Could MS be caused by a mutant form of EBV?

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PLEASE NOTE:
I PUT THE LATEST RESEARCH ARTICLE AS THE LAST ONE IN THE SERIES AND IS LOCATED AT THE END OF THIS THREAD.

THE LATEST WILL BE LABLED ELEVENTH YOU HAVE TO SCOLL DOWN TO THE VERY END!


Premission to repost by Prof. Gavin Giovannoni

FIRST IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

EBV and MS disease clusters

"Most slow, or delayed, viral infections of the brain that result from being infected by common viruses are caused by mutant strains of the virus.

For, example subacute sclerosing panencephalitis (SSPE) is due to a mutant measles virus. Similarly, a mutant strain of the John Cunningham Virus (JCV) causes progressive multifocal leukoencephalopathy (PML).

It has therefore been proposed by many that may be MS is caused by a mutant, or specific, strain of EBV. Is there any evidence for this?

No not at present.

However, you may be interested to know about a mini-epidemic of MS that occurred in a small semi-rural Danish community in the 90's. Eight school mates developed MS in a cluster were all infected with the same EBV subtype that differed to the EBV subtype in EBV seropositive controls.

The odds of this happening are quite remote, not to mention the odds of eight schoolmates developing MS as part of a temporal (time) and geographical (place) cluster.

The background to this comment is that the members of the cluster had all lived in a small community with 74 single-family houses located within an area of 2.7km2. During a 13-year period they had attended the same elementary school with 70-80 pupils for 7 years. The school had a total of 145 pupils during this period. All members of the cluster had been scouts together. Two cases were siblings and two were an aunt and nephew, but MS had not been observed in any of the ancestors of the 8 cases or among the school teachers."

"Could a mutant EBV virus that infected these children have caused their MS as well? One could argue that one cluster of this nature could have occurred by chance. I agree, but it should not be ignored and should be put into the context of several other MS clusters that have been described. Unfortunately, none of the pwMS who were part of these other clusters have had their EBV type studied. This is a great pity."

"This and other data have led many in the field to propose EBV as a potential cause of MS. How EBV causes MS is at present unknown. However an important clue is infectious mononucleosis (IM); people who have IM are more than twice as likely to get MS compared to people who don't have IM. People who don't get infected with EBV are protected from getting MS. This is why we set-up the Charcot Project; its main aim is to investigate the viral hypothesis of MS."


Munch et al. A single subtype of Epstein-Barr virus in members of multiple sclerosis clusters. Acta Neurol Scand. 1998 Dec;98(6):395-9.

OBJECTIVES: Epidemiological studies strongly indicate an infectious involvement in multiple sclerosis (MS). Epstein-Barr virus (EBV), to which all multiple sclerosis patients are seropositive, is also interesting from an epidemiological point of view. We have reported a cluster of MS patients with 8 members from a small Danish community called Fjelsø. To further evaluate the role of EBV in MS we have investigated the distribution of EBV subtypes in cluster members and in control cohorts.

MATERIALS AND METHODS: Blood mononuclear cells were isolated from cluster members, unrelated MS patients, healthy controls, including healthy schoolmates to the Fjelsø cluster patients and finally from persons with autoimmune diseases in order to investigate the number of 39 bp repeats in the EBNA 6-coding region in the EBV seropositive individuals.

RESULTS: We observed a preponderance of the subtype with 3 39 bp repeats in the EBNA 6-coding region both in the MS patients and the healthy controls. In the Fjelsø cluster all 8 cluster members were harbouring this subtype, which is significantly different from the finding in healthy controls (n = 16), which include 8 schoolmates to the cluster members and 8 randomly selected healthy persons (Fischer's exact test P = 0.0047), and also compared to all non-clustered individuals studied (P = 0.017).

CONCLUSION: Infection with the same subtype of EBV links together the 8 persons from the Fjelsø cluster who later developed MS. This finding adds to the possibility that development of MS is linked to infection with EBV.

"As part of Charcot Project 2 we will use viral shedding of EBV as a readout for antiviral drugs targeting EBV. The first drug we will investigate is famciclovir. We propose seeing if it suppresses viral shedding in the saliva and whether it has any utility in treating IM. Please note we can't take Charcot Project forward without generating our own data on EBV shedding in the saliva.

Having our own data will allow us to do accurate power calculations for our proposed clinical trials and will hopefully allow us to convince grant reviewers' that we have all the necessary lab assays working. This is why we are asking you to help us raise the money to do the lab work for this study. I sincerely hope you can help."

"If everyone who visited our site donated £1 will get to our target within a week. As always I would like to thank those of you who have already donated so kindly. Thank you."

Funding Goal for trial has been reached!! ​

I can't tell you how important it is for us not give up on the viral hypothesis of MS. I have a dream, a dream of a world free of MS; the Charcot Project is our attempt at making that dream come true."


CoI: Team G will be recipients of a grant from Crowdacure to perform this research

Comments Posted by Gavin Giovannoni

 

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Premission to repost by Prof. Gavin Giovannoni

https://plus.google.com/106028725044845656156​

SECOND IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

Could EBV interact with genes that predispose you to getting MS?


"We refer to MS as being a complex disease; i.e. a disease that occurs due to an interaction between your genes and the environment. This doesn't exclude one environmental factor as being pivotal in the causal pathway,

in other words if that factor is absent you won't get MS. This is why the observation that MS does not occur in people who don't have EBV is so important. There are some studies who have described a small number of pwMS who are EBV negative, however, most of these studies have used simple antibody, or serological, assays to assess EBV positivity.

When you limit the analysis to studies using more than one technique to assess EBV infection positivity rates are 100%. This is why many of us in the field are very keen to get an EBV vaccination study off the ground to test whether by preventing EBV infection we can prevent MS. Unfortunately, we don't have a protective EBV vaccine at present. I am hopeful this will change in the near future. I am aware that the NIH are working on a new EBV vaccine."

"Could EBV be associated with MS by interacting with the main genetic MS susceptibility genes?

The meta-analysis below looks at the interaction between EBV infection and the presence of the main susceptibility gene (HLA-DRB1*1501).

The authors find that there is a minor interaction between them; in statistical speak this interaction is additive and not multiplicative. My problem with this meta-analysis is that it includes data from studies that have determined the presence, or absence, of EBV infection with simple serological studies. In other words the pwMS who are EBV-negative in these studies are likely to be EBV-positive if they were tested using more sensitive techniques."

"Another obvious question to ask is: could the link between infectious mononucleosis (IM) and MS be explained by genetic factors, in other words do the genes that increase your susceptibility to getting MS simply increase your chances of getting IM? We looked at this several years ago and excluded this possibility in relation to the main genetic risk factor HLA. Therefore it looks as if the link between IM and MS cannot simply be explained by a common genetic factor."

"Based on these and other observation we hypothesise that there must be something specific to the biology of EBV that will explain how it triggers and/or drives MS. This is the main reason why we set-up the Charcot Project." Xiao et al. A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis. Sci Rep. 2015 Dec 11;5:18083. doi: 10.1038/srep18083.

Background: Infection with Epstein-Barr virus (EBV) and HLA-DRB1*1501-positivity is a risk factor for multiple sclerosis (MS), but whether an interaction between these two factors causes MS is unclear.

Objective: We therefore conducted a meta-analysis on the effect of the interaction between HLA-DRB1*1501 and EBV infection on MS.

Methods: Searches of PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and the Wanfan databases through February 2015 yielded 5 studies that met the criteria for inclusion in the meta-analysis. EBV infection and HLA-DRB1*1501-positivity were dichotomized. The additive (S) and multiplicative interaction indexes (OR) between EBV infection and HLA-DRB1*1501 and their 95% confidence intervals (95%CI) were calculated for each study and then combined in a meta-analysis.

Results: EBV infection was significantly associated with MS (OR = 2.60; 95%CI, 1.48-4.59). HLA-DRB1*1501 was associated with a significantly increased risk of MS (OR, 3.06; 95%CI, 2.30-4.08). An interaction effect between EBV infection and HLA-DRB1*1501 on MS was observed on the additive scale (S, 1.43; 95%CI, 1.05-1.95, P = 0.023), but no interaction effect was observed on the multiplicative scale (OR, 0.86, 95%CI, 0.59-1.26).

Conclusion: This meta-analysis provides strong evidence that EBV alone, HLA-DRB1*1501 alone or their interaction is associated with an elevated risks of MS.

Posted by
Gavin Giovannoni​

 

[maryb]

I wish they had a Paypal account, much better when you're trying to raise funds as far as ease for people making donations, well it is for me anyway!.

 

[anciendaze]

Here's a primary prospective study that supports that meta-analysis of linkage between EBV and MS. It looks at EBV antibodies in military personnel, and then compares this with rates of MS that showed up later.

In this large prospective investigation, we found a total absence of incident MS among individuals without detectable serum antibodies to EBV.

 

[Ecoclimber]

Dr. Pender from Australia is also investigating the association of MS with EBV. Interesting the seasonal variation of EBV. Scientist must be cognizant of this fact within research.

Permission to Post Gavin Giovannoni

THIRD IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2


Why is EBV so Important in MS?

Comments by Gavin Giovannoni:

"Did you know that if you develop infectious mononucleosis (IM) due to Epstein-Barr virus (EBV) infection you are more than twice as likely to develop MS than if you acquire EBV without any symptoms (asymptomatic EBV infection)?

Even more impressive is that people who don't get infected with EBV are protected from getting MS.

In addition, if you have been tested and shown to be EBV negative and then go onto develop MS you alway get infected with EBV prior to developing MS.

These epidemiological insights are the main pillars supporting EBV as the likely cause of MS.

What we don't know is how EBV causes MS at a molecular level.
1. Does EBV simply trigger the disease and then have nothing to do with ongoing MS disease activity (the hit and run theory)?
2. Is ongoing EBV infection central to driving MS disease activity (the direct viral hypothesis)?
3. Does EBV trigger another virus to act, for example HERVs (human endogenous retroviruses) (the dual-viral hypothesis)?
4. Does EBV simply act as an essential cofactor in driving autoimmunity (the danger or co-stimulatory signal autoimmune hypothesis)?
5. Does EBV immortalise autoimmune B-cells that drive MS disease activity (B cell hypothesis)?"


"The only way to test these different hypotheses is to do experiments. As there is no good animal model of EBV and MS we need to do these experiments in pwMS. One could argue that the effectiveness of anti-CD20 therapy in MS would suggest that the B-cell is where the money is.
However, this may not necessarily be the case.

Anti-CD20 therapy depletes B-cells and hence we can't be confident that it is working via an anti-EBV mechanism. This is why we want to test drug(s) that specifically target EBV.

If we are able to inhibit EBV replication in the body of pwMS and show it shuts down MS disease activity then this would go a long way to support the direct viral and/or dual viral hypotheses. Sadly, we still don't have a small molecule anti-viral drug that has been licensed to treat EBV infection. Reasons for this are complex and relate to how Pharm works. We are trying to convince Pharma that IM is a worthwhile disease to treat and if they develop anti-EBV drugs there will be a market for them.

Despite this we have circumstantial evidence that an old anti-herpes drug is capable of suppressing EBV infection. We now want to test this in pwMS. Before doing this we need show that it is capable of inhibiting EBV pwMS and to find out what dose is required to do this. Once we have answered these two questions we will be able to design a study to test this drug in pwMS."

"We know that people infected with EBV intermittently shed EBV in their saliva. This shedding is due to active EBV infection in the salivary glands. We can use this shedding to test whether or not this anti-viral drug works against EBV. Before doing the trial we need to know how many pwMS shed virus on their saliva and how long they shed virus for in serial samples collected over months. Evidence exist from studies in healthy people that EBV shedding is intermittent and seasonal (see abstract below and figures). What we need is this information from pwMS."

EBV shedding in saliva of normal people. Figure from Ling et al. J Infect Dis. 2003 May 15;187(10):1571-80. ​

"The good news is that we can answer this question quickly from a saliva samples collected as part of an another study that was measuring stress hormones. We now want to process these samples ASAP so that we can use the data for power calculations for our proposed dose-finding studies of our anti-viral drug. This is why we are asking you to help us raise the money to do the lab work for this study ASAP. I sincerely hope you can help. If everyone who visited this site donated £1 each time they visited we would raise the money we need in 1 or 2 days. I would like to thank all our supporters who have already donated so kindly; things are going well. "


The Funding Goal for the trial has been reached. Thank you!"



I can't tell you how important it is for us not give up on the viral hypothesis of MS."

Ling et al. The dynamics of herpesvirus and polyomavirus reactivation and shedding in healthy adults: a 14-month longitudinal study. J Infect Dis. 2003 May 15;187(10):1571-80.

Humans are infected with viruses that establish long-term persistent infections. To address whether immunocompetent individuals control virus reactivation globally or independently and to identify patterns of sporadic reactivation, we monitored herpesviruses and polyomaviruses in 30 adults, over 14 months. Epstein-Barr virus (EBV) DNA was quantitated in saliva and peripheral blood mononuclear cells (PBMCs), cytomegalovirus (CMV) was assayed in urine, and JC virus (JCV) and BK virus (BKV) DNAs were assayed in urine and PBMCs.

All individuals shed EBV in saliva, whereas 67% had >or=1 blood sample positive for EBV. Levels of EBV varied widely. CMV shedding occurred infrequently but occurred more commonly in younger individuals (P<.03).

JCV and BKV virurias were 46.7% and 0%, respectively. JCV shedding was age dependent and occurred commonly in individuals >or=40 years old (P<.03).

Seasonal variation was observed in shedding of EBV and JCV, but there was no correlation among shedding of EBV, CMV, and JCV (P>.50). Thus, adults independently control persistent viruses, which display discordant, sporadic reactivations.


I thought the comments informative so I have kept them in, Eco
COMMENTS:

· AnonymousWednesday, January 06, 2016 10:49:00 am
So is there a connection, related mechanism, between MS and the chronic fatigue that often follows Epstein Barr infection? Those with chronic fatigue tend not to show high levels of virus. After a very bad second attack of EB, I had a seasonal version that arrived every winter and went away sometime in the summer. It arrived and went away overnight and when it went away (the same night) I always developed a new enlarged lymph node in my neck that stayed. This when on for 6 years.
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AnonymousWednesday, January 06, 2016 11:33:00 am
And what role does IL-6 play in all of this?
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Judy BeveridgeWednesday, January 06, 2016 11:45:00 am
I felt really excited when I read this and donating feels incredibly empowering. I know it's just one little piece of research in the huge MS puzzle but it could bring finding the elusive holy grail one step closer.
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Gavin GiovannoniWednesday, January 06, 2016 12:44:00 pm
Thank you, it is much appreciated.

This is a real community project, which I am very proud of. The ARTEMIS trial was designed by you the community and this project is to enable the ARTEMIS trial. When we were designing the ARTEMIS study someone suggested we use CrowdFunding. I was a bit reticent, but we decided to give it a go. So this is a bit of an experiment. I am not very excited about seeing it through.

As it is a community research project we will keep you updated on its progress at every stage. Doing research this way will demonstrate in real time how long it takes to do research; i.e. from the idea to getting the result.

http://multiple-sclerosis-research.blogspot.com/2015/09/crowdspeak-we-will-be-launching-our.html
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AnonymousWednesday, January 06, 2016 12:30:00 pm
I'm not donating a penny. I've raised and contributed to MS causes for years and seen so little materialise for our efforts. Scientists badly design medical trials and everything eventually falls to pieces. We still don't know why MS happens, yet the disease was discovered and titled in the Victorian era.

I'm boycotting MS.
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1.
AnonymousWednesday, January 06, 2016 12:47:00 pm
Humbug, is that you Ebenezer?
2.
MouseDoctor2Wednesday, January 06, 2016 12:52:00 pm
That's your prerogative but I strongly disagree that we have seen little progress, particularly over recent years.
3.
AnonymousWednesday, January 06, 2016 12:58:00 pm
You might as well contribute to CCSVI research. It is about as valid as MS being directly caused by EBV. If Team G was in charge of the Chorcote 1 trial and it failed why should they be given a second chance?
4.
MouseDoctor2Wednesday, January 06, 2016 2:08:00 pm
"Ever tried, ever failed? No matter.
Try again, fail again, fail better" Kinda thing.
5.
Gavin GiovannoniWednesday, January 06, 2016 3:34:00 pm
Re: "If Team G was in charge of the Charcot 1 trial and it failed why should they be given a second chance?"

This attitude explains why so many European entrepreneurs have to leave the EU to go to America to start their companies. If your start-up goes bankrupt in Europe you are blacklisted from getting more money for several years.

In the US if your first start-up fails you are more likely to get funding second and third time round. Failure is worn as a badge of honor. Failure shows you can do things, your are prepared to take risks and more importantly you are prepared learn from your mistakes.

We doing just that; we are picking ourselves up from the floor, dusting ourselves off and starting again.

This time we are starting at base 1; we need to find out if our antiviral works first. We then need to find the correct dose and finally after these two steps we will do a study in pwMS.

I am not ashamed of the INSPIRE being negative; it is our badge of honor. At least we are prepared to do something about a possible viral cause of MS. Like us or not, we are not going away.
6.
AnonymousWednesday, January 06, 2016 3:36:00 pm
Have you heard of the tall poppy syndrome?
7.
AidanWednesday, January 06, 2016 5:07:00 pm
Perfect time for an Edison quote:
I have not failed. I've just found 10,000 ways that won't work.
8.
MouseDoctorWednesday, January 06, 2016 10:20:00 pm
The tall poppy syndrome is a pejorative term primarily used in the United Kingdom, Australia, New Zealand, and other Anglosphere nations to describe a social phenomenon in which people of genuine merit are resented, attacked, cut down, or criticised because their talents or achievements elevate them above or distinguish them from their peers. This is similar to begrudgery, the resentment or envy of the success of a peer.

A similar saying occurs in Chinese and Japanese culture that translates to "The Nail that stands out gets hammered down"
9.
AnonymousThursday, January 07, 2016 3:14:00 am
Aidan - that quote is the best comment posted in the last 2 weeks!!!

Team G - you go for it - even if your theories are wrong, at least a cause will have been "ruled out", and that is worth something in itself.
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AnonymousWednesday, January 06, 2016 12:47:00 pm
Good luck with this Prof G. If you can get this off the ground and show that EBV is inextricably linked with MS (regardless of what or how) and then show that dealing with EBV prevents or shuts down MS, then it will be as important as development of the cervical cancer vaccine.

I had a full-blown case of EBV when I was 16yo - smack bang in the middle of exams. Also had a couple of suspected later infections of it some years later - although the blood tests came back negative on the later occasions, the Dr advised me that there were various forms of EBV viruses which did not (in those days) show up in blood tests. Then 30 years later, and now in my mid-50s, I'm told I have MS.
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AnonymousWednesday, January 06, 2016 1:59:00 pm
But pofy g if ebb shedding is so variable how can this be a substrate for a clinical trial?
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Gavin GiovannoniWednesday, January 06, 2016 3:26:00 pm
Re: "But Prof G if EBVshedding is so variable how can this be a substrate for a clinical trial?"

You would like to see close to zero shedding in the treatment arm (EBV suppression) compared to x% shedding in the non-treated arm (not suppressed).

We need to do this study to show that our drug suppresses lytic viral infection in pwMS. The real question we have to be able to answer by this enabling study is how many pwMS do we need in each group to be confident that the result is real.

The latter is called powering the study. I will do a post on this tomorrow to explain it in more detail.

AnonymousWednesday, January 06, 2016 10:22:00 pm
But pof g are you going to run a trial in the same time of the year? How will you recruit? Have you really thought this through?

Gavin GiovannoniWednesday, January 06, 2016 10:54:00 pm
Re: "But pof g are you going to run a trial in the same time of the year?"

I am not sure what you mean the same time of the year? It takes x months or years to recruit for trials. Randomisation is how you deal with variables such as season and you can always include that variable as a baseline covariate for which you need to adjust for when you pre-specify your statistical analysis plan.

AnonymousWednesday, January 06, 2016 11:00:00 pm
if season can reduce ebb what's the point of famv?

AnonymousWednesday, January 06, 2016 11:02:00 pm
So why do this study? Just save the money and factor it in the analysis. You can power the study based on this results presented here.

Gavin GiovannoniWednesday, January 06, 2016 11:05:00 pm
Re: "if season can reduce ebb what's the point of famv?"

Seasonal effects refer to salivary shedding and viral load. It does not necessarily affect the virus in the other compartments of the body. Saliva is simply the portal for transmitting the virus.

This data is from healthy controls; we don't know what happens in pwMS. For all we know there is no seasonal variation. Or the seasonal variation could be linked to season variation in vD levels. The latter is another reason for us to do the study.

Gavin GiovannoniWednesday, January 06, 2016 11:08:00 pm
MouseDoctor calls people who find reasons for not doing studies based on theoretical grounds armchair scientists. If we don't know the answer we can theorise until the cows come home and we still won't know the answer. The only way to answer the questions we have posed is to do the studies.

Gavin GiovannoniWednesday, January 06, 2016 11:22:00 pm
Re: "So why do this study? Just save the money and factor it in the analysis. You can power the study based on this results presented here."

If only all peer-reviewer of grants were like you and would accept this. A large number of pwMS on DMTs. What if DMTs reduced viral shedding. If we used these numbers we would under power the study. We discussed this issue at some length and realised we need data from pwMS.

AnonymousThursday, January 07, 2016 10:19:00 am
Pof g the Carter study where these samples are from are part of a trial. Will you be using the placebo arm?

AnonymousThursday, January 07, 2016 10:19:00 am
Pof g how many of these patients are on dmts
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SterntaucherWednesday, January 06, 2016 2:15:00 pm
I'm very happy to read of this crucial work. This seems such an important project, thank you for undertaking it. I wish you all the very best with this.
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Csam0003Wednesday, January 06, 2016 5:37:00 pm
Good luck Prof G, the mouse doctor and the rest of the team!!! I feel a little bit confident every day I read your posts cause I know that there are people who are actively in this for the long haul. This gives me confidence. This gives me hope.
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Nissan GrifterThursday, January 07, 2016 2:00:00 am
Upon doing a literature search briefly on PubMed, I could find only two randomized controlled trials using Valacyclovir. They showed a positive response in highly active MS patients on MRI in one trial and a non-statistically significant clinical improvement in another trial. Why have trials with Famcyclovir and Gancyclovir not have been completed-money? We use these existing drugs daily for many different forms of the herpes virus family. I am afraid your team will all be retired and all MSers will be worse off by the time a new treatment for EBV is from bench to humans. I would expect that if patients in a trial were given one year or lifelong suppressive therapy of the anti-virals after an EBV infection (pre-MS) that it would stop progression/conversion to MS for all the above theories.
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CinaraThursday, January 07, 2016 6:10:00 am
Great news!!! Already will click the link to see how to donate. It is important, through this research many answers can be found to some questions that are already made for some time. And it is the attempts that are the answers. Sir Anthony Epstein and Dr. Yvonne Barr worked hard to prove that EBV, the same virus that they had discovered and which infects 95% of the population in certain people depending on the circumstances and causes various diseases that apparently are not related. The study can look up whether there is a relationship between VD and EBV. Go ahead Docs, do not despair, courage is not for everyone, surely something will come out as a result of this initiative. o//
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XoR XoRThursday, January 07, 2016 4:51:00 pm
EBV is responsible of the "kissing disease". This could maybe explain why immunosuppresion/immunomodulation therapies fail to work sometimes. Most people have partners that they kiss regularly. Maybe the immunosuppresion efficiently get rid of the infected cells and the partner re-infect the MSers regularly... Should our partner be tested for EBV?
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MouseDoctorThursday, January 07, 2016 5:40:00 pm
Most partners will be positive if not all, because the partner with MS will be positive and they would infect the partner and over 90% of people without MS are positive anyway. But if you did rid someone of EBV they may get infected quickly again if treatment was not maintained
XoR XoRThursday, January 07, 2016 6:15:00 pm
How difficult/expensive is it to be tested for the EBV? Would it be possible to ask your GP to be tested for EBV? So if you were to treat MSers with Famciclovir you might want to do the same thing to their partner(s). Maybe it was the reason why charcot 1 failed?
MouseDoctorThursday, January 07, 2016 9:43:00 pm
I dont know the cost sorry. However first thing is does famciclovir does the job
XoR XoRThursday, January 07, 2016 10:45:00 pm
Famvir? Aciclovir? Another one? Which antiviral would they like to test?
XoR XoRThursday, January 07, 2016 10:49:00 pm
Valtrex?
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XoR XoRThursday, January 07, 2016 4:54:00 pm
"viruses outside a cell are as dead as a cow in space". This is a beautiful quote from "Ni dieu, ni genes" a book co-written by the guy who first sequenced the HIV (An estimated virologist as you may have guessed). Quite a change from the textbook view.
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MouseDoctorThursday, January 07, 2016 5:36:00 pm
This may be true for HIV as you leave it on a bench for a few minutes and it is dead as a dodo however not so for others like flu and chickpox, flu can survive on banknotes for days-weeks
XoR XoRThursday, January 07, 2016 6:10:00 pm
My point was that virus are alive contrary to what most people believe, i.e. "Viruses are not alive, so they can’t be ‘killed’." (quote from a great MS researcher). This point immediately raises a question: "How does EBV multiply in an organism?"
AnonymousThursday, January 07, 2016 6:41:00 pm
I think most experts would consider viruses as not a living organisms.

http://www.scientificamerican.com/article/are-viruses-alive-2004/
MouseDoctorThursday, January 07, 2016 9:25:00 pm
Ok infectivelessas a dodo
XoR XoRThursday, January 07, 2016 10:42:00 pm
To Anon :
Not only experts say that. This was the topic of my first Biology class after high school: "How do you define life?" and I was told that viruses are by definition not "alive". Biology is full of dogma like that. Now as a researcher in Biology I have a few examples of that: great discoveries often question dogma.

"Ni Dieu, ni genes" is where this idea comes from, a shame it is not yet translated in English. You have love to read that a "Un virus en dehors d'une cellule est aussi mort qu'une vache dans l'espace".
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XoR XoRThursday, January 07, 2016 10:57:00 pm
An article that might interest you on the link between EBV, MS. They even say that they successfully treated someone with secondary MS.


Michael P Pender and Scott R Burrow "Epstein–Barr virus and multiple sclerosis: potential opportunities for immunotherapy" Clinical & Translational Immunology (2014) 3, e27; doi:10.1038/cti.2014.25


And it is open access, no need for sci-hub:
http://www.nature.com/cti/journal/v3/n10/full/cti201425a.html

Let's call it a (good) day!
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MouseDoctorThursday, January 07, 2016 11:50:00 pm
its a day
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ChrisMonday, January 11, 2016 2:30:00 pm
This has made me think about my fatigue with glandular fever at 19 (awake 6 hours a day, able to function for about 45 minutes in total during that day), and wonder whether my MS fatigue is to do with EBV again. I hadn't realised that EBV stayed in the system. Don't know whether it's a coincidence that after 6 months on tecfidera I had my first autumn since being diagnosed (5 years ago) without major fatigue issues. Good luck.
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AnonymousTuesday, January 12, 2016 3:49:00 am
Good luck with the crowdsourcing and the project

I really, really hope the EBV hypothesis turns out to be correct.
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[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni
http://multiple-sclerosis-research.blogspot.com/2016/01/crowdspeak-researchspeak-ebv-and-hsct.html
http://multiple-sclerosis-research.blogspot.com/2016/01/crowdspeak-researchspeak-ebv-and-hsct.html
FOURTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

EBV and HSCT ​

Could HSCT be working via EBV?​

COMMENTS BY Prof. Gavin Giovannoni

"Yesterday the Mouse Doctor asked me how do we reconcile the results of bone marrow transplantation (BMT) and/or HSCT with the EBV hypothesis of MS?

The simple answer is I don't know. However, all high-efficacy DMTs have effects on B-cells including BMT/HSCT.

This form of therapy may therefore be working via depleting B cells; not too dissimilar to what occurs with cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab)."

"The case studies below show that BMT can actually eliminate EBV from the body or at least a strain of EBV. I am aware of a similar unpublished case with MS who was found to be EBV negative 5 years after having received alemtuzumab treatment for very active MS.

This is why the very promising results of BMT/HSCT trials are not incompatible with the EBV causation hypothesis.

What I can say is that until we do the trial of targeting EBV with a specific anti-EBV drug we won't be able to sort out this issue. Can you imagine what would happen to the field of MS if a small molecule anti-EBV drug proved to as effective as HSCT?

That is what I refer to as a black swan.This is another reason for us to get our Charcot 2 project off the ground as soon as possible.

Our fund raising is going very well with close to 200 donors already. For those of you who have donated already, thank you it is much appreciated. Despite early reservations I am now thrilled to have launched this initiative; it is taking PPI to another level at least in the UK. Once we have reached our target we plan to get the lab work completed as soon as possible. We will also display the results to you in real time and engage you with the design of the next study and the associated grant application. This is what we call citizen-informed science."

Funding Goal for trial has been reached!!​

Gratama et al. Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8693-6.

Background: Wild-type strains of Epstein-Barr virus (EBV) can be distinguished on the basis of variations in the molecular weight of virus-encoded, growth transformation-associated proteins.

Case studies: This approach was used to study the persistence of EBV in two seropositive recipients of allogeneic bone marrow transplants.

The first patient received marrow from her EBV-seronegative brother, became EBV seronegative after grafting, and remained so for greater than 1200 days. Subsequently, she became infected with a new EBV strain that differed from her pretransplant strain but was indistinguishable from the virus isolated from her husband. The second patient received marrow from his EBV-seropositive brother. This patient showed only a transient decrease in IgG antibodies to EBV capsid antigen. His pretransplant strain differed from the virus of his donor. On days 252 and 915 after transplantation, lymphoblastoid cell lines were grown from the peripheral blood of the patient and were found to carry exclusively the virus of the donor.

Conclusions: These results suggest that the latently EBV-infected host cells reside in a cellular compartment that can be destroyed by graft-versus-host reactivity, irradiation, or cytotoxic drugs. Hemopoietic tissue is the most likely candidate.

CoI: Team G will be recipients of a grant from Crowdacure to perform this research

I included the comments as being important, ECO
19 comments:

1. 
   
   AnonymousWednesday, January 20, 2016 11:07:00 am
   I see no incompatibility between the (BMT) and/or HSCT and the EBV hypothesis of MS. EBV leads to the formation of damaged B cells, just like it does in mixed cellularity Hodgkin's lymphoma. The treatment kills those cells, destroying the cancer or the cause of MS. The specific damage to the B cells required to cause MS or cancer probably occurs very infrequently and so the risk of relapse is moderately low. The cancer cells in mixed cell Hodgkin's make up only a tiny part of the lymphoma, most of it is other cells, whose behaviour is disrupted by the cancer cells, are non cancer immune cells. The actual cancer cells do seem to express signs of EBV activity.
   Reply
   Replies
   1. • 
        
        AnonymousWednesday, January 20, 2016 12:39:00 pm
        Hodgkin's lymphoma also causes immune responses, rashes and itching, long before the lymphoma is big enough to be found and in parts of the body no where near the site of the cancer (say the cancer being in the neck and the rash on the legs). Imagine a similar set of mutated B cells either dividing slowly or not at all then they could cause immune responses, like in MS, but be almost impossible to spot.
      Reply
2. 
   
   AnonymousWednesday, January 20, 2016 11:52:00 am
   We need a breakdown of why you guys found Monday's Panorama too be, as MouseDoc said, utter "fluff".
   
   The neurology clinics of every NHS hospital were swamped with calls from desperate MSers demanding HSCT immediately. It may have set a seriously dangerous precedent. Are you ready for it?
   Reply
   Replies
   1. • 
        
        Gavin GiovannoniWednesday, January 20, 2016 12:09:00 pm
        Re: "We need a breakdown of why you guys found Monday's Panorama too be, as MouseDoc said, utter "fluff"."
        
        I am preparing a response and will post it in the next few days. Not necessarily fluff but not an a fair representation of the state of play of both HSCT and what is out there already for pwMS.
      • 
        
        MouseDoctorWednesday, January 20, 2016 12:37:00 pm
        The programme was information light as Matt who I believe has been on the Journey himself said "disappointing"
        
        The programme could have told us what was really involved and to explain the biology and the treatment regime rather than just show a liquid nitrogen tank, it could talk about the risk benefit process and why did one person say they would rather have fight with Mike Tyson.
        
        Lets face it is the ultimate immunosuppression (the non myeoablative) shy of completely destroying the bone marrow the treatments may involve rituximab, cyclophosphamide, anti-thymocyte, Alemtuzumab, clofarabine, it could have been BEAM (although it wasn't) we were not really told what was being used, so how to assess risk. All we saw was people doing well so I am not surprised that the NHS is being deluged with calls.
        
        Foreseeing the information one could ask what is the capacity of the NHS to deal with the deluge of calls. Maybe there is a lot of spare capacity so maybe we could push this through and get the answer. If there was proper follow-up I actually believe that it could be done, but would the trusts pay for it as it has not been NICEd because if a neuro wants it done there is nothing to stop them trying, if the trusts pay for it. This off label issue could have been adressed.
        
        What is the evidence that it really is better than alemtuzumab (excluding the autoimmunity risk). In the phase II trials where people were very active like the HSCT recipients the data was very good. I wonder if Prof Coles could have made the same video with some of his patients
        
        Please do not take this to say that I do not believe that HSCT can work, it clearly can. It would work best for the people who are newly diagnosed as they have accumulated least damage. However at the moment it is being offered to people who have failed everything.
      • 
        
        AnonymousWednesday, January 20, 2016 1:02:00 pm
        If I may suggest: a comparative table of induction therapies is long due.
        
        Some RRMSers are doing well on current high efficacy DMDs but are nearing their 10 year birthday since onset.
        
        My understanding is that the HSCT efficacy window is about 10 years. As such, even good responders on current DMDs are now pondering whether to sit tight or jump ship before its too late...
        
        After all, this blog's mantra has always been "treat early and aggressively (but safely)". Should the treatment algorithms be revisited at this stage in light of the 10yrs window mentioned above?
        
        Tony F
      Reply
3. 
   
   AnonymousWednesday, January 20, 2016 12:13:00 pm
   What would you prefer; a large number of small donors or one big angel donor?
   Reply
   Replies
   1. • 
        
        MouseDoctorWednesday, January 20, 2016 12:15:00 pm
        Either or would be great
      • 
        
        Gavin GiovannoniWednesday, January 20, 2016 12:15:00 pm
        Re: "What would you prefer; a large number of small donors or one big angel donor?"
        
        Both! In terms of the aims of this project in getting the crowd to support it I would prefer 10,000 £1 donations. It would be simply amazing to get as many supporters behind this project as possible. Crowdfunding is about microfinance. However, getting one large donation would be great in that it speeds up the research process.
      • 
        
        Gavin GiovannoniWednesday, January 20, 2016 1:00:00 pm
        I note some £1 donations are coming in. This is good news. Thank you.
      • 
        
        AnonymousWednesday, January 20, 2016 2:57:00 pm
        prof a few students want to donate 50p or so each- this is not possible?
      • 
        
        Gavin GiovannoniWednesday, January 20, 2016 3:23:00 pm
        Re: "prof a few students want to donate 50p or so each- this is not possible?"
        
        I will contact Crowdacure; apologies, but this is out of my control.
      • 
        
        Crowdacure LtdWednesday, January 20, 2016 3:39:00 pm
        Hi Gavin,
        
        The minimum donation with a card is 30p so they should be fine. However, as Stripe has a fixed fee of 20p per payment I would suggest bundling the donations into a bigger one if possible.
        
        Best Regards,
        CTO
        Crowdacure Ltd
      Reply
4. 
   
   SterntaucherWednesday, January 20, 2016 1:47:00 pm
   This is fascinating and compelling. I'll be making a £1 donation to Charcot for sure! And I've asked family members if they'd like to do the same.
   Reply
5. 
   
   SterntaucherWednesday, January 20, 2016 1:53:00 pm
   Just wondering... In the meantime, is there anything a person with MS can do to limit their EBV activity? Apart from maintaining general health. Eat lots of garlic or something? Sorry, I know, nutriceuticals...
   Reply
6. 
   
   AnonymousWednesday, January 20, 2016 2:36:00 pm
   Is this of interest
   
   Drug shows promise for halting cancer virus
   http://www.medicalnewstoday.com/articles/305315.php
   Reply
   Replies
   1. • 
        
        CinaraWednesday, January 20, 2016 6:30:00 pm
        Rapamycin is an immunosuppressant. And this is what I see the positive results including the HSTC: for me is the strong immunosuppression responsible for the positive results, because if EBV infects B lymphocytes strong immunosuppression eliminate the virus or part (perhaps even remain in the lymph nodes or thymus ) ... and this gives even object to another study: if EBV lever MS, individuals who went through the transplant was re-infected by EBV as this new immune system would behave? MS return?
      • 
        
        AnonymousWednesday, January 20, 2016 9:00:00 pm
        They seem, from the press release, to see direct suppression of the virus infected cells, forcing them to become suspended, on top of a killing of cells.
      Reply
7. 
   
   AnonymousWednesday, January 20, 2016 9:20:00 pm
   Is there someway of testing the EBV status of people undergoing alemetuzumab (or HSCT)before and after treatment. Is there a difference between the EBV status of those in apparent 'remission' and in those with reactivation of their disease?
   Reply

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

https://plus.google.com/106028725044845656156
FIFTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

EBV is able to infect neurons​

Is the ability of EBV to infect neurons relevant to MS?​

COMMENT BY Prof. Gavin Giovannoni

"One of the problems with the EBV hypothesis of MS is how does it explain some of the clinical observations we see, for example the treatment effect of natalizumab and other anti-trafficking drugs such as fingolimod, and the rebound that occurs when these drugs are stopped?

I have previously discussed the field hypothesis, i.e. that a virus may infect glial or neuronal cells that are hidden from the immune system by natalizumab and that when you stop natalizumab the immune system finds the virus and causes rebound.

However, this does not explain why MSers don't get symptoms from the viral infection of the glial and/or neuronal cells in the absence of an immune response. This is the flaw in the field hypothesis."

"The study below shows that gamma herpes viruses, including EBV, can infect neuronal cells, with lytic infection (a type of infection that kills the cell).

If this is how EBV causes MS it would almost certainly cause symptoms (relapses), or disease progression (worsening), in MSers on natalizumab of fingolimod. The latter does not appear to happen at least in the short to intermediate term.

In addition, when we and others have looked at which cells express EBV in the brains of people with MS it does not appear to be neurons, but B cells.

Therefore, I am not sure what to make of the conclusions of the study below and whether or not these observations are relevant to MS. Clearly more work needs to be done on this to see if it is relevant to MS and other disease models. Which disease model you may ask? The best model of MS happens to be the Japanese Macaque Encephalomyelitis model that happens to be caused by a gamma herpesvirus."

ha et al. Gammaherpesvirus Infection of Human Neuronal Cells. MBio. 2015;6(6). pii: e01844-15
Background: Gammaherpesviruses human herpesvirus 4 (HHV4) and HHV8 are two prominent members of the herpesvirus family associated with a number of human cancers.

HHV4, also known as Epstein-Barr virus (EBV), a ubiquitous gammaherpesvirus prevalent in 90 to 95% of the human population, is clinically associated with various neurological diseases such as primary central nervous system lymphoma, multiple sclerosis, Alzheimer’s disease, cerebellar ataxia, and encephalitis. However, the possibility that EBV and Kaposi’s sarcoma-associated herpesvirus (KSHV) can directly infect neurons has been largely overlooked.

Methods & Results: This study has, for the first time, characterized EBV infection in neural cell backgrounds by using the Sh-Sy5y neuroblastoma cell line, teratocarcinoma Ntera2 neurons, and primary human fetal neurons.

Furthermore, we also demonstrated KSHV infection of neural Sh-Sy5y cells. These neuronal cells were infected with green fluorescent protein-expressing recombinant EBV or KSHV. Microscopy, genetic analysis, immunofluorescence, and Western blot analyses for specific viral antigens supported and validated the infection of these cells by EBV and KSHV and showed that the infection was efficient and productive.

Progeny virus produced from infected neuronal cells efficiently infected fresh neuronal cells, as well as peripheral blood mononuclear cells.

Furthermore, acyclovir was effective at inhibiting the production of virus from neuronal cells similar to lymphoblastoid cell lines; this suggests active lytic replication in infected neurons in vitro. These studies represent a potentially new in vitro model of EBV- and KSHV-associated neuronal disease development and pathogenesis.

Importance: To date, no in vitro study has demonstrated gammaherpesvirus infection of neuronal cells. Moreover, worldwide clinical findings have linked EBV to neuronal pathologies, including multiple sclerosis, primary central nervous system lymphoma, and Alzheimer’s disease.

In this study, for the first time, we have successfully demonstrated the in vitro infection of Sh-Sy5y and Ntera2 cells, as well as human primary neurons. We have also determined that the infection is predominately lytic.

Additionally, we also report infection of neuronal cells by KSHV in vitro similar to that by EBV. These findings may open new avenues of consideration related to neuronal pathologies and infection with these viruses. Furthermore, their contribution to chronic infection linked to neuronal disease will provide new clues to potential new therapies.

 

[maryb]

Just shared on Facebook so hopefully more will do this and help them reach their target.

My brother's best friend has MS, he was a talented, super fit young man who had trials with Manchester United FC, now confined to bed. Devastating disease.

 

[maryb]

Just bumping this in case anyone wants to donate or share on FB.

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

SIXTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

GOOD NEWS THE TRIAL HAS REACHED ITS FUNDING GOAL SO THE ARTEMIS PROJECT WILL BEGIN!!

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

Antibody response to EBV associated with lesion burden

Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS.
Zivadinov R, Cerza N, Hagemeier J, Carl E, Badgett D, Ramasamy DP, Weinstock-Guttman B, Ramanathan M.Neurol Neuroimmunol Neuroinflamm. 2016 Jan 7;3(1):e190. doi: 10.1212/NXI.0000000000000190. eCollection 2016 Feb.

OBJECTIVE:
Because dysregulated Epstein-Barr virus (EBV)-infected B cells may induce meningeal inflammation, which contributes to cortical pathology in multiple sclerosis (MS), we investigated associations between antibody responses to EBV and development of cortical pathology in MS.

METHODS:
We included 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS), 66 patients with clinically isolated syndrome (CIS), 63 patients with other neurologic diseases (OND), and 178 age- and sex-matched healthy controls (HC). All participants were scanned on 3T MRI. Serum samples were analyzed for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), and their quartiles were determined on the whole study sample. Differences between the study groups were assessed using analysis of covariance adjusted for multiple comparisons.

RESULTS:
More than 30% of patients with MS and CIS presented with the highest quartile of anti-EBV-VCA and -EBNA-1 status compared to ≤10% of HC (p < 0.001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti-EBV-VCA showed significantly increased T2 lesion volume (p = 0.001), T1 lesion number (p = 0.002), and T1 lesion volume (p = 0.04) and decreased gray matter (p = 0.041) and cortical (p = 0.043) volumes compared to patients with MS with lower quartiles. No significant differences of MRI outcomes in patients with CIS, patients with OND, and HC with lower or highest quartiles of anti-EBV-VCA and -EBNA-1 were detected.

CONCLUSIONS:
Humoral response to anti-EBV-VCA and -EBNA-1 is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with MS.​

​

We can all read the conclusions and this suggests that higher levels of EBV-specific antibodies are associted with more grey and white matter lesions. Is it cause and effectoris this further evidence that EBV is related to the pathology​

COMMENT BY MouseDoctor

 

[maryb]

Brilliant news

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

SEVENTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT IN A SERIES ON EBV

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme, GWI, etc.



ResearchSpeak: genetic link to antibody response to EBV proteins


Could the link between EBV and MS be an association and not causal?

Comments from Gavin Giovannoni

"We have know for sometime known that elevated antibodies to the EBV protein EBNA-1 increase your risk of getting MS. This particular EBV protein is part of the complex that keeps EBV in its latent, or sleeping, phase. Why an immune response to this particular EBV protein is linked to EBV risk is unknown. The study below suggests that there is a particular genetic locus, or area, in the genome that increases your antibody response to EBNA-1. Interestingly, this locus also increases your chances of getting MS. This is a novel finding and opens up new ways of looking at genetic risk."

"How we bring all this together in a simple causal pathway is difficult; I am finding it perplexing. Could the antibody response to EBNA-1 simply be an association and not part of the causal pathway? In other words what increases your risk of getting MS increases your antibody response to EBNA-1. The latter however can't explain the other observations around the timing of EBV infection and onset of MS and the observation that if you are EBV negative your chances of getting MS are close to zero."

"I remain convinced that EBV is the cause of MS and we need to pursue our aims of targeting the virus with a vaccination strategy, antiviral drugs and drugs that deplete B cells and plasma cells. This is why we launched the Charcot Project."


Epub: Zhou et al. Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Mult Scler. 2016 Jan 27. pii: 1352458515626598.

BACKGROUND:
Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).

OBJECTIVE:
We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.

METHODS:
We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231).

RESULTS:
We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9).

A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20).

By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8).

CONCLUSIONS:
Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

Posted by Gavin Giovannoni

COMMENTS POSTED

1. AnonymousThursday, February 04, 2016 8:45:00 am
   I agree that EBV is an important factor that needs further research, but I don't understand why you exclude other Herpes viruses from your theory.
   Varicella Zoster Virus for example: Almost everyone had the chickenpox when they were young and the virus is known to stay in neurons for lifetime after infection.
   
   My impression is everyone supporting a viral/infectious hypothesis is looking for "the one" infectious agent responsible while in reality there may be more that share a common mechanism/pathway.
   Reply
   Replies
   1. • 
        
        AnonymousThursday, February 04, 2016 3:26:00 pm
        Very true. I got chicken pox two days after completing my last A level exam when I was 17-years-old. Ten years later the first symptoms of PPMS materialised.
        
        We need more research in this area.
      Reply
2. 
   
   AnonymousThursday, February 04, 2016 11:47:00 am
   Yes, my MS first occurred after I had had a severe case of pox at the age of 24.
   Reply
   Replies
   1. • 
        
        MouseDoctor2Thursday, February 04, 2016 12:19:00 pm
        We have to be carefulwe don't fall into perception bias.
        
        Why do birds
        Suddenly appear
        Every time you are near?
        Most likely
        It is simply
        Perception bias.
        Aaaaah ah ah ah ah ah ah aah Perception bias
        
        Apologies to Burt Bacharach and the Carpenters ;-)
      • 
        
        AnonymousThursday, February 04, 2016 2:14:00 pm
        Yes, with n=1 you'll always have the problem of perception bias.
        On the other hand, focusing narrow-mindedly on "the one" infectious agent might produce 10 negative studies on 10 viruses while in the end it's one underlying mechanism shared by several pathogens.
      • 
        
        SterntaucherThursday, February 04, 2016 3:10:00 pm
        Och! Mouse Doctor #2, I now have that tune stuck in my head! It's not one I like.
        
        Anon 11:47 - Perhaps some / any viral infection can steer up the immune system, leading to flares which bring previously unnoticed MS to the fore? (The flu jab gave me flares, I believe.) But it doesn't mean that this viral infection caused the MS. I don't know.
        
        From what I understand, EBV is the most likely virus, for a whole host of reasons?
        
        "...we need to pursue our aims of targeting the virus with a vaccination strategy, antiviral drugs and drugs that deplete B cells and plasma cells."
        
        I'd rather just take an antiviral. What a dream - not to have to consider all these drugs that essentially just knacker your immune system in various ways. I'm sure they will seem primitive one day in the future.
      • 
        
        MouseDoctor2Thursday, February 04, 2016 3:37:00 pm
        Aw, come on Karen Carpenter had a great voice, in the same vein the guitar solo in Goodbye to Love is one of the alltime greats.
        I think any infection could cause flares as proinflammatory chemicals released by the immune system can upregulate the activity of microglia (not in a good way) which I'm sure are a fundamental part of the disease process in MS including PPMS. You see the same thing apparently in Alzheimer patients with infections and again microglia are increasingly implicated in the pathology.
        Which gets me back to aspirin...................
      • 
        
        SterntaucherThursday, February 04, 2016 4:04:00 pm
        Yes, very nice voice, it's true. And 'Top of the World' was kinda groovy!
        
        Aspirin... Ibuprofen too?
      • 
        
        AnonymousThursday, February 04, 2016 4:18:00 pm
        MD2 - what do you mean by 'gets me back to aspirin'? Plz explain.
      • 
        
        MouseDoctor2Thursday, February 04, 2016 4:36:00 pm
        I'm thinking of epidemiological data suggesting long-term use of NSAIDs (such as low dose aspirin after heart bypass surgery or NSAIDs for arthritis) are protective against the development of Alzheimers.
        http://scholar.google.co.uk/scholar...=0ahUKEwisqtf4w97KAhXGpR4KHW0OAZ8QgAMIIigBMAA
      • 
        
        AnonymousThursday, February 04, 2016 7:37:00 pm
        Modulating the inflammatory properties of activated microglia with Docosahexaenoic acid and Aspirin http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663775/
      • 
        
        Ms UnitesThursday, February 04, 2016 10:29:00 pm
        Why do neurons fall out of my mind?
        Everytime MS drops by...
        Just like me it longs to be too close to you.
      Reply
3. 
   
   CinaraThursday, February 04, 2016 8:22:00 pm
   MD2 may be right...
   
   But already I I'll agree with Prof. G, most people I talk to and who had infectious processes predecessors at the first symptoms of MS had infectious mononucleosis...
   I know some who say they have had infectious episodes caused by other viruses of the herpes family...
   So it may be that several pathogens, viruses specifically, would the action to unleash the ultimate pro inflammatory events of MS...
   
   I can speak for myself. I never had anything in life related to MS, no symptoms at all. In December 2010, at age 25, I made a trip to Santos, in Brazil, a city with a high rate of MS compared to other cities. There developed a strong throat infection it took to pass, I was quite ill and days later I find out it was mono. In 2013 I had the Mono relapse in two episodes during the year, and about six months after I presented the first symptoms of MS. I always thought it had something to do, whatever the trigger for the disease. Every time I had a relapse of Mono thought I would die! It was pretty bad even. And look at that as a child I had mumps, chickenpox and dengue 2x as a teenager (in Brazil dengue is a curse), and when I recovered from all these other infections very well. Now the Mononucleosis I can no longer say that. But perhaps MS may have as to trigger aberrant response of various immune system infections, especially viral ...
   
   Late last year reported that certain genetic variations to combat certain viruses. It may also be the key to understanding aberrant responses to them, included Epstein Barr Virus... http://www.eurekalert.org/pub_releases/2015-10/epfd-gvi100715.php
4. Reply

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

EIGHT IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Wednesday, 10 February 2016
Post by Prof. Gavin Giovannoni ​

ThinkSpeak: do we really need a wrecking ball to crack a nut? ​

Wrecking-ball or molecular tweezers; choose your poison. #ThinkSpeak #MSBlog #MSResearch

ThinkSpeak = thinking aloud


"I have said many time before the autoimmune hypothesis of multiple sclerosis may be wrong. This is why I refer to black swans, field hypotheses and viral causes of MS.

I am not alone in the world when it comes to taking an alternative view of MS. Many of you will argue that I am wrong and that this position, or hypothesis, is incongruent with the effectiveness of induction treatment strategies such as HSCT, alemtuzumab, cladribine/fludarabine, etc.

When you look at all the highly-effective therapies common to them all is an anti-B-cell effect, except for daclizumab which is an outlier. In other words HSCT may be simply be working via its effect on B-cells. If this is the case then the T-cell depletion, general bone marrow suppression and other off-target toxicities are simply collateral damage.

Do we really need a wrecking-ball to crack a nut?

Likewise, if alemtuzumab is working via B-cell depletion do we really need to collateral damage that comes with alemtuzumab's depletion and immunological changes that come from its specific immune system reconstitution pattern (secondary autoimmunity).

Do we really need a sledgehammer to crack a nut?

Cladribine and fludarabine may be safer to use than either HSCT or alemtuzumab, but we would still be using a hammer to crack a nut."

"With a short-term efficacy profile that is looking very good anti-CD20 therapies must be the way to go; they work like heat-seeking missiles to take-out their target and the collateral damage from depleting B-cells seems relatively contained. This view may change with longer follow-up.

What population of B cell is anti-CD20 therapies targeting?

Could it be the EBV infected pool?

If this is the case then we need better drugs; drugs that target EBV hence the need for the Charcot Project. More importantly, are anti-CD20 therapies enough? I suspect not. Stephen Hauser dropped a bomb on the stage at ECTRIMS when he mentioned that many of their patients with active RRMS treated on rituximab for many years have gone onto to develop secondary progressive MS. Why?

It may be that anti-CD20 therapies do not target long-lived plasma cells within the central nervous system and these plasma cells, which produce OCBs may be driving progressive disease. This is why I am so disappointed that MedImmune have put their anti-CD19 MS programme on ice; CD19 is at least expressed on plasma cells and anti-CD19 may be one way of targeting this population of long-lived plasma cells."

"People are often surprised that I am so interested in daclizumab as a treatment for MS.

Why?

Daclizumab is one highly-effective DMT that does not have an obvious upstream impact on B-cell biology. If I am right about the B-cell depletion hypothesis then how is daclizumab working in MS? If we can work out daclizumab's exact mode of action in MS we will be much further along the path of finding out the cause of MS. At present we know that daclizumab as a monotherapy seems not to be immunosuppressive in the classic sense and appears to working as IL-2 modulator. By directing IL-2 away from its high-affinity receptor to its intermediate affinity receptor it expands the population of CD56-bright NK cells. The expansion of this population of cells correlates with daclizumab's efficacy. The function of CD56-bright NK cells is complex; they are part of the innate immune response and have regulatory functions in relation to activated effector T-cells. The latter fits with the autoimmune dogma. Their other role is anti-viral.

Could CD56-bright NK cells be controlling the virus that causes MS? I therefore can't wait to study the impact of daclizumab on HERV and EBV biology in pwMS. This is why I am hoping the FDA and EMA, and NICE, give daclizumab a greenlight. Not only will it provide people with MS another option to treat their MS, but it will allow us to test the daclizumab antiviral hypothesis."

"I am sure many readers will disagree with me on many of the points above. If you do lets have a conversation or debate about the issues. I really don't believe we need wrecking balls, sledgehammers, hammers or heat-seeking missiles to treat MS. I would prefer a precision tool; a set of molecular tweezers that cause no collateral damage."



CoI: multiple​

Reactions:
Posted by Gavin Giovannoni at 09:30
23 comments:

1. 
   
   SterntaucherWednesday, February 10, 2016 10:54:00 am
   I don't normally "shout", but I LOVE THIS POST! Simply wonderful.
   Reply
   Replies
   1. 
      
      AnonymousWednesday, February 10, 2016 6:21:00 pm
      Ditto!
   Reply

• 
  Cristian UntaruWednesday, February 10, 2016 11:33:00 am
  Do the NK cells have any effect on B cells?
  Reply
  Replies
  1. 
     Gavin GiovannoniWednesday, February 10, 2016 8:51:00 pm
     Re: "Do the NK cells have any effect on B cells?"
     
     Yes, they can kill B cells. They can also secrete soluble factors that can activate and promote B cell division. I suspect it is the former function that is more interesting. We know that pwMS on daclizumab have fewer lymphocytes in their CSF; this is likely to be non-specific and secondary to anti-inflammatory effects.
  Reply

• 
  
  AnonymousWednesday, February 10, 2016 11:45:00 am
  What is your opinion on the effect of the anti-CD20 therapies on immunosenescence?
  
  I think the problem with the wrecking ball aproach is that it effects your T-cells and regeneration will be dependent on the thymus which becomes less efficient starting in early adulthood.
  
  I would assume the anti-CD20 therapies would not have this issues because b-cells can be regenerated without a dependancy on the thymic efficiency.
  
  I would appreciate your view.
  Reply
  Replies
  1. 
     Gavin GiovannoniWednesday, February 10, 2016 8:55:00 pm
     Re: "What is your opinion on the effect of the anti-CD20 therapies on immunosenescence?"
     
     I would need to look-up what happens to patients with rheumatoid arthritis on rituximab long-term. I suspect it would have an impact on B-cell function down the road and may reduce antibody levels and response to infectious agents. This can be dealt with by giving hyperimmune globulin to patients; we do this for patients with immunodeficiencies. So in short yes, I suspect anti-CD20 therapy will cause premature senescence of B cell memory. I would be surprised if it didn't.
  Reply

• 
  
  Saddam Khan MsCWednesday, February 10, 2016 12:05:00 pm
  Name me a CD_19 therapy? Is there a licensed drug? What are you fellows doing about it?
  Reply
  Replies
  1. 
     
     MouseDoctor2Wednesday, February 10, 2016 1:22:00 pm
     https://clinicaltrials.gov/ct2/show/NCT01585766?term=Medimmune+AND+"multiple+sclerosis"&rank=1
     Not licensed and trial on ice sadly.
  2. 
     
     Gavin GiovannoniWednesday, February 10, 2016 8:55:00 pm
     MedImmune are pursuing their anti-CD19 therapy in neuromyelitis optica.
  Reply

• 
  steve sWednesday, February 10, 2016 2:13:00 pm
  Until we (scientific community) can figure out what the h*** is going on with this disease, I say use a sledgehammer approach. I would much prefer a scalpel and a fine incision but the varying opinions justify a "napalm" the immune system tactic. This is one tough nut to crack. Whew, lots of metaphors.
  Reply
  Replies
  1. 
     
     AnonymousWednesday, February 10, 2016 2:34:00 pm
     The metaphors make it an interesting read.
  Reply

• 
  VincentinaWednesday, February 10, 2016 2:18:00 pm
  This seems to make a lot of sense to me as a novice MSer. Any ideas of the possible waiting time for the green light on daclizumab?
  Reply

• 
  
  AnonymousWednesday, February 10, 2016 3:42:00 pm
  "Stephen Hauser dropped a bomb on the stage at ECTRIMS when he mentioned that many of their patients with active RRMS treated on rituximab for many years have gone onto to develop secondary progressive MS."
  
  What were the baseline features of the rituximab-treated patients who became SPMS? It's impossible to interpret the claim without this baseline information. Were the patients already EDSS 4 when they started rituximab? If so, then this is not surprising -- and if it took those patients 10 years from baseline to become SPMS, the fact that it took so long would be the remarkable result.
  Reply
  Replies
  1. 
     
     AnonymousWednesday, February 10, 2016 4:18:00 pm
     "......and if it took those patients 10 years from baseline to become SPMS, the fact that it took so long would be the remarkable result." The question is : What is the time to SPMS from diagnosis without treatment? Yes, the goal of DMTs and induction therapies should be to extend this time frame. The researchers from the University of British Columbia have published on this controversial topic of "Do the treatments delay the onset of SPMS?"
  2. 
     
     Gavin GiovannoniWednesday, February 10, 2016 8:58:00 pm
     Re: ".. What were the baseline features of the rituximab-treated patients who became SPMS?"
     
     I am not sure, but we know already from the rituximab PPMS trial that rituximab's impact on non-relapsing progressive MS is very small and seems to be limited to active and young subjects.
  3. 
     
     AnonymousWednesday, February 10, 2016 10:05:00 pm
     "we know already from the rituximab PPMS trial that rituximab's impact on non-relapsing progressive MS is very small and seems to be limited to active and young subjects."
     
     Yes, I am wondering why the data from Hauser's patients tell us anything new. Ten years ago, prior to the anti-CD20 clinical trials, it is very unlikely that an insurance company in the US would have approved rituximab as a first or second line treatment. If these were patients with multiple prior drug failures, on the threshold of SPMS, then it is not surprising that many of them would have transitioned within 10 years. As far as I know, it's still challenging today to get first or second-line approval for off-label rituximab.
     
     These data *may* be very interesting, if these patients had low EDSS when they started rituximab treatment -- but that's precisely what's unknown!
  4. 
     
     Gavin GiovannoniWednesday, February 10, 2016 11:12:00 pm
     Re: ".. These data *may* be very interesting, if these patients had low EDSS when they started rituximab treatment -- but that's precisely what's unknown!"
     
     It is the now old story of early and hard, or early and effective, and let's hope in 15-20 years time there are no problem. It's the hypothesis that the alemtuzumab extension studies are testing and no doubt the ocrelizumab extension studies will do as well. I still think we need to clear the OCBs to be confident that we have cured MS. I kind of put OCBs down as NEDA-8. NED-4 in brain atrophy, NEDA-5 CSF neurofilament levels, NEDA-6 cognition, NEDA-7 a PROM and NEDA-8 disappearance of OCBs. What do you think?
  Reply

• 
  
  MouseDoctor2Wednesday, February 10, 2016 4:01:00 pm
  XoRXoR 13.47
  Can't post your recent comment (for obvious reasons), sorry.
  Reply
  Replies
  1. 
     
     XoR XoRWednesday, February 10, 2016 4:40:00 pm
     No worry, I understand, just hope that a doctor will read it.
  2. 
     
     MouseDoctor2Wednesday, February 10, 2016 4:51:00 pm
     Its been archived.
  Reply

• 
  
  CinaraWednesday, February 10, 2016 5:27:00 pm
  I agree with several points of this publication.
  
  I think I've asked here on the blog if Daclizumab have an action on anti-viral true...
  
  Every time I read a clinical trial of a genetic locus for MS, I think I have read studies citing at least about 50 different SPN...It is as if they were looking for a needle in a haystack. For example now I read a study linking 11 SPN linked to other autoimmune diseases, particularly type 1 diabetes, autoimmune thyroid and celiac disease. But it's something I always wonder also what makes me so my immune system "attacks" oligodendrocytes, and others who share the same genetic affinity attack the pancreatic cells? There's something so beyond the gene regulating all this?
  
  Could EBV hiding in the lymph nodes and thymus? Have they thought about verify the presence of EBV before and after those who undergo the HSTC? I know some people who have done HSTC in Brazil and MS returned. Most had MS and active and could already be making the transition to SPMS...
  
  And that is another question I have: is the patients of Dr. Hause who were treated with Rituximab already had EDSS 4? I ask this because I know a guy who began to express IN to 16 years. She began treatment with Rebif but failed, ended up having a very strong surge with quadriplegia. So your neuro was "innovative" by Brazilian standards: began to treat him with MabThera and now at 19 he's fine, fully recovered from the bout without sequelae.
  So does the very early treatment with anti-CD20 as Rituximab or Ocrelizumabe prevent the transition to SPMS?
  
  Another question I have is why, beyond the amazing effect of daclizumab, do not observe deeper into MS juvenile?
  I think this very early presentation of MS can give several answers ...
  
  So many, many questions
  Reply

• 
  
  AnonymousWednesday, February 10, 2016 5:30:00 pm
  Does anyone know what happens to MS patients treated for B cell lymphomas, does the MS go into remission?
  Reply
  Replies
  1. 
     
     Gavin GiovannoniWednesday, February 10, 2016 9:01:00 pm
     Re: "Does anyone know what happens to MS patients treated for B cell lymphomas, does the MS go into remission?"
     
     Variable. I have two patients one who have developed lymphoma after having developed MS who did very well after their lymphoma treatment and one patient who did very badly because of her lymphoma. This type of question can only be answered by interrogating large country-wide databases, e.g. Denmark or Sweden.
  Reply

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

NINTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

THURSDAY, 3 MARCH 2016
Post by Prof. Gavin Giovannoni ​

ResearchSpeak: EBV creating myelin autoimmunity

How does IM trigger autoimmunity in people destined to develop MS?​

"The study below finds autoantibodies in people with infectious mononucleosus (IM), which are not found in normal controls. One autoantibody reacts to the myelin protein MOG (myelin oligodendrocyte glycoprotein).

The authors suggest that the aberrant immune response that characterises IM may result in autoimmunity. This hypothesis is not new. However, it does not explain the long latency between IM and the clinical onset of MS.

If autoantibodies are present as part of acute IM, why don't these people develop MS soon after their acute EBV infection? In addition, anti-MOG antibody response are not all the same and in general are very rare in typical MS. Anti-MOG responses are more common in children with inflammatory demyelination with a clinical picture that tends to mimic neuromyelitis optic, with very prominent spinal cord involvement.

I do think this group is on the right track studying IM; we need to explain why people with IM are at increased risk of developing MS. This is one of the grand research challenges in MS. Any ideas would be welcome!"

​

Kakalacheva et al. Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein. Viruses. 2016 Feb 12;8(2). pii: E51. doi: 10.3390/v8020051

Background:
A history of infectious mononucleosis (IM), symptomatic primary infection with the Epstein Barr virus, is associated with the development of autoimmune diseases and increases the risk to develop multiple sclerosis. Here, we hypothesized that immune activation during IM triggers autoreactive immune responses.

Methods:
Antibody responses towards cellular antigens using a HEp-2 based indirect immunofluorescence assay and native myelin oligodendrocyte glycoprotein (MOG) using a flow cytometry-based assay were determined in 35 patients with IM and in 23 control subjects.

Results:
We detected frequent immunoglobulin M (IgM) reactivity to vimentin, a major constituent of the intermediate filament family of proteins, in IM patients (27/35; 77%) but rarely in control subjects (2/23; 9%).

IgG autoantibodies binding to HEp-2 cells were absent in both groups. In contrast, IgG responses to native MOG, present in up to 40% of children with inflammatory demyelinating diseases of the central nervous system (CNS), were detectable in 7/35 (20%) patients with IM but not in control subjects. Normalization of anti-vimentin IgM levels to increased total IgM concentrations during IM resulted in loss of significant differences for anti-vimentin IgM titers.

Anti-MOG specific IgG responses were still detectable in a subset of three out of 35 patients with IM (9%), even after normalization to increased total IgG levels. Vimentin-specific IgM and MOG-specific IgG responses decreased following clinical resolution of acute IM symptoms.

Conclusions:
We conclude from our data that MOG-specific memory B cells are activated in subset of patients with IM.

 

[anciendaze]

To reiterate a point made before, we have a situation where some patients respond to depletion of CD20+ B-cells (or CD19+) while others do not. From a therapeutic standpoint this is said to be "not ready for prime time", but good therapies are in short supply, so it is used anyway.

From a research standpoint this is actually a great opportunity. Use flow cytometry to extract CD20+ B-cells prior to therapy, and examine them in vitro to see what is different in those cases where this works. I would not assume all these cells are identical without a great deal of experimental data which is currently lacking. If the cells seemed identical, I would next look at signalling, about which we still know remarkably little.

Cells with multiple epitopes are the rule, not the exception. Monoclonal antibodies typically target cells based on a single epitope.

It happens that friends of mine are going through treatment for breast cancer at this time. One of them is even "lucky" enough to have the HER2+ form for which better treatments are available. Treatment with Trastuzumab (Herceptin) alone had little effect, and they are now being treated with a second monoclonal antibody. The first combination had serious side effects without destroying tumor cells; a second combination looks more promising. I've had to explain that the cells they want to destroy have a combination of characteristics neither drug targets. Cells with only a single match are damaged just like cancer cells. There are a lot of growing cells in the body that are not cancerous. This is why treatment damages gut and hair. We are carpet bombing entire classes of cells.

We are scarcely thinking about damage that will become apparent years later. Unless a disease presents a direct threat to life in a fairly short term such treatments are not considered ethical. The best way forward is to find out precisely what we are doing when a treatment does work. Why is this subject to debate?

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni


TENTH IN A SERIES ON EBV & OTHER HERPES VIRUSES AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

ResearchSpeak: viral infections and relapse

Could reactivation of herpes viruses be triggering relapses?​

Comment by Gavin Giovannoni

"The three cases below of MSers with brainstem lesions and evidence of varicella-zoster virus (VZV or chicken-pox virus) reaction in their CSF is interesting. We have to assume the diagnostic results are real and not false-positives. Believe it or not that when using very sensitive tests such as PCR you frequently get false-positive results.
Could it be that the acute MS activity reactivated the virus that typically lies dormant in sensory neurones?
Or could reactivation of the virus have triggered the MS to become active?"

"We are aware that relapses in MS are frequently triggered by infections; about a third of relapses are known to be preceded by infections.

These are typically viral infections.We have no idea how many relapses are triggered by reactivation of dormant viral infections, such as VZV, CMV and EBV.

The latter is one of the hypotheses underpinning the viral hypothesis of autoimmunity, i.e. that viral infections drive autoimmunity by stimulating or boosting the immune system that allows the autoimmune cells to be easily triggered to damage self. How do we test this hypothesis?

It may have been tested already, but we don't know it. Does interferon beta and interferon alpha, which are antiviral agents work in MS by suppressing viral infections? Some of the original data on exogenous viral infections (colds, flu, etc.) suggests that interferon-beta does not reduce these types of infections, but we don't have data on the impact of these agents on reactivation of persistent viral infections, in particular EBV. As part of the Charcot Project we are hoping to get some information on this."

"Anecdotally, I have looked after a few patients who have had a strong temporal relationship between herpes virus reactivation and relapse. Two of these patients noticed a major reduction in their relapses when they were put onto long term antiviral drugs by their virologists. Interestingly, their relapses were stereotypical suggestive of a MS lesion been reactivated at the same site in the spinal cord. The latter may therefore have simply been a pseudorelapse due to conduction block in a demyelinated pathway rather than a true relapse. This is why it is so hard to do research in this area; sorting out pseudorelapses from true relapses is not easy."

Torkildsen et al. Detection of varicella-zoster virus DNA during medullary and brainstem relapses in multiple sclerosis. BMJ Case Rep. 2016 Feb 23;2016. pii: bcr2016214555. doi: 10.1136/bcr-2016-214555.​

​

We describe three cases of patients with concomitant acute medullary or brainstem multiple sclerosis (MS) lesions and detectable spinal fluid varicella-zoster virus DNA. Herpes simplex virus PCR was also positive in two of the patients. One patient was re-punctured 2 weeks following the relapse, with negative results. The PCR findings greatly delayed correct diagnosis and treatment in all three patients. Based on our cases, we propose that inflammatory medullary and brainstem lesions could result in viral leakage, and possibly viral reactivation, from destroyed sensory neurons, yielding false-positive cerebrospinal fluid PCR results. As this can have diagnostic and therapeutic consequences, further studies are warranted to evaluate the clinical relevance of these findings.​

​

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

ELEVENTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

ResearchSpeak: EBV specific T-cells enriched in the spinal fluid

"As you know I think EBV causes MS, i.e. I think it is the pivotal factor in the causal pathway that leads to the onset of the disease. Studies have consistently shown that the immune response to EBNA-1 (EBV associated nuclear antigen-1) is increased in people at risk of MS and/or who have MS.

Please note the use of 'and/or', because most people develop biological disease, i.e. MS, before their first symptoms. EBNA-1 is a so called latency programme antigen and keeps the EBV genome in hibernation. Some feel EBNA-1 is a molecular mimic and triggers cross-reactive immune responses to self-proteins.

This is one of the main EBV hypotheses.

Another hypothesis is that EBV infects cells within the brain and spinal cord and hence stimulates immune responses, by up-regulating innate immune mechanisms, or danger signals. If EBV does infect the central nervous system you would expect the nervous system to be enriched for T-cells reactive against EBNA-1. The small study below suggests that is the case. However, it does not show a difference between MS and other inflammatory conditions. Maybe this study is just detecting CD8+ T-cells that are prostitutes?"

"When I was in medical school I learnt a clinical sign called the Argyll Robinson pupil, which commonly occurs in people with neurosyphilis. In Victorian times it was also called the Prostitute's Pupil, because it would accommodate, but not react, to light (see figure above); i.e. Argyll Robertson pupils are bilateral small pupils that reduce in size on a near object (they 'accommodate'), but do not constrict when exposed to bright light (they do not 'react' to light)."

"They way they quantified the EBV, or EBNA-1, specific T-cells in this study was to stain them using so called HLA-class 1 pentamers (HLA-B35 & A02 restricted) loaded with know immunogenic peptides from EBNA-1 (HPVGEADYFEY & NLVPMVATV).

The investigators did not assess whether, or not, these cells reacted, or proliferated, to these antigens. We know from many studies that T-cell can accommodate, or bind to, many different peptides that are loaded in so called HLA molecules, either on antigen presenting cells or loaded up into recombinant soluble HLA molecules (pentamers), however this does not tell us anything about whether they get turned on, or activated.

For all we know these cells may be specific, or in love with, some unknown autoantigen, and just happen to bind to EBNA-1 peptide loaded HLA molecules. This study asks more questions than it answers. What we really need to know is a lot more about the function of these cells and whether or not they are reactive against EBV infected cells. More work needs to be done."

Comments by Gavin Giovannoni

Erdura et al. EBNA1 antigen-specific CD8 + T cells in cerebrospinal fluid of patients with multiple sclerosis. Journal of Neuroimmunology. Available online 19 March 2016 - In Press.

Epidemiological data suggests that Epstein–Barr virus may be involved in the pathogenesis of Multiple Sclerosis (MS). We aimed to determine the frequency of CD8 +T cells specific for one EBNA1-derived epitope (HPVGEADYFEY) in cerebrospinal fluid (CSF) and blood of patients with MS and other inflammatory neurological diseases (OIND).

The frequency of specific CD8 + T cells was assessed by HLA-class-I-binding pentamers restricted to HLA-B35. The frequency of HPVGEADYFEY-specific CD8 + T cells did neither differ significantly in blood nor CSF in MS compared to OIND, but was consistently higher in CSF compared to blood regardless of diagnosis.

 

[Ecoclimber]

Premission to repost by Prof. Gavin Giovannoni

ELEVENTH IN A SERIES ON EBV AND THE ARTEMIS CLINICAL RESEARCH CHARCOT PROJECT 2

There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.

ResearchSpeak: EBV specific T-cells enriched in the spinal fluid

"As you know I think EBV causes MS, i.e. I think it is the pivotal factor in the causal pathway that leads to the onset of the disease. Studies have consistently shown that the immune response to EBNA-1 (EBV associated nuclear antigen-1) is increased in people at risk of MS and/or who have MS.

Please note the use of 'and/or', because most people develop biological disease, i.e. MS, before their first symptoms. EBNA-1 is a so called latency programme antigen and keeps the EBV genome in hibernation. Some feel EBNA-1 is a molecular mimic and triggers cross-reactive immune responses to self-proteins.

This is one of the main EBV hypotheses.

Another hypothesis is that EBV infects cells within the brain and spinal cord and hence stimulates immune responses, by up-regulating innate immune mechanisms, or danger signals. If EBV does infect the central nervous system you would expect the nervous system to be enriched for T-cells reactive against EBNA-1. The small study below suggests that is the case. However, it does not show a difference between MS and other inflammatory conditions. Maybe this study is just detecting CD8+ T-cells that are prostitutes?"

"When I was in medical school I learnt a clinical sign called the Argyll Robinson pupil, which commonly occurs in people with neurosyphilis. In Victorian times it was also called the Prostitute's Pupil, because it would accommodate, but not react, to light (see figure above); i.e. Argyll Robertson pupils are bilateral small pupils that reduce in size on a near object (they 'accommodate'), but do not constrict when exposed to bright light (they do not 'react' to light)."

"They way they quantified the EBV, or EBNA-1, specific T-cells in this study was to stain them using so called HLA-class 1 pentamers (HLA-B35 & A02 restricted) loaded with know immunogenic peptides from EBNA-1 (HPVGEADYFEY & NLVPMVATV).

The investigators did not assess whether, or not, these cells reacted, or proliferated, to these antigens. We know from many studies that T-cell can accommodate, or bind to, many different peptides that are loaded in so called HLA molecules, either on antigen presenting cells or loaded up into recombinant soluble HLA molecules (pentamers), however this does not tell us anything about whether they get turned on, or activated.

For all we know these cells may be specific, or in love with, some unknown autoantigen, and just happen to bind to EBNA-1 peptide loaded HLA molecules. This study asks more questions than it answers. What we really need to know is a lot more about the function of these cells and whether or not they are reactive against EBV infected cells. More work needs to be done."

Comments by Gavin Giovannoni

Erdura et al. EBNA1 antigen-specific CD8 + T cells in cerebrospinal fluid of patients with multiple sclerosis. Journal of Neuroimmunology. Available online 19 March 2016 - In Press.

Epidemiological data suggests that Epstein–Barr virus may be involved in the pathogenesis of Multiple Sclerosis (MS). We aimed to determine the frequency of CD8 +T cells specific for one EBNA1-derived epitope (HPVGEADYFEY) in cerebrospinal fluid (CSF) and blood of patients with MS and other inflammatory neurological diseases (OIND).

The frequency of specific CD8 + T cells was assessed by HLA-class-I-binding pentamers restricted to HLA-B35. The frequency of HPVGEADYFEY-specific CD8 + T cells did neither differ significantly in blood nor CSF in MS compared to OIND, but was consistently higher in CSF compared to blood regardless of diagnosis.

 

[TrixieStix]

Here's a primary prospective study that supports that meta-analysis of linkage between EBV and MS. It looks at EBV antibodies in military personnel, and then compares this with rates of MS that showed up later.

there is lots of online info from NIH, and other medical sources about the connection between EBV and MS. It seems to be an accepted thing in the medical world.

 

[Tammy]

I concur with these research projects but I would add that I believe BOTH... CFS and MS are from different strains of the EBV.