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Important Discovery Exposes Autoimmune Nature of ME/CFS - HERVs Implicated

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by Joel (Snowathlete)

iStock_000022784907_ExtraSmall.jpg

Plasmacytoid dendritic cell interacting with a T-cell.

Some dates you remember forever. Yesterday, on Wednesday 20th February 2013, a paper was published that may represent a major breakthrough in understanding the underlying mechanisms and cause of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

The paper, from long-time ME/CFS researchers Dr Kenny De Meirleir, Vincent Lombardi and other colleagues in association with the Whittemore Peterson Institute, reports findings that amount to ME being an autoimmune disease.

Dr Kenny De Meirleir is perhaps best known for the work he has done on the gut and its link to the pathophysiology of ME/CFS, so it is no surprise to hear that this latest finding is related to the major role of the lymphatic immune system in the gut. What will surprise some is that they have been able – despite its massive complexity - to narrow it down to a specific type of cell and to show how this cell ends up creating a state of autoimmunity in the body.

Prompted by reports of associations between other neuroinflammatory diseases and Human Endogenous Retrovirus (HERV) expression, De Meirleir and his team looked for the same type of occurrence in ME/CFS patients. Specifically, they looked in tissue from duodenum biopsies - the duodenum is at the top of the small intestine.


What is being reported?

The paper reports that the Plasmacytoid dendritic cells (pDCs) of eight out of 12 ME/CFS patients studied were found to be immunoreactive to antibodies against HERV proteins. In contrast no immunoreactivity was found in any of the eight controls.

All patients met both the Canadian and Fukuda criteria and were found to have substantial disruption of gut microbiota. Samples were from surplus de-identified clinical biopsies from previous ME patients.

pDCs are part of the innate immune system. They circulate in the blood but occur mostly within the secondary lyphoid organs, which is why they are present in the gut. pDCs are antigen-presenting cells that have a stimulatory role within the immune system. This immunoreactivity to HERV proteins was found uniquely in these pDC cells only. Dendritic cells have the potential to mistakenly identify something as an antigen when they shouldn't, and this may be the cause of some autoimmunity.

HERVs are in our genome. We were born with them, and they are left over viral elements from ancient retroviruses that infected our ancestors' germ line cells millions of years ago and stayed there passively, being replicated and passed on to new generations. They are abundant in our genome (5-8% - Robert Belshaw et al, 2004), but most, probably all, are defective due to mutations and deletions that have occurred in our genome over the millennia. Unlike exogenous retroviruses such as HIV, HERVs are replication incompetent - so they're not a moving target. Our understanding of HERVS is still undergoing change, and there is some evidence that some of this DNA - once thought to be nothing more than junk – actually contributes to our existence by performing various useful tasks within us (J-L Blond et al, 2000). It is known that these HERV elements in our DNA can and do express proteins, though normally they do not provoke a significant immune reaction.

The study reports that proteins found in the ME samples reacted with monoclonal antibodies to HERV proteins and that the immunoreactive cells were pDCs.


What checks did they make?

Positively, having found that the ME patient duoednum tissue was reacting to these HERV antibodies, De Meirleir and his team went a step further and checked to see whether murine retroviral antibodies would also cross react with the tissue - something which should occur if HERV proteins were present - and the results were again positive.

Finally, the team carried out further checks to rule out non-specific reaction and also tested stomach tissue from the same patients and controls, all of which came back negative, as expected.

Now they made efforts to determine exactly which cell types were immunoreactive to the HERV protein antibodies. Via a series of further tests the team hoped to whittle down the potential cell types. First they managed to zoom in on the hematopoietic cell lineage and then further sharpened the result to identify the cells as pDCs. They then double checked via a secondary means to confirm the result.

Having identified that the cells were pDCs, next they counted them and compared that count to the healthy controls. The ME patients were found to have approximately 4.7 times as many pDCs as the controls. Of the pDCs in the duodenum samples from ME patients, approximately 44 percent were found to be reactive to the HERV proteins.

Furthermore, in order to confirm that this was definitely a reaction to identifiable HERV proteins, the team sequenced both the RNA derived from the biopsy samples and from purified pDCs and found matching sequences from known HERVs. Although at this point they cannot definitively rule out that the immunoreaction seen was a result of an infectious exogenous retrovirus, as opposed to a HERV, their identification of matching HERV sequences argues strongly against this possibility.


So the cause of ME/CFS might be autoimmunity to HERVs?

As De Meirleir and his team point out, this would be the first time that an association between pDCs and HERVs has been shown to cause disease, though proven autoimmune diseases such as Multiple Sclerosis and Rheumatoid Arthritis have already been linked with pDC abnormalities and HERV involvement (G Freimanis et al).

The discussion section of the paper suggests that a number of immunological measurements reported in ME/CFS patients in the past, by various groups, may be a result of HERV involvement in pDCs, because pDCs are known to produce a variety of other immunological cells in abundance, such as interferon alpha, which modulates Natural Killer cell (NK) function. Low NK cell function is often associated with ME/CFS (Whiteside TL et al, 1998).

A lot is still unknown about HERVs, but they have been increasingly linked with disease. A study looking at HIV found that HERV expressed peptides were higher in HIV positive patients compared to controls and that T cells responded to these peptides (K E Garrison et al). A pair of studies looking at EBV showed that it could potentially activate retroviral elements in our DNA (Sutkowski et al, 2004 and 1996) and it's possible that something similar could be going on here. Indeed the authors of this paper mention this previous finding and point out the long association between the disease and Herpes viruses, including De Meirleir's previous discovery of herpes viruses in the duodenum of patients with ME/CFS (De Meirleir et al, 2009).

For most of us, immune dysfunction is a hallmark of ME/CFS, and several papers have reported specific immune dysfunction in the disease, particularly in the gut, highlighting the important role that the gut plays in maintaining health. For example, changes in the gut flora can result in incorrect function of the gut mucosal barrier (Shaheen E Lakham et al, 2010). Without these components of the immune system in our gut being correct, we are exposed to increased infection and inflammation and it is thought that this inflammation may be an aggravating factor as there is some evidence of inflammation increasing HERV protein expression and autoimmunity (Lee YK et al, 2011).


What Next?

Replication. That’s what someone (we don’t know who yet) needs to do; someone has to replicate and confirm these findings in a bigger sample of patients. Or disprove them...

We know from experience that we mustn't get ahead of ourselves, and following replication comes more study because it would need to be confirmed that this was the cause of ME/CFS and not some knock-on effect unlinked to the pathogenesis of the disease, but if it checks out then we have a confirmed autoimmune disease and the certainty that goes with it.

We don’t understand autoimmune diseases that well yet, though this finding has the potential to revolutionize our understanding of autoimmunity. If confirmed then these findings could have repercussions for several other autoimmune diseases, particularly those with gastrointestinal dysfunction and neuroinflammation, such as MS, Lupus, and Crohn's, whose cause may follow the same or a similar model. That would be good for everyone. Once again it seems ME/CFS has become sexy, just like it was when the XMRV saga began. Let’s hope this works out better in the long run...

If this research stands up then we are in a great position, because we already understand quite a bit about where the problem is happening. The bad thing about HERVs is that they're immutable - they're in our DNA and we can't do much to change that. On the plus side, everyone has HERVs, so if they are linked with disease then it's important to get to the bottom of how and why, for everybody's sake.

Treatments for autoimmune diseases tend to be immune-modulating drugs to tone down the immune system's effect and limit damage, and initial ‘treatment’ may also involve reducing gut inflammation. The theory is that if you can cut inflammation then you should get less autoimmune reaction, though that alone would be unlikely to fix the problem.

It’s too early to talk about fixes - the first thing we need is for someone to confirm these findings...until then, hold fire...


A Reason to be Hopeful

If it works out then this discovery will be a breakthrough in understanding the cause and mechanisms of ME/CFS. With that reality will come greater recognition, greater funding, greater focus, and ultimately – in the long run – treatments!

Of course none of this will happen overnight, we still have some way to go, but it could mean the beginning of the end, and we have waited for the end to this illness for so long. We deserve this to work out. Don’t we?

But you don’t always get what you deserve. Only time will tell if we remember Wednesday 20th February 2013 as a significant milestone on the long journey we are on to get to the bottom of this illness.



Joel was diagnosed with ME/CFS in 2009 but struggled with the illness for some time prior to this. He loves to write, and hopes to regain enough health to return to the career he loved and have his novels published.



REFERENCES

De Meirleir et al. 2013. Plasmacytoid Dendritic Cells in the Duodenum of Individuals Diagnosed with Myalgic Encephalomyelitis Are Uniquely Immunoreactive to Antibodies to Human Endogenous Retroviral Proteins. 2013.

Robert Belshaw et al. Long-term reinfection of the human genome by endogenous retroviruses. 2004

Jean-Luc Blond et al. An Envelope Glycoprotein of the Human Endogenous Retrovirus HERV-W Is Expressed in the Human Placenta and Fuses Cells Expressing the Type D Mammalian Retrovirus Receptor. 2000.

Sutkowski N et al. Epstein-Barr Virus latent membrane protein LMP-2A is sufficient for transactivation of the Human Endogenous Retrovirus HERV-K18 superantigen. Journal of Virology. 2004.

G Freimanis et al. A role for human endogenous retrovirus-K (HML-2) in rheumatoid arthritis: investigating mechanisms of pathogenesis. 2010.

Whiteside TL et al. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. 1998.

K E Garrison et al. T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection. 2007.

Sutkowski N et al. Virus-encoded superantigens. Microbiological Reviews. 1996.

De Meirleir et al. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. 2009.

Shaheen E Lakhan et al. Gut inflammation in chronic fatigue syndrome. 2010.

Lee YK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. 2011.






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Hello to everybody,

As many of you, I'm trying to fully understand the mechanism proposed in the recent publish paper from KDM et al.

I've read all your comments and reports, and they are great, but they seem not to address a few issues that for me, are the most important things to understand. So, I am going to write down the questions that I am not able to solve, with the target of being able to explain in very simple words the proposed mechanism, mainly for the Spanish CFS community, who mostly does not manage in English, and are eager to know what is all this about.

The whole study is very well summarized here:

http://phoenixrising.me/archives/16017

(thank you Joel for the great article!)

Questions:


My goal is to complete /correct the following sketch:
http://www.sfc-em-investigacion.com/download/file.php?id=236&mode=view
(it's just an ugly-fast made drawing I made while reading the article and researching, but it'll be "nicer" when finished! :)

pDCells express HERVs genome, transcribing HERVs' proteins (gag and env). They don't say, but I assume that they go to the cytoplasm after being transcribed, where they may act as superantigents, that after being processed by phagocytosis will create the HLA-DR (MHC II) membrane receptor, that distinguishes the Antigen Presenting Cells from the rest (APCs). But this process is carried out in an abnormal way, so that the Lymphocytes T that stick onto these receptors in order to be activated, and thus are"told" what antigen to attack, are improperly and non-specifically activated. A lot of lymphocytes are activated by this way, then they activate in turn lymphocytes B that will synthesize antibodies against HERVs's proteins.


2- Where do these antibodies go?:

a- To the cell membrane of the pDCs? If so, do they die, or are just wrecked as a response, b/c the lymphocytes attacking those antibodies are not efficient due to the "non-especific activation"? The immunohistochemical assay shows that only pDCs shown reactivity against HERV proteins, so the only way this can happen (that I know), is if in their membrane, they express antibodies against HERV proteins. To my knowledge, this may happen independently of whether gaga and env proteins are only inside the cell or also in the serum.

b- To the HERV proteins, provided they go out of the cell. Do they? this is important in the sense that these proteins could travel throughout the whole body, so, they could be attacked in any place, explaining a systemic immune activation: systemic inflammation, coming from the gut! (this is the main idea...).

c- To ANY free protein in serum or inside cells that resembles the HERVs' proteins. This is the basis of molecular mimicry, and this is actually the way that it's proposed for the origin of autoimmunity, that is, lymphocytes and other members of the acquired response would attacked self proteins or self cells, in ANY part of the body.
Moreover, if we have a bunch of Lymphocytes "trained" to attack ANYTHING with antobodies against HERVs' proteins, they would attack ANY cell expressing these proteins...

So, in short, based on the above, this is my main question:

Where do the antibodies against HERVs' proteins go?, and what would be the exact process by which they are responsible for the autoimmunity? (Some of the possibilities I have listed above? A combination?)

2- Last question: they explain that the humoral response (Th2) against the HERVs' proteins leads to autoimmunity through molecular mimicry. Ok, the process I have described, if I have got it correctly would be exactly this, what would explain a shift of Th1 to Th2. So then, we would have two pathways that could cause symptomatology:

- Deffective Th1 response b/c of improperly activated lymphocytes T, and

- Excess Th2 response by the process I've explained of molecular mimicry involving antibodies anti- HERV proteins, and directly by the effect of dysrupted pDCs: low NKs, inflamation, etc.

So, the last quesion: What are the mechanism that wrecks the normal function of pDCs in the first place? I have assumed there may be two ways: 1- the improper Antigen Presentation process and 2- the attack of pDCs by lymphocytes.

I would really appreciate if any of you could help me with all this questions. More than one brain think better than only one (especially if layman and brain fogged!).

I, of course, do not have the knowledge to understand all this on my own, and would like to apologize beforehand for taking the risk of trying to understand things that are beyond my knowledge (that's why I'm asking to more expert people).

Thanks in advance for your insights!
Sergio
 
Hello everyone. I brought this up before: ok, viruses, but so many of kdm's patients are testing positive for borrelia. This is not a virus. It's the result of a tick.

How does this connect to all this?

Or is it that we all have borrelia from time immemorial and our immune system keeps it down, and when sick with CFS-me, the latent infection surfaces.

I am having some difficulty with this, particularly having seen folks with true Lyme.
 
Thanks Mya, glad you liked it.
Good questions!
1. In short; yes. But, we dont know exactly what is happening here yet. If something is not right with the pDCs then that will affect a lot of the other immune cells in consequnce.
2. Maybe. It would explain a lot wouldn't it.
3. Um. HIV immunity isn't my area of knowledge - however, I am aware that people with HIV have higher HERV proteins, and researchers are wondering if they can use this as a means of targeting HIV. The problem with HIV (well not the only problem, obviously...) is that it mutates so rapidly so therapys to kill it dont work. The hope is the they may be able to target HIV via the HERV proteins. I dont know the specifics of that, but I read something along those lines.

To elaborate more on your question - I wonder (and this is speculation) whether HERVs in our genome is not really a random accident, but rather some kind of positive mechanism to pass on information on viruses to the next generation, to help with immunity.

Thank you for taking the time to answer my questions.
 
Hello everyone. I brought this up before: ok, viruses, but so many of kdm's patients are testing positive for borrelia. This is not a virus. It's the result of a tick.

How does this connect to all this?

Or is it that we all have borrelia from time immemorial and our immune system keeps it down, and when sick with CFS-me, the latent infection surfaces.

I am having some difficulty with this, particularly having seen folks with true Lyme.

Helene - I've tested negative for Borrelia via KdM - dont know what the actual %age of his patients test positive.
 
Helene - I've tested negative for Borrelia via KdM - dont know what the actual %age of his patients test positive.
Good morning to you all,
Well, I was tested at igenex, and neuroscience and these were inconclusive. KDM tested and I was negative ( twice). He suggested infectolabs, and it came out positive. I know of several other folks in this category.
 
Good morning to you all,
Well, I was tested at igenex, and neuroscience and these were inconclusive. KDM tested and I was negative ( twice). He suggested infectolabs, and it came out positive. I know of several other folks in this category.

Thanks very interesting - seems that some lab testing is a waste of time then? Were your first tests with KdM done at Redlabs?
 
I
I wonder how to reconcile those older abstracts with the reports in the past two years about levamisole causing increased autoimmune skin diseases when it was used as an adjuvant in cocaine. They seem to be contradictory.

http://medicine.ucsf.edu/news/fom/frontiers.html?key=5

Either way, levamisole sure sounds like nasty stuff. I'd like a way to reduce autoantibodies but wouldn't touch this stuff with a ten foot pole!

Thanks for the links!
 
Thanks very interesting - seems that some lab testing is a waste of time then? Were your first tests with KdM done at Redlabs?
Hi,
In 2009 dec. I was tested at igenex. On the basis of that a couple of doctor's suggested possibility of Lyme, but the tests were inconclusive really. Then in 2011 and 2012 I was tested at redlabs, and the tests were negative. KDM suggested the lab in Germany. These tests were done relatively recently, and they came out positive with an active infection. I present as classic CFS.

I really do not know how to put all this together. Several KDM patients who were classified as ME are now positive for borrelia and/or other associated confections.

If anyone can shed any light, please do
 
Hello everyone. I brought this up before: ok, viruses, but so many of kdm's patients are testing positive for borrelia. This is not a virus. It's the result of a tick.

How does this connect to all this?

Or is it that we all have borrelia from time immemorial and our immune system keeps it down, and when sick with CFS-me, the latent infection surfaces.

I am having some difficulty with this, particularly having seen folks with true Lyme.

Hi Helene,
There is a lot we don't know yet, but I find it very interesting that plenty of people test positive for Lyme, often patients are very surprised, often they have had negative results previously.
I have lots of thoughts on Lyme and Borrelia and am going to be covering it in my next Zoonotics article (here is the intro to that series). There is a lot to talk about there and plenty of research papers for me to read through first.
It is not impossible for Lyme/Borrelia to be a cause or a component of ME/CFS. We have not done enough to rule it out yet, though we have taken some steps on that road, which is good. On the other hand some people may have Lyme, but think that they have ME/CFS. Everyone should be tested in my view. How much and what tests is still something I am researching. Finally, there is no rule to say that someone with ME/CFS cannot have Lyme/Borrelia as a coinfection, even if it is not a cause of their ME/CFS, and given the immune disfunction in ME/CFS that may be a reason why some people cant get over Lyme even when treated.

Similar story with other infections like Bartonella, Babesia etc.
 
Hi,
In 2009 dec. I was tested at igenex. On the basis of that a couple of doctor's suggested possibility of Lyme, but the tests were inconclusive really. Then in 2011 and 2012 I was tested at redlabs, and the tests were negative. KDM suggested the lab in Germany. These tests were done relatively recently, and they came out positive with an active infection. I present as classic CFS.

I really do not know how to put all this together. Several KDM patients who were classified as ME are now positive for borrelia and/or other associated confections.

If anyone can shed any light, please do

Helene, may I ask did you do the western blot igg and igm at Infectolab or the Ltt elispot, or perhaps both? I did the ltt elispot at infectolab which came out negative. Don't know whether should do the western blot too to be sure, just more money to pay out...
 
For example, changes in the gut flora can result in incorrect function of the gut mucosal barrier (Shaheen E Lakham et al, 2010). Without these components of the immune system in our gut being correct, we are exposed to increased infection and inflammation and it is thought that this inflammation may be an aggravating factor as there is some evidence of inflammation increasing HERV protein expression and autoimmunity (Lee YK et al, 2011).

Is this suggesting that if the changes in the gut flora are corrected (I take it gut flora changes means too much bad bacteria?) this could bring benefit/resolve the subsequent immune problems? is this why some find correcting gut helpful? is it suggested that gut treatments are important?

Leachim shared above that 'De Meirleir's model of the disease process starts with disruptions in the gut flora causing an array of immune dysfunction'. Does KDM believe then if the gut is treated at the start of the illness the downstream processes can be stopped and these few patients if caught early enough can make good recoveries? I know of one young woman who hadn't been ill for long, saw kdm, followed his gut treatments and made a full recovery. Dont know whether it lasted. Know others ill longer, saw KDM, did his gut treatments with little to no benefit.
 
Hi Forebearance, I should have gone over this in the article really, sorry.
What they did was Immunohistochemistry. You can read about that here on wikipedia. They apply a solution of antibodies (in this case HERV antibodies) to the tissue and they have been conjugated with enzymes that show up a color if there is a reaction (if the antibodies find the expected antigen that they are looking for (in this case HERVs). You can see in the actual paper the photographs of the tissue with colored cells where it has reacted (pages 4, 5 and 6).

The vaccine link is an interesting one. Not sure but its potentially possible. Its widely accepted (i think) that we do have antibodies to various animal tissue in our bodies as a result of medications and vaccines developed using animals. Doesn't get talked about much for some reason. I always thought it was quite remarkable!

Thanks, snowathlete!
 
Is this suggesting that if the changes in the gut flora are corrected (I take it gut flora changes means too much bad bacteria?) this could bring benefit/resolve the subsequent immune problems? is this why some find correcting gut helpful? is it suggested that gut treatments are important?

Leachim shared above that 'De Meirleir's model of the disease process starts with disruptions in the gut flora causing an array of immune dysfunction'. Does KDM believe then if the gut is treated at the start of the illness the downstream processes can be stopped and these few patients if caught early enough can make good recoveries? I know of one young woman who hadn't been ill for long, saw kdm, followed his gut treatments and made a full recovery. Dont know whether it lasted. Know others ill longer, saw KDM, did his gut treatments with little to no benefit.

Yes bad bacteria, but also potentially other pathogens and toxins. There are other people on here with more experience of the gut than me. My own gut is generally good. It was bad at first then got better and the last month has been a little off again, but not as bad as before. I am waiting on test results though as I am told that your gut can be a mess even if you dont get lots of symptoms, so maybe mine is a mess. Dont know yet.
I think the paper is suggesting that the better state you can get your gut in so that it is functioning well and with the minimum of inflammation then the lower your expression of HERV proteins. HERVs aside, as you say, some people have had improvement by getting their gut right so worth trying in that area I think. Like you say though, some people still have problems even if they improve that area. I think as a general rule the longer your illness the worse your chances, but thats just my personal view. I may be wrong about that.
In the case of HERV expression, I dont know if fixing your gut would stop HERV expression altogether, and resolve the immune problem(s), but I think this paper, and other papers talking about HERVs, are saying that you should have less of a problem at least.
I'm going to be paying close attention to my gut test results and trying to improve there in any way I can.
 
Helene, may I ask did you do the western blot igg and igm at Infectolab or the Ltt elispot, or perhaps both? I did the ltt elispot at infectolab which came out negative. Don't know whether should do the western blot too to be sure, just more money to pay out...


Yes, they are very very expensive. I suggest you write to them and ask just what you asked me. That is, can there still be a positive with the other tests.

I did the whole set for borrelia, as well as two other infections.
 
Is this suggesting that if the changes in the gut flora are corrected (I take it gut flora changes means too much bad bacteria?) this could bring benefit/resolve the subsequent immune problems? is this why some find correcting gut helpful? is it suggested that gut treatments are important?

Leachim shared above that 'De Meirleir's model of the disease process starts with disruptions in the gut flora causing an array of immune dysfunction'. Does KDM believe then if the gut is treated at the start of the illness the downstream processes can be stopped and these few patients if caught early enough can make good recoveries? I know of one young woman who hadn't been ill for long, saw kdm, followed his gut treatments and made a full recovery. Dont know whether it lasted. Know others ill longer, saw KDM, did his gut treatments with little to no benefit.


But what does KDM give for the gut. Arabinogalactan. Daosin. And of course, antibiotics to kill of bad bacteria.

I have been interested in fecal transplants for this reason you all site regarding the gut. Dr. Broody in Australia has had some success with CFS using fecal transplants.

Two Canadian doctors have just invented synthetic feces for fecal transplants and this will be extraordinary. But it is. It widely available. And only to Canadians, and only for reclctrant cdifficile.

Fixing the gut is hard, I have found, and probiotics have not really lived up to expectations, at least the ones readily available.
 
The question that comes to my mind is WHY - we all have HERVs, so why do some people react to them and not others. This is similar to EBV - most people have EBV, so why do some people have reactivations and not others. So this is just another symptom.

Also very small study, and still needs to be replicated.

Not impressed at this time. (Although well written article!)
 
But what does KDM give for the gut. Arabinogalactan. Daosin. And of course, antibiotics to kill of bad bacteria....
Fixing the gut is hard, I have found, and probiotics have not really lived up to expectations, at least the ones readily available.

He also gives other things to individual patients depending on tests.

Best,
Sushi