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

by Joel (Snowathlete)

Plasmacytoid dendritic cell interacting with a T-cell.

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.

 

'I was completely lost and in the dark before I found this website. I can never express what this place means to me.' Phoenix Rising forum member

 

{ 95 comments… add one }

  • Sherezade February 20, 2013, 10:01 pm

    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.

  • alex3619 February 20, 2013, 10:18 pm
  • 5150 February 20, 2013, 11:38 pm

    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.

  • Mya Symons February 20, 2013, 11:51 pm

    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)?

  • Valentijn February 21, 2013, 12:44 am
    5150

    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.

  • Valentijn February 21, 2013, 12:45 am

    Great article, snowathlete – going to link to it so my friends and family have something more comprehensible than the actual research paper to read 😀

  • Allyson February 21, 2013, 1:28 am

    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

  • Kati February 21, 2013, 1:30 am
    5150

    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!!!! :-)

  • lansbergen February 21, 2013, 3:45 am
    Mya Symons

    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.

  • lansbergen February 21, 2013, 3:47 am
    5150

    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.

  • ana_bxl February 21, 2013, 3:58 am

    Joel………..THANKS A LOT for explaining it to us in "normal language" :O) THANKS,THANKS A LOT!

  • taniaaust1 February 21, 2013, 4:00 am

    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.

  • taniaaust1 February 21, 2013, 4:02 am

    Oh and thanks Joel.

    I didnt think I'd ever see anyone write a medical article as well as Cort does, when it comes to bridging things and making the medical stuff more easy to understand. You've just filled a big gap ive had with this site since Cort left.

  • Valentijn February 21, 2013, 4:42 am
    lansbergen

    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.

  • lansbergen February 21, 2013, 5:38 am
    Valentijn

    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.

    Yep

  • Gijs February 21, 2013, 5:44 am

    i think this finding is the result of the autonomic overdrive i.e. abnormal stressrespons started by (nor) adrenaline. This finding does not fit in a causal model.

  • lansbergen February 21, 2013, 6:09 am
    Gijs

    i think this finding is the result of the autonomic overdrive i.e. abnormal stressrespons started by (nor) adrenaline. This finding does not fit in a causal model.

    I disagree

  • beaverfury February 21, 2013, 6:30 am

    Is it true to say all autoimmune conditions can only be managed, and not cured?

  • snowathlete February 21, 2013, 6:34 am
    Sherezade

    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?

  • Gijs February 21, 2013, 6:38 am

    In addition, I think that researchers like Lombardi and the WPI after the XMRV debacle not be taken seriously. I hope for those researchers that at least the research is carried out professionally this time. This model (HERV) does not explain the symptoms and findings by other researchers. How and what is infected in de nervous system that explains the chronic overstimulated autonomic part or the abnormal stressrespons by (HERV). It makes no sense. I am not so optimistic. It is one of the many abnormalities.

  • snowathlete February 21, 2013, 7:01 am
    Mya Symons

    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)?

    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.

  • lansbergen February 21, 2013, 7:04 am
    Gijs

    . This model (HERV) does not explain the symptoms and findings by other researchers. How and what is infected in de nervous system that explains the chronic overstimulated autonomic part or the abnormal stressrespons by (HERV). It makes no sense. I am not so optimistic. It is one of the many abnormalities.

    It fits my hypothese and can be caused by the pathogen I always suppected. Still no test for that pathogen for living patients.

    For the record that is not herpes.

  • lansbergen February 21, 2013, 7:11 am
    beaverfury

    Is it true to say all autoimmune conditions can only be managed, and not cured?

    Levemisole decreases autoantibodies in several diseases .

    I think if the causing pathogen can be eliminated the disease will vanish.

  • Gijs February 21, 2013, 7:41 am

    I know it is not herpes. But this researchers suggest that herpes 4 and 6 can be an important modulator of HERV-k18. Quote: ''Dr. Bridget Huber showed that HERV-K18 expression could be induced by herpes viruses such as Epstein-Barr virus and human herpes virus 6 (HHV-6) (34,61). Consistent with that work and with the data presented here, both of these viruses have been observed in the duodenum of individuals with ME (62)''. This is not correct according to recent research done by Komaroff et. al. Clin Infect Dis. 2013 Feb 13. [Epub ahead of print]
    Human Endogenous Retrovirus-K18 Superantigen Expression and Human Herpesvirus-6 and Human Herpesvirus-7 Viral Loads in Chronic Fatigue Patients.
    Oakes B, Hoagland-Henefield M, Komaroff AL, Erickson JL, Huber BT.

  • snowathlete February 21, 2013, 7:54 am
    Valentijn

    Great article, snowathlete – going to link to it so my friends and family have something more comprehensible than the actual research paper to read 😀

    Thanks Val. Glad you liked it, and good idea telling friends and family. Most don't have time to read the whole paper and digest it, but it's worth them hearing about.

    ana_bxl

    Joel………..THANKS A LOT for explaining it to us in "normal language" :O) THANKS,THANKS A LOT!

    You're more than welcome ana!

    taniaaust1

    Oh and thanks Joel.

    I didnt think I'd ever see anyone write a medical article as well as Cort does, when it comes to bridging things and making the medical stuff more easy to understand. You've just filled a big gap ive had with this site since Cort left.

    Thanks tania. Those are big shoes to fill, so if I'm filling them, even in part, then that's praise indeed!

  • snowathlete February 21, 2013, 8:05 am
    Gijs

    I know it is not herpes. But this researchers suggest that herpes 4 and 6 can be an important modulator of HERV-k18. Quote: ''Dr. Bridget Huber showed that HERV-K18 expression could be induced by herpes viruses such as Epstein-Barr virus and human herpes virus 6 (HHV-6) (34,61). Consistent with that work and with the data presented here, both of these viruses have been observed in the duodenum of individuals with ME (62)''. This is not correct according to recent research done by Komaroff et. al. Clin Infect Dis. 2013 Feb 13. [Epub ahead of print]
    Human Endogenous Retrovirus-K18 Superantigen Expression and Human Herpesvirus-6 and Human Herpesvirus-7 Viral Loads in Chronic Fatigue Patients.
    Oakes B, Hoagland-Henefield M, Komaroff AL, Erickson JL, Huber BT.

    The Komaroff study was only looking at HERV-18 though, and only in the blood and saliva. It doesn't rule out other HERVs and it doesn't rule out the problem being in the gut – specifically the duodenum. It also didnt look for EBV (HHV-4), which surprised me – given the previous studies, why not look for that too?

  • Gijs February 21, 2013, 8:18 am

    The findings of Kenny et. al. are not specific to ME. These are also found in other diseases. This study again showed no breakthrough.

  • acer2000 February 21, 2013, 11:31 am

    Maybe I'm missing something here. This is an interesting finding suggesting that HERVs may be present/activated in some people with symptoms of ME. But what does it have to do with auto-immunity?

  • snowathlete February 21, 2013, 11:57 am
    beaverfury

    Is it true to say all autoimmune conditions can only be managed, and not cured?

    Existing treatments tend to be about management and limiting damage by supressing the immune system. There are new treatments being developed for autoimmune diseases though that show promise. Here is an interesting article about just one of the many things that people are trying out in MS. This could work as a cure, in theory, though it is early days.

    It still is not well understood what triggers autoimmunity in the first place. If we understood that then we would be able to develop better treatments and maybe even cures, as well as preventative measures. One theory is that HERVs are involved and there is growing evidence for this. But it is complicated further because even if that is right, you then have to answer the question of what triggered the problem with the HERVs? One theory is that viruses might be that trigger, and some evidence has already been collected to show that EBV could be one such virus. The good thing is that depending on the actual mechanism, one finding in any one autoimmune disease could have positive implications for understanding other autoimmune diseases.

    Having an autoimmune disease would not be great, but it is better than having an autoimmune disease (or any other type of disease for that matter) and not knowing it, the illness being misunderstood and neglected etc.

  • Valentijn February 21, 2013, 12:25 pm
    acer2000

    Maybe I'm missing something here. This is an interesting finding suggesting that HERVs may be present/activated in some people with symptoms of ME. But what does it have to do with auto-immunity?

    HERVs are present in everyone … it's part of the human DNA. The issue is that we seem to have an immune reaction to a protein produced by HERVs. Since it's part of our DNA, reacting to it would be auto-immune.

  • Ema February 21, 2013, 12:40 pm
    beaverfury

    Is it true to say all autoimmune conditions can only be managed, and not cured?

    There is some (limited) evidence and ongoing studies using IgG therapy to reverse autoimmune conditions. Many of the people I know on Hizentra (sub Q IgG) have had substantial reductions in the number of autoantibodies present.

    The doses used are generally higher than for IgG replacement therapy. And of course, since it is not FDA approved for this purpose, generally impossible to get from a financial standpoint unless you have a concurrent primary immunodeficiency disease (which is not out of the realm of possibility for many of us). I was luckily able to qualify for Hizentra through their patient assistance program.

    Ema

  • Legolas February 21, 2013, 12:48 pm
    acer2000

    Maybe I'm missing something here. This is an interesting finding suggesting that HERVs may be present/activated in some people with symptoms of ME. But what does it have to do with auto-immunity?

    I gonna quote from the article;

    HERV proteins and serum antibodies against HERV's have been associated with a number of autoimmune diseases, including MS and SLE.
    … it is widely believed that the humoral immune response against HERV proteins leads to autoimmunity through a process of molecular mimicry. HERV proteins are known to act as superantigens.

    So the antibodies that you make to attack HERV proteins also (accidently) attack other cells/parts in the body.
    At least, this is how is see it.

  • Leachim February 21, 2013, 1:14 pm

    Thank you, Joel, for a very well written article!

    As a comment to some of the comments: From what I know from different sources De Meirleir (I'm a patient of his) doesn't think this autoimmune reaction is the cause of ME, rather one of the later consequences of the disease process, the cause of disabling symptoms though, and probably also a factor in upholding the web of interacting pathological processes. De Meirleir's model of the disease process starts with disruptions in the gut flora causing an array of immune dysfunctions, and I suppose the autoimmunity should be one of the consequences of some parts of the immune system being hyperactive (parts of the innate immune system and Th2/the b-cells).

  • Gijs February 21, 2013, 1:32 pm
    Leachim

    Thank you, Joel, for a very well written article!

    As a comment to some of the comments: From what I know from different sources De Meirleir (I'm a patient of his) doesn't think this autoimmune reaction is the cause of ME, rather one of the later consequences of the disease process, the cause of disabling symptoms though, and probably also a factor in upholding the web of interacting pathological processes. De Meirleir's model of the disease process starts with disruptions in the gut flora causing an array of immune dysfunctions, and I suppose the autoimmunity should be one of the consequences of some parts of the immune system being hyperactive (parts of the innate immune system and Th2/the b-cells).

    The immune system is hyperactive because the stressrepons or autonomic nervous system is hyperactive; (nor) adrenaline-cortisol-immune system etc… the problem is in the CNS. NOT DUE TO PSYCHOSOCIAL STRESS BUT BECAUSE THE SYSTEM IS BROKEN.

  • Forebearance February 21, 2013, 2:37 pm

    I don't understand what this means:
    "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. "

    What does it mean to be immunoreactive to antibodies against HERV proteins?
    Can someone put it into plainer English for me?
    Thank you!!!

    Also, I wonder how this study would relate to Dr. Jamie Deckoff-Jones' theory that we are getting retrovirus fragments from vaccines which are completing or activating HERVs. Apologies to her if I'm not stating her theory correctly.

  • snowathlete February 21, 2013, 3:38 pm
    Forebearance

    I don't understand what this means:
    "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. "

    What does it mean to be immunoreactive to antibodies against HERV proteins?
    Can someone put it into plainer English for me?
    Thank you!!!

    Also, I wonder how this study would relate to Dr. Jamie Deckoff-Jones' theory that we are getting retrovirus fragments from vaccines which are completing or activating HERVs. Apologies to her if I'm not stating her theory correctly.

    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!

  • Sushi February 21, 2013, 3:53 pm
    snowathlete

    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!

    I can't add to the scientific discussion but just want to thank Joel for writing this article. It is very helpful when you put it along side the published article. So Thanks! :thumbsup:

    Sushi

  • liquid sky February 21, 2013, 6:07 pm
    lansbergen

    Levemisole decreases autoantibodies in several diseases .

    I think if the causing pathogen can be eliminated the disease will vanish.

    Where can you obtain Levamisole, lansbergen? I know it is used to treat worms in animals, but I have not been able to find it anywhere.

  • serg1942 February 21, 2013, 6:39 pm

    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

    PS. I'm a CFS patient myself, student of medicine, vice-president of a National spanish association of people affected by mercury from amalgam fillings (including many PWCFS), and collaborator with many ME/CFS associations and institutions.

  • Ema February 21, 2013, 6:52 pm
    lansbergen

    Levemisole decreases autoantibodies in several diseases .

    I think if the causing pathogen can be eliminated the disease will vanish.

    Are you sure levamisole decreases autoantibodies? I thought it was the opposite.

    Ema

  • serg1942 February 21, 2013, 6:55 pm

    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

  • perrier February 21, 2013, 9:00 pm

    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.

  • lansbergen February 22, 2013, 3:31 am
  • Mya Symons February 22, 2013, 3:34 am
    snowathlete

    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.

  • maryb February 22, 2013, 5:04 am
    Helene

    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.

  • perrier February 22, 2013, 7:57 am
    maryb

    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.

  • maryb February 22, 2013, 8:19 am
    Helene

    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?

  • Ema February 22, 2013, 9:21 am

    I

    lansbergen

    Some links

    http://www.ncbi.nlm.nih.gov/pubmed/21621152

    http://www.ncbi.nlm.nih.gov/pubmed/447410

    http://www.ncbi.nlm.nih.gov/pubmed/366145

    http://www.ncbi.nlm.nih.gov/pubmed/7913970

    more links

    http://www.ncbi.nlm.nih.gov/pubmed/21497280

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541217/

    http://www.ncbi.nlm.nih.gov/pubmed/71868

    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!

  • lansbergen February 22, 2013, 9:34 am
    Ema

    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.!

    Low dosis and high dosis have opposite effects.

  • perrier February 22, 2013, 10:39 am
    maryb

    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