Exciting Research Connects Epstein-Barr to MS Brain Lesions & Potentially Other Disor

[Firestormm]

Exciting Research Connects Epstein-Barr to MS Brain Lesions & Potentially Other Disorders Involving the CNS

ProHealth.com: http://www.prohealth.com/library/sho...fm?libid=16743

January 6, 2012

Study demonstrates how EBV sequestered in the brain causes the nerve cell damage of MS suggests it may play a role in other disorders, and may respond to rituximab, or antiviral therapies the researchers are now preparing for trial

A new study by researchers at Queen Mary, University of London shows how the Epstein-Barr virus tricks the immune system into triggering an acute inflammatory process and nerve cell damage in the brain, which is known to cause MS.

Previous research has suggested a link between the Epstein-Barr virus (EBV) and multiple sclerosis, but until now the research has remained controversial, since scientists had failed to substantiate the link.

The new study proves the virus is involved in a manner more sophisticated and subtle than previously imagined, and may offer new ways to treat or prevent the disease.

MS is a neurological condition that affects around 100,000 people in the UK. It can cause vision problems and difficulties with walking and fatigue, and tends to strike mainly young and middle-aged women.

Its root causes are not completely understood, but both genes and environment are known to play a role. Some previous research has suggested that EBV triggers MS, but subsequent studies had failed to find the connection.

The new research, published Jan 3 by the journal Neurology, looked at post mortem brains of MS patients, examining areas where neurological damage had recently occurred. (See Association of innate immune activation with latent Epstein-Barr virus in active MS lesions.)

Dr. Ute-Christiane Meier from Barts and the London Medical School, part of Queen Mary, led the research. She explained:

EBV is quite a clever virus; when its not growing and spreading it can hide away in our immune cells... In this study we used a different technique which allowed us to detect the virus in the brains of some people affected by MS, even when it was hiding away in the cells.

Dr Meier and her team of collaborators found that, although the virus was not actively spreading, it was releasing a chemical message into areas of the brain nearby.

This chemical message - made up of small RNA molecules - was activating the bodys immune system, causing inflammation. This damages nerve cells in the brain and causes MS symptoms.

Dr Meier continued:

We have to be careful and have to study more MS brains, but this is potentially very exciting research. Now we understand how EBV gets smuggled into the brain by cells of the immune system and that it is found at the crime scene, right where the attack on our nervous system occurs. Now we know this, we may have a number of new ways of treating or even preventing the disease.

Possible Target for Rituximab or Anti-Virals

One possibility is the widely-used cancer treatment Rituximab; a drug which is known to kill the cells of the immune system in which the virus hides. It is now being trialed as a treatment for MS - as well as myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Another possible approach, using anti-viral treatment, will be tested in clinical trials currently in preparation by Professor Gavin Giovannoni and colleagues, also at Queen Mary.

Dr. Meier adds:

If we can pinpoint EBV as a trigger, its possible that we could alter the course of MS or potentially even prevent the condition by treating the virus. MS so often strikes young women, and its unpredictable nature makes it an incredibly difficult disease to live with. We desperately need better ways to tackle the condition.

Interestingly, the research also hinted that infection with EBV and its action on the immune system could also be playing a role in other brain diseases such as cancer (e.g., lymphoma) and stroke.

This research was supported by the Medical Research Council and MS charities, Roan Charitable Trust and Aims2Cure.

Source: Based on Queen Mary University of London press release, Jan 4, 2012

Same report slightly different/more text/comment:

Research proving link between virus and MS could point the way to treatment and prevention

http://www.healthcanal.com/brain-ner...revention.html

A new study from researchers at Queen Mary, University of London shows how a particular virus tricks the immune system into triggering inflammation and nerve cell damage in the brain, which is known to cause MS.

Previous research has suggested a link between the Epstein-Barr virus (EBV) and multiple sclerosis but the research has remained controversial since scientists have so far failed to substantiate the link.

The new study proves the virus is involved in a manner more sophisticated and subtle than previously imagined, and may offer new ways to treat or prevent the disease.

MS is a neurological condition that affects around 100,000 people in the UK. It can cause vision problems, difficulties with walking and fatigue, and tends to strike mainly young and middle-aged women.

Its causes are not completely understood but both genes and environment are known to play a role.

Some previous research has suggested that EBV triggers MS but subsequent studies have failed to find the connection.

The new research, which is published in the journal Neurology, looked at post mortem brains of MS patients, examining areas where neurological damage had recently occurred.

Lead researcher, Dr Ute-Christiane Meier explained: EBV is quite a clever virus; when its not growing and spreading it can hide away in our immune cells.

In this study we used a different technique which allowed us to detect the virus in the brains of some people affected by MS, even when it was hiding away in the cells.

Dr Meier and her team of collaborators found that, although the virus was not actively spreading, it was releasing a chemical message into areas of the brain nearby. This chemical message - made up of small RNA molecules - was activating the bodys immune system, causing inflammation. This damages nerve cells in the brain and causes MS symptoms.

Dr Meier continued: We have to be careful and have to study more MS brains but this is potentially very exciting research. Now we understand how EBV gets smuggled into the brain by cells of the immune system and that it is found at the crime scene, right where the attack on our nervous system occurs. Now we know this, we may have a number of new ways of treating or even preventing the disease.

One possibility is the widely-used cancer treatment Rituximab; a drug which is known to kill the cells of the immune system in which the virus hides. It is now being trialed as a treatment for MS.

Another possible approach, using anti-viral treatment, will be tested in clinical trials currently in preparation by Professor Gavin Giovannoni and colleagues, also at Queen Mary.

If we can pinpoint EBV as a trigger, its possible that we could alter the course of MS or potentially even prevent the condition by treating the virus, Dr Meier added.

MS so often strikes young women and its unpredictable nature makes it an incredibly difficult disease to live with. We desperately need better ways to tackle the condition.

Interestingly, the research also hinted that infection with EBV and its action on the immune system could also be playing a role in other brain diseases such as cancer and stroke.

This research was supported by the Medical Research Council and MS charities, Roan Charitable Trust and Aims2Cure.

 

[Enid]

Very exciting firestormm - fits me to a tee from MRI brain imaging and Neurologist suspecting MS. Why oh why did EBV not show up early in blood tests though. (Basic NHS).

 

[Firestormm]

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

http://www.neurology.org/content/78/1/15.short?rss=1

J.S. Tzartos, DPhil G. Khan, PhD A. Vossenkamper, MD M. Cruz-Sadaba, PhD S. Lonardi, MSc E. Sefia, MSc A. Meager, PhD A. Elia, PhD
J.M. Middeldorp, PhD M. Clemens, PhD P.J. Farrell, PhD G. Giovannoni, PhD U.-C. Meier, DPhil

ABSTRACT

Objective:

To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain.

Methods:

White matter postmortem MS (n
10) and control tissue (n
11) was analyzed for the expression of the proinflammatory cytokine interferon
(IFN
) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization.

Results:

We detected overexpression of IFN
in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFN
in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFN
was overexpressed in these preselected active MS lesions. EBER cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFN
production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFN
production in vitro.

Conclusion:

These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFN
production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.

Neurology January 3, 2012 vol. 78 no. 1 15-23

I haven't read it all through yet. Excuse the text t'was a copy and paste job from the full paper.

It is very intriguing though - this association and of course the rituximab - for obvious reasons. I can't help but feel that they too might run up against the same problems with this line of enquiry as 'we' have.

Then again perhaps they have more clearly defined patient cohorts to study because of the ability to clearly diagnose? I don't know.

Certainly is exciting for those I know in the MS world - but I need to read it all through.

 

[heapsreal]

Any mention of how to treat this, any new ideas in this department??

 

[Enid]

Looking forward to your comments when read firestormm.

 

[Firestormm]

Any mention of how to treat this, any new ideas in this department??

Well rituximab is mentioned but the paper says only that their research might lead to better treatments of course. Thing is - or one of them I guess - is that nobody really autopsies CFS/ME folk.

There have been some studies but nothing on a par with this one for MS. So whilst MS shares similar symptoms with ME it is not enough to draw conclusion from the above that - for example - the 'lesions' reported in ME are the same as in MS or that EBV associations might also be similar.

Then again, this research might prompt similar in ME. But the main reason for posting was the Rituximab reference really. Still the paper is interesting and several places are looking at biobanks now aren't they...

Dunno. Another 'watch this space' I guess. In terms of Rituximab trials in the UK though, I understand the MEA and the Ramsay Research Fund are in discussion about co-sponsorship with possibly the MRC. RRF are one of those establishing a biobank and who will undertake post-mortem donations.

Edit:

Here's a bit from the editorial from Neurology:

http://www.neurology.org/content/78/1/11/suppl/DC1

'The findings reported by Tzartos et al.7 revitalize a debate that was heading toward a negative conclusion, that is, EBV-infected B cells are a rare and coincidental finding in MS brains.46 In contrast to the aforementioned studies, however, Tzartos et al.7 focused only on inflammatory B-cell containing white matter MS lesions rather than meningeal areas or CSF samples.

Moreover, the authors used a highly sensitive method to detect EBER transcripts in CNS tissue. In contrast to Serafini et al.3 and in line with the studies mentioned above, the authors conclude that active EBV infection is not a characteristic feature of inflammatory MS lesions based on the rare detection of viral lytic protein expression.'

He concludes:

'Several susceptibility factors and mechanisms contribute to the pathogenesis of a complex and heterogeneous disease such as MS. Seroepidemiologic studies, histopathologic observations, and immunologic data suggest that EBV infection is one of the factors involved. Studies that address mechanistic underpinnings of the reported associations are much needed in order to generate testable hypotheses as to how EBV contributes to the development of MS.'

Also the study only looked at 7 cases of MS. So I dare say they would want to do a larger study too. As usual it would seem nought is conclusive from one study alone - they will hopefully though stimulate more research.

 

[adreno]

Any mention of how to treat this, any new ideas in this department??

Lithium perhaps?

J Immunol. 2008 Jul 1;181(1):338-45.
Lithium prevents and ameliorates experimental autoimmune encephalomyelitis.
De Sarno P, Axtell RC, Raman C, Roth KA, Alessi DR, Jope RS.
Source
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL 35294, USA. desarno@uab.edu
Abstract
Experimental autoimmune encephalomyelitis (EAE) models, in animals, many characteristics of multiple sclerosis, for which there is no adequate therapy. We investigated whether lithium, an inhibitor of glycogen synthase kinase-3 (GSK3), can ameliorate EAE in mice. Pretreatment with lithium markedly suppressed the clinical symptoms of EAE induced in mice by myelin oligodendrocyte glycoprotein peptide (MOG35-55) immunization and greatly reduced demyelination, microglia activation, and leukocyte infiltration in the spinal cord. Lithium administered postimmunization, after disease onset, reduced disease severity and facilitated partial recovery. Conversely, in knock-in mice expressing constitutively active GSK3, EAE developed more rapidly and was more severe. In vivo lithium therapy suppressed MOG35-55-reactive effector T cell differentiation, greatly reducing in vitro MOG35-55- stimulated proliferation of mononuclear cells from draining lymph nodes and spleens, and MOG35-55-induced IFN-gamma, IL-6, and IL-17 production by splenocytes isolated from MOG35-55-immunized mice. In relapsing/remitting EAE induced with proteolipid protein peptide139-151, lithium administered after the first clinical episode maintained long-term (90 days after immunization) protection, and after lithium withdrawal the disease rapidly relapsed. These results demonstrate that lithium suppresses EAE and identify GSK3 as a new target for inhibition that may be useful for therapeutic intervention of multiple sclerosis and other autoimmune and inflammatory diseases afflicting the CNS.
PMID: 18566399

 

[Abha]

Hi Firestorm..Thanks for posting the interesting article.I'm unable to access the links(says page not found)Any ideas how i can get around this.
Thanks.

 

[Waverunner]

Thanks for posting this study, Firestormm. Very interesting.

 

[currer]

(Quote) These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFN production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases (Quote.)

95% of adults have evidence of EBV infection.
So why is it reactivated in these MS patients?

 

[Waverunner]

95% of adults have evidence of EBV infection.
So why is it reactivated in these MS patients?

I don't know the answers to these questions but one point of overall interest is the fact that we still lack practical diagnostic tests for brain and CNS regarding all kinds of pathogens and regarding inflammation. As long as these spots remain a spot of ambiguity they can act as reservoir for all kind diseases which could lead to all kind of symptoms as well as a lack of treatment.

 

[Firestormm]

(Quote) These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFN production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases (Quote.)

95% of adults have evidence of EBV infection.
So why is it reactivated in these MS patients?

Dunno. But apparently - according to the editorial write-up - it is 100% in MS patients which makes them - apparently - rather unique.

The full paper and the editorial are on the other forum currer having been 'booshed'.

 

[merylg]

Interesting thread thanks Firestormm. Here is another related review:

http://www.ncbi.nlm.nih.gov/pubmed/22132878

 

[heapsreal]

In an MS site i read where one ms patient improved alot with valtrex but this effect seems as reliable as in cfs patients as many said they had tried valtrex with no improvement. The MS community group seem less knowledgable then me/cfs group on antivirals, i think maybe some of these other non repsonders to be positive to other viruses like cmv/hhv6 but nothing is mentioned.

Does it say how they are testing for ebv eg high igg antibody titres etc? I know it says 100% in ms but there are a few people with cfs who have/had been infected with ebv and then have lost their antibodies. More improved levels of testing i think are needed for us??

cheers!!!

 

[anniekim]

This is interesting. I was wondering how this would fit in with Dr terry wahl recently sharing she managed to make her progressive MS go into remission due to her modified paleo diet? Do all the nutrients from her diet repair the myelin damage caused by the inflammation?

 

[Firestormm]

Interesting thread thanks Firestormm. Here is another related review:

http://www.ncbi.nlm.nih.gov/pubmed/22132878

Abstract

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON B CELL SUBSETS IN DISEASE Transitional B cells in systemic lupus erythematosus and Sjgren's syndrome: clinical implications and effects of B cell-targeted therapies. Clinical and Experimental Immunology 2012, 167: 7-14. Reconstitution after haematopoietic stem cell transplantation - revelation of B cell developmental pathways and lineage phenotypes. Clinical and Experimental Immunology 2012, 167: 15-25.

'The recent success of therapies directed at B cells has highlighted their potential as central players in multiple sclerosis (MS) pathogenesis. Exciting new data showed that B cell depletion led to reduced clinical and magnetic resonance imaging (MRI) evidence of disease activity. However, the mechanisms of action remain unknown, but could involve autoantibody production, antigen presentation and/or cytokine production by B cells. Another exciting line of investigation in the field of MS comes from latent infection of memory B cells by Epstein-Barr virus (EBV). These cells are hijacked as 'Trojan horses' and 'smuggle' the virus into the central nervous system (CNS). Thus, these new anti B cell treatments will also be likely to have anti-viral effects. We briefly review recent findings in the field of MS pathogenesis, and highlight promising new targets for therapeutic intervention in MS.'

B Cells and Autoimmune Conditions - add CFS/ME to those two - and throw in Rituximab - and maybe there is some hope for all? Much work to do though I suppose. And I certainly don't hold out much hope for Rituximab - but the more knowledge the better for all of us.

 

[Firestormm]

I think some of my concerns about Rituximab and CFS/ME arose from reading the response by Fluge and Mella to the concerns raised by van der meer in PlosOne. But I haven't really looked into their own study too closely to be honest. Still they do mention other conditions and lesions specifically in this response - for interest:

'...The full consequences of the action of Rituximab in other autoimmune diseases are only partly known, and also which of the known modes of action that are of greatest relative importance in individual patients [7]. CFS/ME is not a disease with evident widespread inflammatory lesions as in some established autoimmune conditions and the mode of action could thus be different from that seen in for example rheumatoid arthritis or lupus. Reduction of autoantibody levels (wash-out by reduced production following B-cell depletion) to a critical level before clinical responses become evident could therefore be one plausible mechanism explaining what we observed...'

'...Importantly, we have not demonstrated that CFS/ME is an autoimmune disease with disease-specific autoantibodies, but we have stated as a hypothesis that the observed clinical pattern of responses and relapses could be compatible with such a mechanism. Alternatively, influence on other aspects of B-cell function could be the key to understand the effects of B-cell depletion in CFS/ME, such as antigen-presentation to T-cells, influence on other immune cells such as dendritic cells, or changes in Th1 and Th2 balance.'

However...

'We admit the strong and repeated responses to new Rituximab infusion seen in our three pilot patients may have influenced us. We have later treated another lymphoma patient with preexisting CFS/ME who also experienced a clear response on all CFS/ME symptoms from four months after start of treatment (8 cytotoxic chemotherapy courses (CHOP) with addition of Rituximab), and she still has response of CFS/ME symptoms 2 years later. Other physicians treating patients having both CFS/ME and lymphoma elsewhere in the world have informed us of similar responses to Rituximab. The total experience with Rituximab in our opinion warrants a study to optimize the use of the drug...'

Then this of course:

'CFS/ME according to Fukuda or Canadian criteria is in many patients a very serious and debilitating disease. Current treatment is for many patients highly unsatisfactory and we believe it is justified to find new interventions and learn more of the pathophysiology, of which we at the time being know little. The side effects of Rituximab in this particular patient group of patients is of course presently largely unknown, although there is vast experience with the drug in B-cell lymphomas and established autoimmune diseases. We believe the severity of disease in many CFS/ME patients balances the known risks. That was also the opinion of most patients who were given the option to participate in the current study at a time when only three pilot patients had been treated with the drug.'

http://www.plosone.org/annotation/l...notation/43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c

I understand that the ME Association is in discussion with the MRC here in the UK about a co-sponsored clinical trial - and of course the Norwegians are on to the next phase too - so some of these uncertainties might be addressed.

Out of interest, Dr Charles Shepherd recently said that if a trial were to take place on the above grounds he would like to see tests of immune function included as measures: 'in particular autoantibody status; Bcells, pro-inflammatory cytokines and immunoglobulins'.

 

[Enid]

Thanks for the info firestormm - very interesting especially possible immune function study.

 

[globalpilot]

Is the idea then that an inactive infection is causing the inflammation ? If the infection is inactive, that must mean the immune system is able to stop it's replication. Why then, would it still be present. Is this a problem with the body's inability to clear cellular debris. This is confusing - I can see an active infection causing a problem. Maybe I"m not understanding this correctly.

Well rituximab is mentioned but the paper says only that their research might lead to better treatments of course. Thing is - or one of them I guess - is that nobody really autopsies CFS/ME folk.

There have been some studies but nothing on a par with this one for MS. So whilst MS shares similar symptoms with ME it is not enough to draw conclusion from the above that - for example - the 'lesions' reported in ME are the same as in MS or that EBV associations might also be similar.

Then again, this research might prompt similar in ME. But the main reason for posting was the Rituximab reference really. Still the paper is interesting and several places are looking at biobanks now aren't they...

Dunno. Another 'watch this space' I guess. In terms of Rituximab trials in the UK though, I understand the MEA and the Ramsay Research Fund are in discussion about co-sponsorship with possibly the MRC. RRF are one of those establishing a biobank and who will undertake post-mortem donations.

Edit:

Here's a bit from the editorial from Neurology:

http://www.neurology.org/content/78/1/11/suppl/DC1

'The findings reported by Tzartos et al.7 revitalize a debate that was heading toward a negative conclusion, that is, EBV-infected B cells are a rare and coincidental finding in MS brains.46 In contrast to the aforementioned studies, however, Tzartos et al.7 focused only on inflammatory B-cell containing white matter MS lesions rather than meningeal areas or CSF samples.

Moreover, the authors used a highly sensitive method to detect EBER transcripts in CNS tissue. In contrast to Serafini et al.3 and in line with the studies mentioned above, the authors conclude that active EBV infection is not a characteristic feature of inflammatory MS lesions based on the rare detection of viral lytic protein expression.'

He concludes:

'Several susceptibility factors and mechanisms contribute to the pathogenesis of a complex and heterogeneous disease such as MS. Seroepidemiologic studies, histopathologic observations, and immunologic data suggest that EBV infection is one of the factors involved. Studies that address mechanistic underpinnings of the reported associations are much needed in order to generate testable hypotheses as to how EBV contributes to the development of MS.'

Also the study only looked at 7 cases of MS. So I dare say they would want to do a larger study too. As usual it would seem nought is conclusive from one study alone - they will hopefully though stimulate more research.

 

[Firestormm]

Nah. I couldn't get my head around that either. I mean they looked at dead people! So how could lesions be 'active/inactive'?!! Lol

The editorial and full paper actually helped clear this up a little - well kind of (it was heavy going) - I'll dig a bit more out of it later. Shattered now. Bed I think.