The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis

[ash0787]

I also really doubt this one, EBV link has been suggested many times before but there doesn't seem to be any results which are supporting it as particularly relevant, also notice what he says about PEM being caused by physical disturbance of the nerves, if that were true then it should be able to be provoked by external forces like riding in a vehicle of some type, e.g. I have a mobility scooter which has hard plastic wheels, if you ride it over cobblestones it shakes the entire body vigorously, so I think that sort of scenario would be common enough that someone would have noticed by now if there was a link to PEM.

 

[AdamS]

also notice what he says about PEM being caused by physical disturbance of the nerves, if that were true then it should be able to be provoked by external forces like riding in a vehicle of some type

Yeah I'm pretty sure Alan Light found changes in gene expression following exertion which better explain some of the symptom exacerbations seen in PEM, to me this seems more tangible than the nerves thing:

RESULTS: In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48h. These postexercise increases correlated with behavioural measures of fatigue and pain.

From: https://www.ncbi.nlm.nih.gov/m/pubmed/21615807/

 

[wastwater]

I don't really understand the paper but I'm definitely ebv onset and it mentions a few keywords for me.

 

[Old Bones]

This is an interesting hypothesis. . . .

2. Another aspect I like is he suggests the use of some muscles might cause PEM more readily than others, depending on which nerves are infected. That fits somewhat with my experience. When I use my arms that is normally the end for me, but I can walk a bit.

@Murph I also find this hypothesis interesting. Like you, my arms (and upper back) are most affected by muscle weakness/PEM. It can take weeks, or months, for my arms to recover from minimal, but unaccustomed, use.

I've recently thought that if my legs were weakened by activity like my arms are, I'd be in a wheelchair. It seems I'm one of the fortunate ones in this respect.

 

[heapsreal]

I was tested for EBV about a month after post-infectious onset. The result showed that I'd never been infected with EBV, which I guess is somewhat unusual in itself (although I was only in my early 20's, and so still might have been exposed eventually). In recent years, someone suggested to me that the result might have been a sign that my immune system was unable to make antibodies to EBV, but I feel like that explanation probably falls on the wrong side of Occam's razor.

My cfs started at 31 yo with cmv mono and at the time negative to ebv, several months later it felt like mono again and ebv tested which was igg positive, so within those last months i had picked up ebv.

Igg suppose to be life long. A couple of years later i tested totally negative and retested again in a couple more years totally negative. Not suppose to happen and currently 46yo and work on the health industry, how could i not have come across ebv????

The loss of igg antibodies to ebv was a common finding in the lake tahoe cfs outbreak patients.

 

[lansbergen]

and currently 46yo and work on the health industry, how could i not have come across ebv????

Miracle?

 

[Helen]

The loss of igg antibodies to ebv was a common finding in the lake tahoe cfs outbreak patients.

Interesting. FWIW, it has been suggested, or maybe even stated, that a minority of people with an ongoing Lyme infection isn´t able to produce antibodies which contributes to unreliable results from some of the available tests. Could it it be that PWME belong to this minority?

 

[heapsreal]

Im sure ebv triggers a few cases of cfsme but like many immune disorders, these virus can reactivate especially if a cfsers has low nk function and for some can worsen symptoms. Treating ebv isnt a cure for cfs but if its an issue for a particular person then treating it can help.

Im not sure research is that current when its commonly quoted 95% of adults have been exposed to ebv etc, especially when you think of the many children that rarely leave the house and interact with us as much as what use to happen. A lot of interaction is online so less chance of passing on ebv also??

 

[TracyD]

Eriksen provided me with more information regarding his hypothesis - this time on gut issues and the timing of recovery. The part on the gut should apply to almost any explanation that involves the nervous system. The new information is here: https://tracyduvall.com/2017/06/14/mecfs-eriksen-on-gut-issues-and-timing/

 

[imitate-past-reign]

Wouldn't this imply that at least for step 3, Rituximab is useless?

Its effect would be countered by the cortisol administered, and only one in a million B-cells are infected with EBV. Also, Rituximab depletes B-cells when the b-cell response to EBV is already suboptimal, further compounding the problem.

I wonder how easy it would be to test this hypothesis. It might require specialized testing at autopsy.

You could do a lymph biopsy but it is not necessary, since CFS patients have defective T and B cell control against EBV even in plasma, the effect is compounded in lymph.

Would such an EBV infection disappear in symptoms entirely within 5 days and not show up at all on a blood test a month later which was specifically looking for it ?

If you do not have an IgG response but have EBV, it could be fatal, so this is unlikely.

Theories are a dime a dozen, we need data

He attempted a pilot trial but no one was interested. This was a last resort. He works every day to get that trial. Data shows that CFS patients that are patient with EBV have, homogeneously, defective T and B cell responses to EBV.

Not all cass of ME/CFS are triggered / caused by EBV

Conservatively, this would effect about 8 million people, or 40% of CFS patients. The subset it could improve would be EBV +, EBNA +, and women that got ill pre-pregnancy.

95% of CFS patients are positive with EBV, and symptoms worsen with CMV, which both use the same treatment (CMV can be vectored in this treatment). Also, semantically, no one has any idea what causes CFS, so this is irrelevant.

I suspect this treatment would improve aerobic capacity in healthy EBV-infected patients just like HBOT improves healthy cognitive functioning, at unjustifiable expense.

 

[imitate-past-reign]

This seems like the same-old hypothesis. Some patients had never had EBV at the time of their diagnosis, so at best this could only explain a subset. The explanation seems far too speculative for me to get excited about at this stage, though I may be swayed with high quality data.

Is there a single unifying cause of depression? Multiple Sclerosis? These all have subsets but no known etiology. The leading idea, PDH certainly will not explain fast-onset CFS, they have not even attempted to reconcile it.

I addressed this already, but it is critical to point out that Valcyte / Acyclovir have poor lipophilicity and poor evidence for use, are still being used, and that is the problem. Stanford uses valganciclovir but does not use this more effective (against EBV, not against CFS necessarily), cheaper therapy with less side effects.

I was tested for EBV about a month after post-infectious onset. The result showed that I'd never been infected with EBV, which I guess is somewhat unusual in itself (although I was that the result might have been a sign that my immune system was unable to make antibodies to EBV, but I feel like that explanation probably falls on the wrong side of Occam's razor.

CMV might be an option, but you're right, sorry.

Nancy Klimas did a proof of concept autologous infusion which improved patients. I'm not sure what she did to the cells , but from memory she grew up whatever was low. It was back in the early nineties I think. I have no idea why it wasn't pursued. It made total sense to me at the time ( not that I understood it). But patients did improve. It may have been a problem that they would need to continue doing it. Someone should try to dog it out or ask Nancy about it

Patients had to go under surgery twice for the treatment, which is not necessary. Just the sponsor requirement. This is a better treatment for gradual onset, because its a generalized immune shift. No company can profit from this treatment, because it is patented and abandoned. Autologous NK cell treatment is available in Japan, at malls. That is how simple the treatment is to execute.

EBV link has been suggested many times before but there doesn't seem to be any results which are supporting it as particularly relevant.

Original, Replication. He is attempting to be diplomatic and inclusive with regards to the nervous system.

 

[Janice Hargreaves]

I know that the herpes viruses have been looked at for many years and the links have never been made.

I feel there are many reasons for this ranging from the selection criteria of the subjects,the blood collection and storage methods,tissues selected for testing, the testing methods themselves not being sufficiently sensitive and precise, etc., etc..

However over the last 10 - 15 years there has been an exponential improvement in precision and accuracy with all the -omics methods.
Many old paradigms are being over-turned. However that in it's self leads to validation problems.

I found this paper by Loebels v intersting

"Serological profiling of the EBV immune response in Chronic Fatigue Syndrome using a peptide microarray."

Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, Borchmann P, Rüffer JU, Hiepe F, Ruprecht K, Behrends U, Meindl C, Volk HD, Reimer U, Scheibenbogen C.

PLoS One. 2017 Jun 12;12(6):e0179124. doi: 10.1371/journal.pone.0179124. eCollection 2017.

PMID: 28604802 Free PMC Article

 

[TracyD]

Eriksen has provided an update: https://tracyduvall.com/2018/09/20/eriksens-me-cfs-hypothesis-an-update/

 

[frederic83]

Eriksen says :

there is a drug under testing that might be capable of doing that. This drug has been developed by a team at the Wistar Institute in USA, and is designed to stop latently EBV-infected cells from reproducing themselves. If the trials with this drug is successful, it would be of enormous significance for a range of patient groups with EBV-related disorders, and possibly also for ME/CFS patients.

Anyone heard about this new drug ?

 

[TracyD]

Eriksen says :


Anyone heard about this new drug ?

As far as I can tell, it's in early stages of development: https://wistar.org/research-discove...ery-pipelines/ebv-targeted-anticancer-therapy

 

[Limitless1]

As far as I can tell, it's in early stages of development: https://wistar.org/research-discove...ery-pipelines/ebv-targeted-anticancer-therapy

The drug looks interesting. Another drug that appears to be promising is BS-69. In the recent breakthrough Epstein Bar Paper titled "Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity", it is the drug that is recommended which is already available. It inhibits EBNA2 transcription factor...

More info on BS-69: http://eng.tcu.edu.tw/a-breakthroug...standing-of-the-virus-mediated-tumorigenesis/

"Notably, 4 of the top 20 TFs that co-occupy EBNA2 disorder loci with EBNA2 (MED1, p300, NFKB1 and NFKB2) can be targeted by at least one available drug, and a recent study shows that the C-terminal domain of the BS69 (ZMYND11) protein can bind to and inhibit EBNA2. These results offer promise for the development of future therapies for manipulating the action of these proteins in individuals harboring risk alleles at EBNA2-bound loci."

Full Text to paper above: https://emerge.mc.vanderbilt.edu/wp-content/uploads/2018/04/SS395-Harley-EBNA2-in-autoimmunity.pdf

To fully understand the significance of these finding in laymens terms, read here: https://medicalxpress.com/news/2018-04-epstein-barr-virus-linked-diseases.html

 

[frederic83]

The pdf link is dead. Do they say they made a drug version of BS-69 or is it another drug on the market (which one) ? My understanding is that BS-69 is a human protein.

 

[TracyD]

The pdf link is dead. Do they say they made a drug version of BS-69 or is it another drug on the market (which one) ? My understanding is that BS-69 is a human protein.

The PDF link worked for me just now.

 

[frederic83]

I've just used a proxy and it works, indeed. Something blocks the connexion between the site and me.

 

[Limitless1]

So at second glance, it looks like there are two ways to target EBNA2 Transcription factor, one is through BS69 protein and then I am having trouble finding the drug they referance. If you go to the discussion of the full text, it says the drug is mentioned in source # 45 titled "DGIdb: mining the druggable genome."

You can download the full text for free to this article here: https://www.researchgate.net/publication/257754973_DGIdb_-_Mining_the_druggable_genome

Although I am not seeing the drug they are referring too. It might require a deep dive as I dont believe it is directly mentioned next to keywords like "EBNA". Ill take a deeper look soon...