New study on link between EBV & MS

[Persimmon]

Researchers at the Australian National University (ANU) have just published a paper which contains new evident of the link between Ebstein Barr virus and Multiple Sclerosis.

They found that individuals with EBV antibodies (ie evidence of past infection), who also exhibit certain genetic predisposing factors, are at 20 times the normal risk of developing MS. The predisposing genetic factors are immunological abnormalities.

Various papers (over many years) have linked MS & EBV. This paper provides strong evidence to support that body of research, but also points to the specific mediating role played by the immune system.

(Please feel free to correct me if I've got any of that wrong.)

Here's the press release from ANU:
http://news.anu.edu.au/?p=9941

The paper is being published in the 22 July 2011 issue of Neurology, which is not yet up on that journal's website.

 

[Esther12]

It just seems crazy that the viruses most heavily linked to CFS are also known to cause other neurological damage, yet so many feel willing to presume that such damage plays no role in perpetuating disability in CFS - or at least, talk to patients as if it plays no role.

 

[Valentijn]

They found that individuals with EBV antibodies (ie evidence of past infection), who also exhibit certain genetic predisposing factors, are at 20 times the normal risk of developing MS. The predisposing genetic factors are immunological abnormalities.

But 95% of all adults have EBV antibodies, so it doesn't seem very meaningful that people with MS have had it, unless maybe people with MS are at 100% or something. Or is the study saying that EBV + naughty genes = MS? When EBV is so universal, it seems just as likely that naughty genes = MS. Though if EBV were actively involved, at least that might help with treatment, or getting a vaccine developed.

 

[Esther12]

But 95% of all adults have EBV antibodies, so it doesn't seem very meaningful that people with MS have had it, unless maybe people with MS are at 100% or something. Or is the study saying that EBV + naughty genes = MS? When EBV is so universal, it seems just as likely that naughty genes = MS. Though if EBV were actively involved, at least that might help with treatment, or getting a vaccine developed.

There's been quite a lot linking EBV to MS over the years. I don't know enough to explain the technicalities, but it now seems fairly accepted. There was a paper on EBV, vitamin D and MS a few months ago which seemed to convince a lot of sceptics.

Maybe I'm wrong, but I get the impression that a link between EBV and MS is now widely accepted.

 

[Persimmon]

But 95% of all adults have EBV antibodies, so it doesn't seem very meaningful that people with MS have had it, unless maybe people with MS are at 100% or something. Or is the study saying that EBV + naughty genes = MS? When EBV is so universal, it seems just as likely that naughty genes = MS. Though if EBV were actively involved, at least that might help with treatment, or getting a vaccine developed.

I haven't read the actual paper, but presumed from the wording of the press release that the researchers had concluded that (i) EBV antibodies in the absence of these naughty genes are not a predisposing factor; (ii) the naughty genes in the absence of EBV antibodies are not a predisposing factor; but (iii) the presence of the two puts an individual at (at least) a massively increased risk of MS.

 

[heapsreal]

in reguards to ebv and cfs, ebv probably reactivates due to low natural killer cell function, nk cells are known to help control viral infections etc so if there not working well its possible that these common viruses that almost everyone has, is reactivating in those with cfs and poor nk function. ALso other herpes infections like cmv, hhv6 and the rest would also reactivate in the same way. So dont take it for granted when your doc says its an old infection unless he has tested titres levels of the viruses or specific lymphocytes are elevated like cd8 cells.

cheers!!!

 

[August59]

But 95% of all adults have EBV antibodies, so it doesn't seem very meaningful that people with MS have had it, unless maybe people with MS are at 100% or something. Or is the study saying that EBV + naughty genes = MS? When EBV is so universal, it seems just as likely that naughty genes = MS. Though if EBV were actively involved, at least that might help with treatment, or getting a vaccine developed.

95% of the healthy public has antibodies to EBV. The problem comes in when some of those 95% have elevated levels of the multiple antibodies for EBV and keep those levels for extended periods of time.

 

[Ecoclimber]

Since many patients have high titers of EBV and addition many have lesions as evidence by SPECT scans ( http://tinyurl.com/bzgwxhl) , I thought these studies might be of interest as a confirmation of a prior research study.

http://www.ncbi.nlm.nih.gov/pubmed/23242282

J Neuropathol Exp Neurol. 2013 Jan;72(1):29-41. doi: 10.1097/NEN.0b013e31827bfc62.
B-cell enrichment and epstein-barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis.
Magliozzi R, Serafini B, Rosicarelli B, Chiappetta G, Veroni C, Reynolds R, Aloisi F.
Source

From the Department of Cell Biology and Neuroscience, Istituto Superiore diSanità, Rome, Italy (RM, BS, BR, GC, CV, FA); and Wolfson Neuroscience Laboratories, Imperial College, Faculty of Medicine, London, UK (RR).
Abstract

ABSTRACT: Gray matter lesions are thought to play a key role in the progression of disability and cognitive impairment in multiple sclerosis (MS) patients, but whether gray matter damage is caused by inflammationor secondary to axon loss in the white matter, or both, is not clear. In an analysis of postmortem brain samples from 44 cases of secondary progressive MS, 26 cases were characterized by meningeal inflammation with ectopic B-cell follicles and prominent gray matter pathology; subpial cortical lesions containing dense perivascular lymphocytic infiltrates were present in 11 of these cases. Because intracortical immune infiltrates were enriched in B-lineage cells and because we have shown previously that B cells accumulating in the MS brain support an active Epstein-Barr virus (EBV) infection, we investigated evidence of EBV in the infiltrated cortical lesions. Cells expressing EBV-encoded small RNA and plasma cells expressing EBV early lytic proteins (BZLF1, BFRF1) were present in all and most of the intracortical perivascular cuffs examined, respectively. Immunohistochemistry for CD8-positive cells, granzyme B, perforin, and CD107a indicated cytotoxic activity toward EBV-infected plasma cells that was consistently observed in infiltrated cortical lesions, suggesting active immune surveillance. These findings indicate that both meningeal and intraparenchymal inflammation may contribute to cortical damage during MS progression, and that intracortical inflammation may be sustained by an EBV-driven immunopathologic response, similar to findings in white matter lesions and meninges.


http://multiple-sclerosis-research.blogspot.com/2012/12/research-b-cell-follicles-driving.html

Research: B cell follicles driving progression
#MSBlog: Is EBV the cause of MS? I think so.

Epub: Magliozzi et al. B-Cell Enrichment and Epstein-Barr Virus Infection in Inflammatory Cortical Lesions in Secondary Progressive Multiple Sclerosis. J Neuropathol Exp Neurol. 2012 Dec

http://www.ncbi.nlm.nih.gov/pubmed/23268369

Ann Rheum Dis. 2012 Dec 25. [Epub ahead of print]
Epstein-Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis.
Croia C, Serafini B, Bombardieri M, Kelly S, Humby F, Severa M, Rizzo F, Coccia EM, Migliorini P, Aloisi F, Pitzalis C.
Source

1 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK.
Abstract
OBJECTIVES:

Rheumatoid arthritis (RA) is associated with an increased Epstein-Barr virus (EBV) blood DNA load, a robust immune response to EBV and cross-reactive circulating antibodies to viral and self-antigens. However, the role of EBV in RA pathogenesis remains elusive. Here, we investigated the relationship between synovial EBV infection, ectopic lymphoid structures (ELS) and immunity to citrullinated self and EBV proteins.
METHODS:

Latent and lytic EBV infection was investigated in 43 RA synovial tissues characterised for presence/absence of ELS and in 11 control osteoarthritis synovia using RT-PCR, in situ hybridisation and immunohistochemistry. Synovial production of anti-citrullinated protein (ACPA) and anti-citrullinated EBV peptide (VCP1/VCP2) antibodies was investigated in situ and in vivo in the severe combined immunodeficiency (SCID)/RA chimeric model.
RESULTS:

EBV dysregulation was observed exclusively in ELS+ RA but not osteoarthritis (OA) synovia, as revealed by presence of EBV latent (LMP2A, EBV-encoded small RNA (EBER)) transcripts, EBER+ cells and immunoreactivity for EBV latent (LMP1, LMP2A) and lytic (BFRF1) antigens in ELS-associated B cells and plasma cells, respectively. Importantly, a large proportion of ACPA-producing plasma cells surrounding synovial germinal centres were infected with EBV. Furthermore, ELS-containing RA synovia transplanted into SCID mice supported production of ACPA and anti-VCP1/VCP2 antibodies. Analysis of CD4+ and CD8+ T-cell localisation and granzyme B expression suggests that EBV persistence in ELS-containing synovia may be favoured by exclusion of CD8+ T cells from B-cell follicles and impaired CD8-mediated cytotoxicity.
CONCLUSIONS:

We demonstrated active EBV infection within ELS in the RA synovium in association with local differentiation of ACPA-reactive B cells.

http://jem.rupress.org/content/204/12/2899.long

Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain
Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, has been associated with multiple sclerosis (MS), an inflammatory disease of the central nervous system (CNS), but direct proof of its involvement in the disease is still missing. To test the idea that MS might result from perturbed EBV infection in the CNS, we investigated expression of EBV markers in postmortem brain tissue from MS cases with different clinical courses. Contrary to previous studies, we found evidence of EBV infection in a substantial proportion of brain-infiltrating B cells and plasma cells in nearly 100% of the MS cases examined (21 of 22), but not in other inflammatory neurological diseases. Ectopic B cell follicles forming in the cerebral meninges of some cases with secondary progressive MS were identified as major sites of EBV persistence. Expression of viral latent proteins was regularly observed in MS brains, whereas viral reactivation appeared restricted to ectopic B cell follicles and acute lesions. Activation of CD8+ T cells with signs of cytotoxicity toward plasma cells was also noted at sites of major accumulations of EBV-infected cells. Whether homing of EBV-infected B cells to the CNS is a primary event in MS development or the consequence of a still unknown disease-related process, we interpret these findings as evidence that EBV persistence and reactivation in the CNS play an important role in MS immunopathology.

Maybe we should call ME/CFS (Multi-Systemic Infectious Disease Syndrome - MSIDS) if Lipkin's current research bears out a pathogen related cause as he suspects? ( Thoughts, Opinions, Anyone)

Eco

 

[August59]

I noticed along withat article there was another mentioned to the side that was titled "Dysregulated EBV infection in the MS brain. That word "Dysregulated Epstein Barr virus" stood out to me and went on to mention CD8+ and T-cell lymphocytes. It is probably a dysregulated EBV in PWC in the brainstem. Judging by the way these studies were written is there no way to identify them actually being there except after an autopsy. Them being so deeply embedded in cells is probably why it takes Dr. Lerner and others to see a response from either Valcyte or Valtrex.

I wonder if Dr. Lipkin and those have developed an assay to find something hidden that deep into tissue. It would have re-enter the bloodstream before they could pick it up. However if they do use spinal fluid as stated at one point then it may be possible?

 

[alex3619]

The existence of antibodies to EBV in MS (and other viruses in the case of ME) doesn't say a lot. Mapping out what those viruses are doing, where they are doing it, and under what conditions, might yet change our understanding completely.

To give some flavour of the complexity of these issues, I would like to comment on gamma delta T cells. http://www.eurekaselect.com/68566/article

Subsets of these cells migrate to sites of inflammation, and they have been found in MS lesions. They alter the cytokines in the lesions, and physically infiltrate the area. What are they doing? These cells have been variously implicated as both helping and causing harm in MS.

How about all the other cell types? There are a lot of things going on in MS lesions.

To really understand all this we need to know a lot more than we do. EBV might well cause MS if it establishes too much inflammation in zones in the brain. We need more research to understand either EBV or MS, a well-worn mantra.

I am mindful that similar arguments against EBV as a cause of ME have been raised, and the same for enteroviruses. Yet now we have reason to believe, including Lerner's and Chia's work, that these arguments are wrong. If they are wrong in ME, they can be wrong in MS too. I do not know enough about EBV latency proteins and the like to comment further, only that we need to be very very sure EBV is not involved before dismissing it. If its dismissed prematurely then research could be derailed for a generation.

Bye, Alex

 

[alex3619]

Maybe we should call ME/CFS (Multi-Systemic Infectious Disease Syndrome - MSIDS) if Lipkin's current research bears out a pathogen related cause as he suspects? ( Thoughts, Opinions, Anyone)

Eco

After reading one of these papers it is clear they are tracking well known EBV latency proteins in MS. Lipkin et. al. should be able to detect those in ME if they are looking.

Unless Lerner's findings of atypical EBV antibodies in ME is explained away, the idea that EBV can cause ME (though might not be the only cause) is still an open question.

As always though, as is happening with MS, the question will remain until we have a better understanding: are EBV and other infections a cause of ME, or are they a consequence of immune issues .... or even is there mutual reinforcement between the infection and immune issues to collectively create the condition?

 

[heapsreal]

phanu are supposedly going to do an nk function bright/dim cell study comparing me, ms and ra, comparing this with ebv would also make it interesting?? Nk function could be a cause of ebv reactivation or maybe a biomarker. They must being seeing something very similar between these illnesses to do a study comparing them??

 

[bel canto]

I would love to see someone look at the genetics involved in those three - me, ms and ra, also.

 

[alex3619]

There is a biomarker that so far as we are aware is only present in quantity in ME, MS and RA, though I suspect some infections might induce it also. Its the 37 kDa RNase L. While RNaseL levels rise in viral infections, in these three diseases that the short form of the enzyme is cyclically elevated. It was looked at as a diagnostic biomarker for CFS for a while, but it was not reliable enough.

 

[Waverunner]

As always though, as is happening with MS, the question will remain until we have a better understanding: are EBV and other infections a cause of ME, or are they a consequence of immune issues .... or even is there mutual reinforcement between the infection and immune issues to collectively create the condition?

That's they key issue. I've been thinking about this for several weeks now. As you pointed out, there are three possibilities for the pathogenesis of ME/CFS and this makes it so hard to actually solve the puzzle.

1. Infection: We get infected by something, we can't get rid of the infection, many symptoms.
2. Immune/Autoimmune/Inflammatory cause: Somehow our immune system gets dysfunctional, maybe even starting through an infection, we get all kinds of symptoms. Treating the infection will not solve the dysfunction.
3. Worst Case: Mutual reinforcement: Infection and immune dysfunction go hand in hand and mutual reinforce each other, in all kind of pathways.

What was first, the chicken or the egg? Infection and autoimmune disease have a key difference. In the first case, the body fights a true invader, in the second case, the body fights itself. So while you might want to lower inflammation in the autoimmune case, you might want to increase it in case of a true infection.
All these studies, looking for viruses etc. have a huge flaw. We never know if the infection is a consequence of a dysfunctional immune system or the cause. The next huge problem is, that even if someone is positive for EBV, HHV-6 etc. we never know what the virus is actually doing. It might cause disease is some and others might be perfectly healthy.

 

[heapsreal]

one of the infections we currently have was probably the trigger??
The other infections we get are due to the immune dysfunction from these chronic infections or the trigger infection which also causes further immune dysfunction.

or we had an initial immune dysfunction that didnt shows its ugly head until the initial trigger that then opened the flood gates. We do know from studies that the longer one is ill the more infections one has.

In my case i believe the several infections one after the other before recoverying was enough to damage my immune system and allow the infections to get much deepr then if i just had one infection to recover from.

 

[natasa778]

I would love to see someone look at the genetics involved in those three - me, ms and ra, also.

imo much of the genetic risk to those diseases will be in actual ERV polymorphisms + epigenetic mechanisms (past exposures, including prenatal and trans-generational) that affect their activation.

I believe there is already some research showing this being the case in MS.

 

[natasa778]

Re above, just located a few:

Human Endogenous Retrovirus-K18 env as a risk factor in multiple sclerosis

In summary, we found that sequence variations in the HERV-K18 env, which encodes a superantigen transactivated by EBV, are significantly associated with risk of MS. This finding, combined with the strong evidence linking EBV infection to MS, supports the possibility that HERV-K18 env is a susceptibility gene for MS.

and

The Etiology of Multiple Sclerosis: Genetic Evidence for the Involvement of the Human Endogenous Retrovirus HERV-Fc1

SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis.

 

[bel canto]

Thanks, Natasha, for the links.

 

[Ecoclimber]

Conclusions: These findings indicate that both meningeal and intraparenchymal inflammation may contribute to cortical damage during MS progression, and that intracortical inflammation may be sustained by an EBV-driven immunopathologic response, similar to findings in white matter lesions and meninges.

​

Temporal profile of serological changes post EBV infection. The anti-EBNA1 response is predictive of disease activity.​

"These results will almost certainly be controversial. Other researchers can't seem to reproduce this groups findings. We will need to wait and see if these results are reproduced. Despite this controversy there is mounting evidence that EBV is strongly associated with MS and some investigators, including myself, believe this association is causal. That has therapeutic implications in that if you prevent EBV infection you may be able to prevent MS or if you target EBV with an anti-viral drug you may suppress MS disease activity. This is what we are trying to do with the Charcot Project."

Sorry for the large image. Any attempt to resize, reverts back

Eco