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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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Wow Joel, you are on top of everything! Thank you for keeping us updated. ;)

Is curious because i've spent the whole day researching for autoinmune syndromes, because i just got tested for that. That was the only test that my infectologist allowed me to run, based on my symptoms.

Anyway, every night before going to bed i pray to God to give the scientifics and the doctors, the wisdom to find the true about this disease and the right treatment. No one deserves this. Articles like yours gives me some hope though.
 
Re "autoimmune" : how does the very obvious fact(in my cohort anyway) that CFS/ME is Contagious , fit into the HERV implicated theory? I was fine until I was exposed to someone else's really powerful and bad HERV? Because I was just great until that event, after which my life went to hell. So there's an extremely virile contagious HERV out there? and where did it come from? indigenous somewhere? or what. Thanks.
 
Very interesting article. Thank you. I am wondering a couple things after reading this. 1st, do these antibodies to HERV's have any connection to the strange B-Cell blood test results some of us have (a lot of immature B-Cells and too low a number of mature B-Cells)? 2nd, are these antibodies responsible for some of the confusion with the Mikovitz, Lombardi etc. XMRV studies. Did they mistake these antibodies for a current unknown retroviral infection (in this case XMRV)? Finally, and this is far fetched, is it possible that a person who has many antibodies to several different types and fragments of HERV's could be immune to HIV (as in the immune system would recognize the virus as an infectious retrovirus before it had time to hide and replicate)?
 
Re "autoimmune" : how does the very obvious fact(in my cohort anyway) that CFS/ME is Contagious , fit into the HERV implicated theory? I was fine until I was exposed to someone else's really powerful and bad HERV? Because I was just great until that event, after which my life went to hell. So there's an extremely virile contagious HERV out there? and where did it come from? indigenous somewhere? or what. Thanks.

Autoimmune disease is likely to be triggered in some cases by viruses - such as Coxsackie B being implicated in Type I Diabetes. It's a matter of correlation thus far (more type I diabetics than non-diabetics have had the virus), but it's pretty suggestive.
 
THanks for the article; lymph is also a connective tissue so it may be just part of the picture where all connective tissue is affected- including the gut... hence immune system involvement.
There are some who think it is a genetiic condition, so in addition to ymphatic involvement the blood vesssels are also defective and do not constrict adequately to return blood to the brain and heart..
see this link for more

http://forums.phoenixrising.me/index.php?threads/is-me-due-to-ehelrs-danlos-syndrome-stretchy-veins.20351/#post-310872
 
Re "autoimmune" : how does the very obvious fact(in my cohort anyway) that CFS/ME is Contagious , fit into the HERV implicated theory? I was fine until I was exposed to someone else's really powerful and bad HERV? Because I was just great until that event, after which my life went to hell. So there's an extremely virile contagious HERV out there? and where did it come from? indigenous somewhere? or what. Thanks.

Well 5150, this research provides another piece of the puzzle, and providing more reasons
1) for governments to fund research for ME,
2) for researchers especially in virology and immunology, to be interested in researching us and push a bit further
3) for physicians to get interested in our disease this much more
4) for patients to be willing to give a piece of their duodenum for research!!!! :)
 
2nd, are these antibodies responsible for some of the confusion with the Mikovitz, Lombardi etc. XMRV studies. Did they mistake these antibodies for a current unknown retroviral infection (in this case XMRV)?

8 out of 12 is 67% if I am not mistaken. Same procent as the Lombardi study. Makes me wonder.

The authers say they can not exclude an exogenous retro.

Not the Silverman XMRV but maybe another exogenous.

Anyway retro's are back in the picture and there is a lot of work to do to solve the mistery.
 
Re "autoimmune" : how does the very obvious fact(in my cohort anyway) that CFS/ME is Contagious , fit into the HERV implicated theory? I was fine until I was exposed to someone else's really powerful and bad HERV? Because I was just great until that event, after which my life went to hell. So there's an extremely virile contagious HERV out there? and where did it come from? indigenous somewhere? or what. Thanks.


HERVs can be activated by another infection.
 
Its sad thou that govs will probably need to see a big part of the ME puzzle before they ever will get serious with funding it. But while its all in the too hard basket.. they dont want to fund.

...

There are some who think it is a genetiic condition

I think this discovery would explain the genetic link too.. as after all we are inheriting that so call junk "HERV" DNA from our parents so would have similar DNA.

Re "autoimmune" : how does the very obvious fact(in my cohort anyway) that CFS/ME is Contagious

Sounds like we may be giving others our secondary co-existing viruses we pick up due to having this.. which in turn could go and actiivate this HERV issue in them too. So an interplay happening between HERV and other viral things be in EBV or whatever.

I suspect I carry some reacitiving viral things and have issues with what appears to be herpes inside my mouth at times. (I wouldnt be surprised if I have reactiving EBV happening too). Im also carry antibodies to CMV and toxoplasmosis.. so I wouldnt doubt I have reactiving stuff which could trigger something off in others and make them vulerable to the HERV stuff.
 
8 out of 12 is 67% if I am not mistaken. Same procent as the Lombardi study. Makes me wonder.

The authers say they can not exclude an exogenous retro.

Not the Silverman XMRV but maybe another exogenous.

Anyway retro's are back in the picture and there is a lot of work to do to solve the mistery.

These current results also might explain the prior XMRV results that weren't replicated. The impression I got is that the current results, if indicating an immune reaction to an HERV protein, could explain a false positive showing up for XMRV due to the cross-reactivity. WPI's involvement therefore might have been based on their previous findings being wrong, but then looking at how those false positives could have been produced.
 
Wow Joel, you are on top of everything! Thank you for keeping us updated. ;)

Is curious because i've spent the whole day researching for autoinmune syndromes, because i just got tested for that. That was the only test that my infectologist allowed me to run, based on my symptoms.

Anyway, every night before going to bed i pray to God to give the scientifics and the doctors, the wisdom to find the true about this disease and the right treatment. No one deserves this. Articles like yours gives me some hope though.

You're welcome. I'm glad you liked it. I'm keeping an eye on your thread about your autoimmune results - very interesting. I wonder how many of us have undergone similar tests?