Author information

Abstract
Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis (MAP) have been associated to multiple sclerosis (MS). We searched for antibodies against the homologous peptides Epstein-Barr virus nuclear antigen 1 (EBNA1)400-413, MAP_0106c protein (MAP)121-132, and myelin basic protein (MBP)85-98 on a MS Sardinian cohort, showing that these antibodies are highly prevalent among MS patients compared to healthy controls.

Competitive assay demonstrated that antibodies recognizing EBNA1400-413 and MAP121-132 cross-react with MBP85-98, possibly through a molecular mimicry mechanism. Indeed, the fact that peptides from different pathogens can be cross-recognized by antibodies targeting self-epitopes supports the hypothesis that EBV and MAP might trigger autoimmunity through a common target.

 

[helen1]

Dr Charles Stratton and colleagues at Vanderbilt U believe MS is likely caused by chlamydia pneumoniae chronic infection in a large subset of MS patients, up to 70%.

http://cpnhelp.org/multiple_sclerosis_and_th

This is interesting to me as I have chronic c.pneumoniae. Stratton has an antibiotic protocol using 3 types of abx designed to target the 3 life stages of the c.pneumoniae bacteria, recommending long treatment times, 6-18 months.

 

[Ecoclimber]

Why this is important to ME/CFSers is the the fact that if these trials are successful, their research (Charcot/Inspire Trial) could impact ME/CFS research.

 

[Jonathan Edwards]

I think it is reasonable to think of EBV as being part of the story in MS. As for ME/CFS there is an interesting possibility that it is not the encounter with EBV that matters, since more or less everyone encounters it, but the circumstances of that encounter might be important to the way the immune response is re-fashioned subsequently. Of course from my point of view this points the finger at B cells and antibodies. I see that the beneficial effect of rituximab is quoted in evidence although I do not know how it was presented. I tried to persuade my old neurology boss at Guy's Hospital to try rituximab in MS in about 2000 but it took another few years before Genentech actually tried it in the US. The fact that rituximab blocks new lesions suggests to me that repeated entry of B cells into the CNS is crucial in RRMS. Other cells like T cells and macrophages may be important in the inflammatory response and blcoking mediators may help reduce the damage but I suspect the B cells are upstream.

I am less excited by the report of cross reacting antibodies. Antibodies in real life bind to whole proteins, not peptides. I do not understand why people look at antibody responses to peptides because the antibody may be binding to the back side of the peptide that in the whole protein is hidden inside. The fact that you can get cross reactivity with two different micro-organisms seems to me an indication that you can probably find it wherever you like. The old two hit model of genes and environment and the molecular mimicry chestnut keep coming up and that always worries me. But the general drift of a role for EBV transformation of the B cell repertoire does seem worth pursuing both in MS and ME. I like the idea that both of these (at least for a subset of ME) may be diseases of antibodies that are not being regulated properly, but not necessarily truly autoantibodies.

 

[anniekim]

@Jonathan Edwards , you write above 'As for ME/CFS there is an interestingpossibility that it is not the encounter with EBV that matters, since more or less everyone encounters it, but thecircumstances of that encounter might be important to the way the immune response is re-fashioned subsequently.' Are you able to give a hypothetical example of a circumstance that could effect the immune response to an encounter with EBV? Many thanks.

 

[Jonathan Edwards]

@Jonathan Edwards , you write above 'As for ME/CFS there is an interestingpossibility that it is not the encounter with EBV that matters, since more or less everyone encounters it, but thecircumstances of that encounter might be important to the way the immune response is re-fashioned subsequently.' Are you able to give a hypothetical example of a circumstance that could effect the immune response to an encounter with EBV? Many thanks.

The most obvious thing is that a high proportion of people get their EBV infection as infants and the 10-20% or so who get mono as teenagers may respond differently partly because of all the things their immune system has seen before and partly because T cell selection is different at that age.

But there is still the question of why maybe only 1% of those 20% go on to get long term ME. This is where I would suggest a random factor.

Take as example the film 'The Imitation Game' about Alan Turing and the cracking of the Enigma code during the war. The code was cracked at a certain time for all sorts of unidentifiable reasons. It might have been a chance that the machine tried the right answer for that day's code in the time available. It would also be partly due to Turing having picked maybe four colleagues with certain skills. But one of those colleagues was there because she saw an advert in the paper by chance. And so on.

The specific immune response to a virus involves certain B cells and T cells getting activated and replicating until you have a strong cellular and antibody reaction. There are trillions of possible T cells and B cells (much more). Moreover, for B cells, the antibodies they make can react with any of maybe twenty proteins in a virus and for each protein they can bind to maybe twenty different places four different ways around. And everything is competing with everything else. In an immune response just by chance certain T cells and B cells win the race - just as Turing's colleagues won the race to be on the team. But each cell or team member has slightly different skills - how tightly it binds the protein, whether it blocks out a patch that another antibody might bind to ... The possibilities are more or less infinitely complicated.

So to go back to the film. One of the team had a brother on a ship that was going to be torpedoed. If the codebreakers had used their knowledge to stop that they would have lost the war by telling the enemy they had cracked the code. Their success would have been its own undoing. What if the person with EBV has seen a similar virus before and so already has antibodies that bind weakly to EBV at one place. That might skew the production of new antibodies towards binding at another place (there are specific reasons for this). What if an antibody that binds the virus at this other place has some peculiar effect that it helps the virus to be carried to somewhere where it triggers a signal that mistakenly switches off regulatory cells that keep the antibody response under control? And four other chance effects are going on at the same time. Immunological theory tends to assume that all these weird chance effects will even out in the end - but autoimmunity seems to prove that this is not always true. Occasionally the randomness of how things come about seems to have a devastating effect on the outcome. Sometimes cracking the code lets the enemy in through the back door.

So I doubt we would ever be able to find out what makes one person get ME after EBV and another not, apart from some weak genetic predispositions that for instance the Dubbo study has suggested. On the other hand if we know what process the mistake occurs in we may be able to 'reboot' that process and clear out the errors without needing to know what they are.

I hope that makes sense.

 

[anniekim]

Thank you @Jonathan Edwards for such a helpful reply. As a non scientific person, I appreciated the movie analogy to explain the complicated process as it helped greatly in my understanding.

 

[heapsreal]

http://www.msaustralia.org.au/news/queensland-researchers-make-major-breakthrough-ms-treatment

NEW Queensland research suggests that controlling infection with Epstein-Barr virus (EBV) – the most common cause of glandular fever – may be beneficial in treating multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the brain and spinal cord affecting more than 23,000 Australians.

The study led by Professor Michael Pender with collaborators at the QIMR Berghofer Medical Research Institute, The University of Queensland School of Medicine, and the Royal Brisbane and Women’s Hospital describes a new treatment that boosts CD8 T cell immunity to EBV with adoptive immunotherapy that could potentially treat progressive MS and other chronic autoimmune diseases. There are currently no disease-modifying treatments available for progressive MS patients.

The researchers administered a six week treatment course to a 43 year old man with secondary progressive MS. The treatment had no adverse effects and within two weeks of commencing treatment the patient began to experience clinical improvement. These improvements were sustained up to the most recent follow-up 21 weeks later.

- See more at: http://www.msaustralia.org.au/news/...reakthrough-ms-treatment#sthash.Fz5Yit2G.dpuf

 

[cigana]

The most obvious thing is that a high proportion of people get their EBV infection as infants and the 10-20% or so who get mono as teenagers may respond differently partly because of all the things their immune system has seen before and partly because T cell selection is different at that age.

But there is still the question of why maybe only 1% of those 20% go on to get long term ME. This is where I would suggest a random factor.

The specific immune response to a virus involves certain B cells and T cells getting activated and replicating until you have a strong cellular and antibody reaction. There are trillions of possible T cells and B cells (much more). Moreover, for B cells, the antibodies they make can react with any of maybe twenty proteins in a virus and for each protein they can bind to maybe twenty different places four different ways around. And everything is competing with everything else. In an immune response just by chance certain T cells and B cells win the race - just as Turing's colleagues won the race to be on the team. But each cell or team member has slightly different skills - how tightly it binds the protein, whether it blocks out a patch that another antibody might bind to ... The possibilities are more or less infinitely complicated.

So I doubt we would ever be able to find out what makes one person get ME after EBV and another not, apart from some weak genetic predispositions that for instance the Dubbo study has suggested. On the other hand if we know what process the mistake occurs in we may be able to 'reboot' that process and clear out the errors without needing to know what they are.

I hope that makes sense.

A fascinating view!

One thing that always troubles me about the idea of a completely random causation is that there doesn't seem to be (to the best of our knowledge) a precedent for widespread chronic neuro immune disease in the past. If this type of disease state were purely random, wouldn't we likely see patches of this phenomenon in history?

Don't you think it's more likely there is a random component combined with some other environmental factor (e.g. a pathogen) that predisposes us? i.e. something that is new in the environment since circa 1981? I just find it hard to believe the landscape of human illness can change so drastically in form without some catalysing entity (albeit working in hand with random events).
NB: I realise you are not necessarily advocating a completely random etiology!

 

[Jonathan Edwards]

I am not aware of any evidence that ME is new. ME type symptoms have had other names over many centuries.

 

[Sasha]

I am not aware of any evidence that ME is new. ME type symptoms have had other names over many centuries.

What about the key symptom of PEM (which I'd describe as flu-like aching and malaise after trivial effort, delayed by 24 to 48 hours)?

Has that been described before?

I'd agree it would be very weird indeed if this was a new illness but I wonder if this symptom is one that has been noted, historically.

 

[Jonathan Edwards]

What about the key symptom of PEM (which I'd describe as flu-like aching and malaise after trivial effort, delayed by 24 to 48 hours)?

Has that been described before?

I'd agree it would be very weird indeed if this was a new illness but I wonder if this symptom is one that has been noted, historically.

Maybe not in its present form, but I would not be surprised if it had.
There was of course something called effort syndrome, which was characterised by severe pain or other symptoms precipitated by effort.

 

[adreno]

There was of course something called effort syndrome

Sounds more fitting than CFS!

 

[Butydoc]

Hi Jonathan,

I find the above information very interesting. I believe in some people the genetic association is very strong concerning a genetic defect which predispose to neuroimmune dysfunction. My mother died from Takayasus arteritis a uncommon autoimmune disorder, my bother died from MS and my younger brother developed ME when he was twenty. It seems to me that there is a group of people who respond abnormally to a trigger, like a virus, then develop the above syndromes. I wonder what gene is the abnormal one to cause these varied immune syndromes. Maybe attention should be placed on the gene responsible rather than the trigger like EBV.
Best,
Gary

 

[Aurator]

Maybe not in its present form, but I would not be surprised if it had.
There was of course something called effort syndrome, which was characterised by severe pain or other symptoms precipitated by effort.

There was also Chronic Weakness (see p. 399), as described by Thomas Withers in his monograph of 1777, the full text of which can be seen here.

 

[Jonathan Edwards]

There was also Chronic Weakness (see p. 399), as described by Thomas Withers in his monograph of 1777, the full text of which can be seen here.

That's avery interesting document. Even if some features are unfamiliar it certainly looks as if something like ME was 'common' in 1777.

 

[Jonathan Edwards]

Hi Jonathan,

I find the above information very interesting. I believe in some people the genetic association is very strong concerning a genetic defect which predispose to neuroimmune dysfunction. My mother died from Takayasus arteritis a uncommon autoimmune disorder, my bother died from MS and my younger brother developed ME when he was twenty. It seems to me that there is a group of people who respond abnormally to a trigger, like a virus, then develop the above syndromes. I wonder what gene is the abnormal one to cause these varied immune syndromes. Maybe attention should be placed on the gene responsible rather than the trigger like EBV.
Best,
Gary

I agree that genes are worth investigating, Gary. OMI are doing some genomics but it would be good to see others involved. There is one paper on NK genetics that looks interesting but doe snot seem to have been replicated.

The downside of looking at genes is that there are probably hundreds of genes that can predispose to autoimmunity or disordered immunity and for the ones we know about even if you have the gene it is usually a toss up when or whether you get a problem.

What I am suggesting is that it is the 'toss-up' that is worth investigating. It was investigating the random aspect that made us think of using rituximab in rheumatoid arthritis. You may not even need a 'trigger' if you have an inherently unstable immune system with random dynamics. That is what the recent paper on cancer epidemiology shows - random change is enough.

The odd thing about EBV is that it looks as if it could almost form another 'genetic' factor in that by the time we are adult EBV is part of our genes. But since everybody's EBV genes are the same it would seem that it is only 'permissive' if it has a role. The human race might be better off without EBV but who knows? Maybe we have evolved to make use of it, just as it has evolved to make use of us.

 

[Butydoc]

I agree that genes are worth investigating, Gary. OMI are doing some genomics but it would be good to see others involved. There is one paper on NK genetics that looks interesting but doe snot seem to have been replicated.

The downside of looking at genes is that there are probably hundreds of genes that can predispose to autoimmunity or disordered immunity and for the ones we know about even if you have the gene it is usually a toss up when or whether you get a problem.

What I am suggesting is that it is the 'toss-up' that is worth investigating. It was investigating the random aspect that made us think of using rituximab in rheumatoid arthritis. You may not even need a 'trigger' if you have an inherently unstable immune system with random dynamics. That is what the recent paper on cancer epidemiology shows - random change is enough.

The odd thing about EBV is that it looks as if it could almost form another 'genetic' factor in that by the time we are adult EBV is part of our genes. But since everybody's EBV genes are the same it would seem that it is only 'permissive' if it has a role. The human race might be better off without EBV but who knows? Maybe we have evolved to make use of it, just as it has evolved to make use of us.

Hi Jonathan,

I was thinking about having my genome and my brother's genome sequenced to see if there is a common gene defect. If there is a common defect, maybe an abnormal protein product is produced or maybe the protein from the abnormal gene isn't made at all. There are several other people with CFS/ME in this board who also have similar genetic backgrounds. Since a subset of people with CFS/ME started with a viral infection as an acute illness and ultimately developed CFS/ME by the CCC definition possible this group might be the key to understanding what defect is ultimately responsible for this disease.

Best,
Gary

 

[Mij]

Dr Charles Stratton and colleagues at Vanderbilt U believe MS is likely caused by chlamydia pneumoniae chronic infection in a large subset of MS patients, up to 70%.

http://cpnhelp.org/multiple_sclerosis_and_th

This is interesting to me as I have chronic c.pneumoniae. Stratton has an antibiotic protocol using 3 types of abx designed to target the 3 life stages of the c.pneumoniae bacteria, recommending long treatment times, 6-18 months.

They've also detected c.pneumonaie in Alzheimer's pts brains.

http://www.ncbi.nlm.nih.gov/pubmed/20863379

I remember watching a program where a physician in Canada claimed to have improved his pts AD with antibiotics and high dose vitamin C. He said he also had some success treating his heart pts with the same protocol.