Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.

[snowathlete]

Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome.
Full free text available here.

Says published Jan 2014, but I hadn't seen it. Maybe others didn't either?

Abstract
Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported. In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients. Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication. Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

 

[Bob]

Thanks for posting, snowathlete.

There is an earlier thread on this, in case you haven't seen it yet:
http://forums.phoenixrising.me/inde...patients-with-chronic-fatigue-syndrome.27634/

Edit: lol, you've done what I always do, and you've completely forgotten posting about it:
http://forums.phoenixrising.me/inde...h-chronic-fatigue-syndrome.27634/#post-421030

 

[snowathlete]

Thanks for posting, snowathlete.

There is an earlier thread on this, in case you haven't seen it yet:
http://forums.phoenixrising.me/inde...patients-with-chronic-fatigue-syndrome.27634/

Edit: lol, you've done what I always do, and you've completely forgotten posting about it:
http://forums.phoenixrising.me/inde...h-chronic-fatigue-syndrome.27634/#post-421030

LOL. At least I didn't post the original thread and only commented on it. I used to have a fantastic memory...I think.

 

[Bob]

LOL. At least I didn't post the original thread and only commented on it. I used to have a fantastic memory...I think.

Hehe... Yes, I used to have a good memory as well! >I think!<

I have actually come across interesting "new" papers, and then found that I had not only previously posted it as a new thread, but had also analysed the paper in depth, and plastered a large number of posts all over the thread! It's a little disconcerting when that happens!

 

[Ema]

Sometimes when I'm scanning through a thread, I don't notice the post authors and I will read a reply that I think is especially in line with my own beliefs...only to discover I wrote it and have no recollection of it! At least my multiple personalities agree with each other.

 

[bootsydan]

Really interesting, snowathlete.

I had EBV and recovered in 3 weeks. Then I relapsed and couldn't recover the second time, developing CFS, which fits "an impaired ability to control early steps of EBV reactivation" to a dime.

The next obvious question: Does anyone know what can boost the "EBV-specific B- and T-Cell memory response?"

 

[heapsreal]

Really interesting, snowathlete.

I had EBV and recovered in 3 weeks. Then I relapsed and couldn't recover the second time, developing CFS, which fits "an impaired ability to control early steps of EBV reactivation" to a dime.

The next obvious question: Does anyone know what can boost the "EBV-specific B- and T-Cell memory response?"

An Australian doctor has used an ebv vaccination to treat ms with success. I'm guessing a vaccination would possibly work??

 

[anciendaze]

@heapsreal

I think you are talking about Michael Pender's treatment of secondary progressive MS. This used adoptive immunotherapy, which is considerably more than vaccination.

 

[Woolie]

An Australian doctor has used an ebv vaccination to treat ms with success. I'm guessing a vaccination would possibly work??

Can you tell me more about this, @heapsreal? I thought that vaccines only worked preventitively. So once the horse was bolted, so to speak, they were no good?

 

[Woolie]

@heapsreal

I think you are talking about Michael Pender's treatment of secondary progressive MS. This used adoptive immunotherapy, which is considerably more than vaccination.

Thanks, @anciendaze, just saw this, your reply to Heaps.

 

[heapsreal]

@heapsreal

I think you are talking about Michael Pender's treatment of secondary progressive MS. This used adoptive immunotherapy, which is considerably more than vaccination.

Yes,

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

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

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

Results of the study were published today in the international Multiple Sclerosis Journal.

The treatment involves collecting immune cells known as T cells from the patient’s blood, growing them in the laboratory with an EBV vaccine and then transferring the cells back to the patient by intravenous infusion. The treatment was developed by Professor Rajiv Khanna of the QIMR Berghofer Medical Research Institute to treat patients with EBV-related malignancy and does not require the use of any drugs.

- See more at: http://www.msaustralia.org.au/news/...reakthrough-ms-treatment#sthash.0x3rtRBp.dpuf

 

[bootsydan]

@heapsreal

Mate, really interesting!

Something to print out and take to my doctor...

 

[Woolie]

@heapsreal, just wanted to say thanks again for this! I've seen other articles in the lit that have used this type of treatment (for things other than MECFS, lymphoma I think), and I've always thought it sounded like the answer we needed - at least those of us with the kind of MECFS being described at the top of this thread.
If I had all the money in the world, and permission to try any treatment I felt like, this would be the one I'd go for!

 

[heapsreal]

@heapsreal, just wanted to say thanks again for this! I've seen other articles in the lit that have used this type of treatment (for things other than MECFS, lymphoma I think), and I've always thought it sounded like the answer we needed - at least those of us with the kind of MECFS being described at the top of this thread.
If I had all the money in the world, and permission to try any treatment I felt like, this would be the one I'd go for!

Agree. I think they will find ebv and treating it, will be important in treating some autoimmune, cancers and immune deficiencies, which I think mecfs for some is a combo of this.

I hope they can use this same technology for cmv as it seems to be the infection that's driving my cfs. Maybe could be directed at other infection eg Lyme etc

 

[Woolie]

@heapsreal, re that article about MS from UQ that you posted recently, here is a study that seems to use a related approach? Its for a condition they call "Chronic active EBV" (mild to moderate) which is not the same as ME, but has enormous overlap in symptoms. Looks to me like it might be a more severe variant of one ME subtype.

Savoldo, B., Huls, M. H., Liu, Z., Okamura, T., Volk, H. D., Reinke, P., ... & Rooney, C. M. (2002). Autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood, 100(12), 4059-4066.

http://www.bloodjournal.org/content/100/12/4059.long?sso-checked=true

 

[heapsreal]

@heapsreal, re that article about MS from UQ that you posted recently, here is a study that seems to use a related approach? Its for a condition they call "Chronic active EBV" (mild to moderate) which is not the same as ME, but has enormous overlap in symptoms. Looks to me like it might be a more severe variant of one ME subtype.

Savoldo, B., Huls, M. H., Liu, Z., Okamura, T., Volk, H. D., Reinke, P., ... & Rooney, C. M. (2002). Autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood, 100(12), 4059-4066.

http://www.bloodjournal.org/content/100/12/4059.long?sso-checked=true

Research into viruses like ebv isn't that old and also need technology to catch up than I think they will see they are implicated in a lot more situations

 

[anciendaze]

@heapsreal, re that article about MS from UQ that you posted recently, here is a study that seems to use a related approach? Its for a condition they call "Chronic active EBV" (mild to moderate) which is not the same as ME, but has enormous overlap in symptoms. Looks to me like it might be a more severe variant of one ME subtype.

Savoldo, B., Huls, M. H., Liu, Z., Okamura, T., Volk, H. D., Reinke, P., ... & Rooney, C. M. (2002). Autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood, 100(12), 4059-4066.

http://www.bloodjournal.org/content/100/12/4059.long?sso-checked=true

This answers a number of questions I have long had. First, it suggests there is already a recognized clinical disease with many characteristics of ME/CFS which is known to have a lethal progressive form. I had already said I did not think the chronic illness could exist in isolation, but I could not be certain which recognized clinical disease might be considered a progressive form. Since many ME/CFS patients go through a period when they exhibit such clinical signs as lymphadenopathy, fever and flu-like symptoms it is possible we would be considered mild-to-moderately affected examples of chronic active EBV infection -- if diagnosed at the right time.

Second, these patients generally do not show antibodies to EBV nuclear antigen. This strongly suggests to me that the virus is manipulating immune response to protect itself. If the virus is capable of exploiting clonal expansion of B-cells, without lytic replication, any replication of viral DNA must be taking place in one of several "latent" phases. Infected cells could then produce more infected cells via mitosis. The common finding that ME/CFS patients exhibit polyclonal expansion of B-cells makes me think this is in fact taking place.

Third, limited success of treatment with antivirals, or with specific B-cell depletion with Rituximab, has suggested to me that adoptive immunotherapy might produce even more striking results. In this case we have 5 patients who were clearly deteriorating who responded to this therapy without adverse effects. One of these showed recurrence of symptoms after a delay of one year. This success rate for a condition that is notably difficult to treat is stunning. (How many patients here would be willing to pay for a remission lasting a full year? By that standard all five patients responded.)

Finally, this research has been out there since 2002, and widely ignored. If you check the notices you will find it marked as an advertisement. This actually means only that the authors had to pay page costs to get it published because the editors of various journals did not think it worth publishing if they were not paid. (You do not see numerous studies on the effectiveness of antidepressants marked as advertisements even though a pharmaceutical company may have paid for the entire trial.)

With the exception of these doctors and their patients, it appears that nobody else gives a damn.

 

[Sidereal]

@heapsreal, re that article about MS from UQ that you posted recently, here is a study that seems to use a related approach? Its for a condition they call "Chronic active EBV" (mild to moderate) which is not the same as ME, but has enormous overlap in symptoms. Looks to me like it might be a more severe variant of one ME subtype.

Savoldo, B., Huls, M. H., Liu, Z., Okamura, T., Volk, H. D., Reinke, P., ... & Rooney, C. M. (2002). Autologous Epstein-Barr virus (EBV)–specific cytotoxic T cells for the treatment of persistent active EBV infection. Blood, 100(12), 4059-4066.

http://www.bloodjournal.org/content/100/12/4059.long?sso-checked=true

Wow, great find. I have a feeling they are calling this "chronic active EBV" instead of CFS for political reasons. This is obviously the EBV subset of ME that was studied in the US around the time of the Incline Village outbreak. They actually cite those papers:

Jones et al. Chronic Epstein-Barr virus infection. Annu Rev Med.1987;38:195-209.

Straus et al. The chronic mononucleosis syndrome. J Infect Dis. 1988;157:405-412.

Rickinson. Chronic, symptomatic Epstein-Barr virus infections. Immunol Today.1986;1:13-14.

Jones et al. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N Engl J Med.1988;318:733-741.

I can't believe this was published in 2002 and no one's followed it up. Well, actually, I can.

Given his work on EBV and MS, I wonder if Prof Pender is aware of this clinical entity of ME and whether he has any interest in it.

 

[Woolie]

Finally, this research has been out there since 2002, and widely ignored. If you check the notices you will find it marked as an advertisement. This actually means only that the authors had to pay page costs to get it published because the editors of various journals did not think it worth publishing if they were not paid. (You do not see numerous studies on the effectiveness of antidepressants marked as advertisements even though a pharmaceutical company may have paid for the entire trial.)

Happily, @anciendaze, it might not mean this at all. Blood is a very prestigious journal. Many high-status rapid publication journals require a publication fee routinely, and this is no indicator of quality of the submission (the most prestigious of these in my area is the Proceedings of the National Academy of Sciences, all articles are accompanied by the "advertisement" disclaimer). These top journals trade on their god-like reputation and high impact factor (how often their papers get cited), so accepting extra cash for weaker pubs is just not good business! Happily too, this particular paper has been very widely cited.

Wow, great find. I have a feeling they are calling this "chronic active EBV" instead of CFS for political reasons. This is obviously the EBV subset of ME that was studied in the US around the time of the Incline Village outbreak.

@Sidereal, not sure the exact relation between CAEBV and ME, because I'm not sure how many ME people have some or all of the key features. But it looks to me more than just another name for a ME/CFS subset (more like a more severe but possibly related clinical entity, like anciendaze suggests). I've given a formal set of criteria below, which are pretty much what Savoldo et al used in the above paper.

Perhaps people could comment - these kinds of counts of EBV viral capsid antigen and early antigen - how common are they in members of this forum?

The criteria for CAEBV suggested by a recent review (Okano et al., 2005) are:

1. Persistent or recurrent mononucleosis-like symptoms. These include fever, swelling of lymph nodes, and hepatosplenomegaly; additional complications include hematological, digestive tract, neurological, pulmonary, ocular, dermal, and/or cardiovascular disorders (including aneurysm and valvular disease) that mostly have been reported in patients with IM

2. Unusual pattern of anti-EBV antibodies with raised anti-VCA and anti-EA, and/or detection of increased EBV genomes in affected tissues, including the peripheral blood (ordinarily, VCA-IgG 1:640 and EA-IgG 1:160; positive IgA antibodies to VCA and/or EA are often demonstrated)

3. Chronic illness which cannot be explained by other known disease processes at diagnosis

4. Additionally, more than 102.5 copies/mg EBV DNA are generally detected in peripheral blood mononuclear cells.​

This is pretty much what the authors of the Savoldo paper used too.

Third, limited success of treatment with antivirals, or with specific B-cell depletion with Rituximab, has suggested to me that adoptive immunotherapy might produce even more striking results. In this case we have 5 patients who were clearly deteriorating who responded to this therapy without adverse effects. One of these showed recurrence of symptoms after a delay of one year. This success rate for a condition that is notably difficult to treat is stunning. (How many patients here would be willing to pay for a remission lasting a full year? By that standard all five patients responded.)

Yes, I would pay many thousands! Just tell me where to sign up

 

[anciendaze]

Happily, @anciendaze, it might not mean this at all. Blood is a very prestigious journal. Many high-status rapid publication journals require a publication fee routinely, and this is no indicator of quality of the submission (the most prestigious of these in my area is the Proceedings of the National Academy of Sciences, all articles are accompanied by the "advertisement" disclaimer). These top journals trade on their god-like reputation and high impact factor (how often their papers get cited), so accepting extra cash for weaker pubs is just not good business! Happily too, this particular paper has been very widely cited.

I have a modest proposal. Since grants often include money to cover publication costs, and many groups funded by NIH or CDC amount to government-funded lobbies for further funding, why not include an advertising disclaimer on all publications produced by this process?