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Autoimmune disease: A role for new anti-viral therapies?

Discussion in 'Other Health News and Research' started by Bob, Jul 24, 2012.

  1. Bob

    Bob

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    This is not a new research paper. It was published in August 2011, but it's fascinating.
    Credit goes to 'XMRV Global Action' for posting it on their twitter stream.

    I didn't know which sub-forum to post this under, because although it doesn't actually mention ME/CFS, it could almost have been written specifically for ME/CFS. It mentions: autoimmunity; treatment of autoimmune conditions with anti-retrovirals; Rituximab; B-cells; viruses hiding in B-cells; expression of human endogenous retroviruses (HERVs); EBV; B-cells expressing HERVs; and Memory B cells being the reservoir of infection of EBV. Basically, it seems to bring almost all of our current research into ME under a single research paper!


    Autoimmune disease: A role for new anti-viral therapies?
    David H. Dreyfus
    Pediatrics, Yale University School of Medicine, New Haven, CT, United States.
    Received 17 July 2011. Accepted 11 August 2011. Available online 18 August 2011.

    Abstract
    Many chronic human diseases may have an underlying autoimmune mechanism. In this review, the author presents a case of autoimmune CIU (chronic idiopathic urticaria) in stable remission after therapy with a retroviral integrase inhibitor, raltegravir (Isentress). Previous reports located using the search terms "autoimmunity" and "anti-viral" and related topics in the pubmed data-base are reviewed suggesting that novel anti-viral agents such as retroviral integrase inhibitors, gene silencing therapies and eventually vaccines may provide new options for anti-viral therapy of autoimmune diseases. Cited epidemiologic and experimental evidence suggests that increased replication of epigenomic viral pathogens such as Epstein-Barr Virus (EBV) in chronic human autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus Erythematosus (SLE), and multiple sclerosis (MS) may activate endogenous human retroviruses (HERV) as a pathologic mechanism. Memory B cells are the reservoir of infection of EBV and also express endogenous retroviruses, thus depletion of memory b-lymphocytes by monoclonal antibodies (Rituximab) may have therapeutic anti-viral effects in addition to effects on B-lymphocyte presentation of both EBV and HERV superantigens. Other novel anti-viral therapies of chronic autoimmune diseases, such as retroviral integrase inhibitors, could be effective, although not without risk.

    http://www.sciencedirect.com/science/article/pii/S1568997211001753
    currer, adreno and CJB like this.
  2. currer

    currer Senior Member

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    Very interesting Bob. You are right in that this paper pulls together everything we have been hearing about.
    It would be great if the Lipkin study(s) could cast some more light on this new approach.

    Is the complete text available?
  3. user9876

    user9876 Senior Member

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    I think there is quite a bit of interesting work in this area.

    I found a paper on a similar subject although I haven't finished reading it yet.

    http://www.hindawi.com/journals/ad/2012/189096/

    Abstract CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

    Also I posted a different paper on a similar subject (autoimmunity and viral activity) on a different thread. Alex provided a useful summary.
    http://forums.phoenixrising.me/index.php?threads/a-neuro-immune-model-of-me-cfs.18083/page-10
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  4. alex3619

    alex3619 Senior Member

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    Hi user9876, this looks like an interesting paper. I have not fully read it yet either, I am more than a little sleep deprived, but their model appears to have many of the hallmarks that I would regard as necessary. For a start they have a mechanism for how autoimmunity can be linked to localized phenomena. If I wanted to expand this to CFS and ME then I would suggest we have an autoimmune focal point in the gut.

    Under this model many supposedly different autoimmune diseases have the same unifying mechanism. From a reductionist viewpoint thats very tempting, being a relatively simple unifying hypothesis. However it also worries me that it might be an attempt to over-simplify the situation. What is nice though is that, if validated, many autoimmune disease are basically the same, its just the location and targets of autoimmune acitivity vary. With different targets comes different "diseases". As a result a successful treatment for any of them might lead to a treatment for all the others, including ME.

    Bye, Alex
  5. user9876

    user9876 Senior Member

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    I was wondering about the insula cortex being a focus point (I've not seen any evidence though!). I've seen a few bits talking about chemical messaging and pain in the insula cortex around fibromyalga. The reason I was wondering about this is that it seems to be part of the brain responsible for regulating many of the bodys basic systems and I thought this may explain the wide varitey of symptoms along with the variability.

    I remember reading a paper by jonathan edwards talking about using rituximab on RA patients and speculating on a autoimmune cycle involving T and B cells and hence explaining the slow reaction given that Rituximab reduces the b cell count very quickly. I think fluge and Mella were having a similar slow reaction. I think I had read about other autoimmune diseases where the reaction was quicker. One suggested:
    http://bloodjournal.hematologylibrary.org/content/101/10/3857.full

    Suggesting that there are a range of mechanisms for auto immune disease but several may have similar mechanisms?
  6. currer

    currer Senior Member

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    This is a very interesting approach, but how do we account for epidemic type outbreaks? The cohort Dr Bell studied in the Lyndonville outbreak had features typical of ME. I think the underlying mechanism and causative factors must be complex and require some new conceptual thinking.

    Also how do we account for the fact that ME has become so much more prevalent in recent years?
  7. user9876

    user9876 Senior Member

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    Although these papers talk of immune system mechanisms and other auto immune disease I thought I would speculate on the issues you raise.

    One guess is that you have lots of viral outbreaks but a few will be amongst groups with more people who are suseptable to auto immune disease (particularly ME) hence when a virus which can trigger that state in the immune system spreads you may expect some clusters. Another guess would be some viruses are more likely to trigger ME than others. There are researchers who are starting to build up knowledge of how the immune system works and how it related to auto immune disease. My feeling is that this work is still quite early, but it will be helped by improved sensors and scanning techniques. Hopefully this will lead to new conceptual thinking.

    The question of an increasing prevalence of ME is interesting. I know there is an increase in diagnosis but were there a lot of people previously with ME who got missed and generally ignored especially prior to universal healthcare. A different way to speculate would be that Pender's paper talks about the role of Vitamin D in keeping the ratio of CD8+/CD4+ cells correct. They relate this to the chances of getting an auto immune disease. It would be interesting to know how Vit D levels have changed over time. My expectation is that in general they have gone down. However, I know there were many problems of Rickets in victorian cities due to smog and a lack of sunlight so that theory may not hold up.
  8. alex3619

    alex3619 Senior Member

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    Hi currer, all good questions. I will come back to them.

    If the EBV/autoimmune model is accurate, it is likely we should be doing lymph node biopsies. Given the gut connection, that means lymph nodes called Peyers Patches in the gut. Lymph nodes are most common in the connective tissue lining the gut, lung and urinary system. These are primary routes for infection, so it makes sense they are there. Other possibilities include thymus, tonsils and spleen.

    The issue with epidemics, currer, is there is a difference between triggers and perpetuating factors. The EBV/autoimmune model, or indeed the generalized pathogen/autoimmune model is about perpetuating factors. It requires the establishment of infection/inflammation/autoimmune zones. Other things can set up these zones and enable the pathogen/autoimmune cycle to commence.

    A trigger could be almost anything that sets off inflammation - including viruses, bacteria or toxins. Even injury would do it. If there is a large EBV burden in the body then it could dump EBV into the inflamed area, resulting in increased B cell activity and potentially autoimmune reactions. So for those of us who have CFS or ME related injury areas, these would also be sites suitable for biopsy.

    In the case of ME I most strongly suspect interactions between pathogens, including coxsackie (gut/muscle) and EBV (blood, nerve).

    As to prevalence in recent years, the first issue is whether or not this is correct. We are largely guessing as to prevalence. I think it probably is indeed increasing in prevalence, but there have been no epidemics reported for a long time. On the epidemic reporting, I think outbreaks are occuring, localized clusters, but since we now know a lot more about triggering pathogens I think they are being reported based on pathogen outbreak, with post viral consequences being seen as a result of the pathogen, and not being reported as a separate ME or CFS cluster. This is supported by the many Q fever outbreaks, which would have resulted in huge numbers of ME patients, but the only epidemics that are officially registered are Q fever epidemics. (e.g. Holland, I think) From this line of reasoning it follows that ME outbreaks were possibly labelled as such only because the pathogen was unknown.

    Presuming that prevalence is rising, there are many possible candidates. One that came to my attention this year is the increased use of folic acid. Its a possible toxin to most older people and a subset of younger people. Its suspected of suppressing NK cell function. This is a problem. If supplementation of the general population were with folinic acid this would be safer, but folinic acid is less stable and has a shorter shelf life.

    The second possibility is organic toxins. From petroleum products to plastics, the exudation of toxins from these substances is much higher now than at any time in history. This includes pesticides and herbicides, and there is potential for multiple toxins to interact to produces pathophysiological effects that the individual toxins would never have been tested for in safety testing.

    A third possibility is vaccination. Vaccination rates are very high now for most countries. If its vaccines, its unlikely to be all vaccines are equally responsible. Its much more likely that specific vaccines, or specific adjuvants, or the practice of combined vaccines or rapid vaccination schedules, are the inflammatory triggers.

    Of course, none of these are incompatible with each other. Combinations of factors would be more powerful than single factors.

    I am still thinking about this, and have yet to really read the paper as I have only just woken up.

    Bye, Alex
  9. Bob

    Bob

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    Not that I know of, currer. It would be interesting to read it.
  10. user9876

    user9876 Senior Member

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    Not sure if this is useful but I've come across haematologists doing CT scans of lymph nodes, Gut biopsys and bone marrow tests when bone marrow transplant patients get EBV. (followed by a course of Rituximab to remove the virus).
    currer likes this.
  11. Enid

    Enid Senior Member

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    Keep thinking alex - it was very evident to me in my early days the immune system was totally overcome. (And allowing presentation of latent viruses normally kept under control). So what singlely (or combination) may send into an autoimmune state which can follow. Rituximab wiped out what infection in the immune system ?. Switched on (overactive) against what and why - I'm assuming it is normally a biological preservation system but overcome. Pretty sure viral tips the balance.
  12. currer

    currer Senior Member

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    Thanks everyone for your responses. This thread makes me feel such regret for the opportunities that have been missed to do some much needed, exciting, and challenging epidemiological and immunological studies on this disease. Really very little is known for certain about it. I find this situation disgraceful after so long - for all of us.
    However it is true that there is much more interest now (since all the publicity generated by XMRV). So maybe the future will really be better for us.
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  13. Chris

    Chris Senior Member

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    Thanks all for a fascinating thread. But in relation to the Dreyfus paper, I just want to remind that the DVD "Fat, Sick and nearly Dead" records the story of two fat men with Urticaria (the autoimmune disease featured in that paper) cured themselves of both that and their fatness and other symptoms by going on a 90 day juice fast of greens, carrots, beets, etc. It worked! And no bad side effects, and not much expense. A movie worth watching, I think. Best, Chris
  14. Marlène

    Marlène Senior Member

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    Very interesting document.Thank you for posting this.

    I have low positive ANA in my blood since childhood (40-320) and doctors are always arguing whether or not I have lupus (I have rash in the face, burn and feel sick after sun, ...). Only a few weeks ago I found out one of children was born with B12 and folic acid deficiency. He was in IC shortly after birth 16 years ago. Doctors told me he had a virus but papers say it was sepsis and macrocytosis (low B12 and folic acid).

    My B12 is about 50 pmol now, very low, EBV IgG +750 as well as other disturbing elements.
    If ME is a neuro-immune illness, then B12 plays a key role to me.
  15. HowToEscape?

    HowToEscape? Senior Member

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  16. HowToEscape?

    HowToEscape? Senior Member

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    "A third possibility is vaccination."

    Then again, could vaccines be holding the incidence down? If we had more diseases fully developed, that would be much more stress on the immune system than the vaccine against x disease. I'm not an expert, just working on effects of scale .
  17. alex3619

    alex3619 Senior Member

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    Hi HowToEscape, its possible that vaccination could indeed lower ME prevalence rather than increase it. The issue though is: vaccination to what? Not all pathogens seem to trigger ME. Those that do, with the possible exception of Hepatitis B, do not even have vaccines. Where is the Coxsackie virus vaccine for instance? These pathogens are the ones that medical science has simply not proceeded to develop vaccines for as they were not considered sufficiently dangerous. In my opinion it is the ignoring of these types of pathogens has potentially led to the current epidemic of immune related disease. Whether or not this is true is a matter of empirical enquiry - science will tell us eventually.

    For example, if we vaccinated young children against EBV there is every chance that the public health load in adults would decline substantially. EBV is not particularly harmful to children, its moderately to very harmful to teenagers or older, and closely associated with a range of autoimmune diseases. Coxsackie virus is probably as dangerous as influenza (though I am not certain about this) yet we have influenza vaccines and no Coxsackie vaccines. One of the reasons is that, while Coxsackie is as dangerous in individuals, its not as prone to mass epidemics and pandemics.

    The history of vaccination is the history of vaccination to lethal pathogens. Disabling pathogens have been largely ignored.

    I suspect, but its not possible to be certain, that mass vaccination in children to EBV and Coxsackie virus would massively increase public health at low cost, and might even substantially reduce the incidence of both ME and MS, to name just two. Vaccination does not have to be the enemy.

    However in recent years we have combination vaccines - multiple vaccinations in a single shot. We also have a rise in accelerated vaccine schedules. Travellers and soldiers for example often have to have a very large number of vaccinations in a very small number of days. Both of these practices would substantially increase the short term immune burden, which might be a problem in susceptible individuals.

    Bye, Alex
  18. adreno

    adreno 3% neanderthal

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    How would immune enhancers/modulators work in relation to this? Beta glucans, for example, enhance CD8+ T cell activity. However, they also enhance B cell activity. Strengthening the immune system would make the autoimmune reactions worse, but at the same time give the body a better chance to fight the pathogens.
  19. lansbergen

    lansbergen Senior Member

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    http://www.ncbi.nlm.nih.gov/pubmed/21497280
    Modulation of serum anti-thyroglobulin and anti-thyroid microsomal autoantibody levels by levamisole in patients with oral lichen planus.

    Lin HP, Wang YP, Chia JS, Sun A.
    Source

    Graduate Institute of Clinical Dentistry, National Taiwan University, Taipei, Taiwan.
    Abstract

    BACKGROUND/PURPOSE:

    Several types of serum autoantibodies including anti-thyroglobulin (TGA) and anti-thyroid microsomal autoantibody (TMA) were detected in patients with oral lichen planus (OLP). This study evaluated whether Chinese OLP patients had significantly higher frequencies of serum TGA and TMA than healthy control subjects, and whether levamisole treatment could modulate serum TGA and TMA levels in Chinese OLP patients.
    METHODS:

    This study used a semi-quantitative microtiter particle agglutination test to measure the baseline serum levels of TGA and TMA in a group of 278 Chinese OLP patients and 53 healthy control subjects. Forty-one TGA-positive and 48 TMA-positive OLP patients were treated with levamisole for a complete period of 1 year, and their serum TGA and TMA levels were measured after treatment.
    RESULTS:

    We found that the frequencies of serum TGA and TMA in patients with OLP (21.6% and 24.5%, respectively), erosive OLP (21.8% and 24.5%, respectively), or non-erosive OLP (19.0% and 23.8%, respectively) were significantly higher than those (1.9% and 1.9%, respectively) in healthy control subjects. After 1 year of levamisole treatment, the serum TGA and TMA titers decreased partially or became undetectable in 36 (88%) TGA-positive and 46 (96%) TMA-positive OLP patients. At least 9 months or 3 months of levamisole treatment were needed to reduce the mean serum TGA or TMA titer to a significantly lower level in OLP patients, respectively.
    CONCLUSION:

    Significantly higher frequencies of serum TGA and TMA were found in Chinese OLP patients than in healthy control subjects. After 1 year of levamisole treatment, serum TGA and TMA levels were reduced partially or became undetectable in approximately 88% of TGA-positive and 96% of TMA-positive OLP patients.
  20. lansbergen

    lansbergen Senior Member

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

    Modulation of serum antinuclear antibody levels by levamisole treatment in patients with oral lichen planus.

    Lin HP, Wang YP, Chia JS, Sun A.
    Source

    Graduate Institute of Clinical Dentistry, National Taiwan University, Taipei, Taiwan.
    Abstract

    BACKGROUND/PURPOSE:

    Serum autoantibodies, including antinuclear antibodies (ANAs), have been found in patients with oral lichen planus (OLP). This study evaluated whether Taiwanese OLP patients had significantly higher frequencies of serum ANAs than healthy control subjects, and whether levamisole treatment could modulate the antibody levels.
    METHODS:

    This study used an indirect immunofluorescence technique to measure the baseline serum levels of ANA in a group of 583 Taiwanese OLP patients and 53 healthy control subjects. Seventy-nine ANA-positive OLP patients were treated with levamisole under a regular follow-up schedule in our dental clinic, and their serum ANA levels were measured after treatment.
    RESULTS:

    We found that the frequencies of serum ANA in patients with OLP (23.2%), erosive OLP (EOLP, 23.8%), major EOLP (31.5%), and minor EOLP (18.1%) were all significantly higher than that (5.7%) in healthy control subjects. In addition, major EOLP patients had a significantly higher serum ANA positive rate than minor EOLP or non-erosive OLP patients. Of 135 ANA-positive OLP patients, 79 were treated with levamisole under a regular follow-up schedule. We found that treatment with levamisole for a period of 2-38 months (mean, 12 ± 9 months) effectively reduced the high mean serum ANA titer (557 ± 98) at baseline to an undetectable level (0) in all ANA-positive OLP patients, regardless of different high initial serum titers of ANA.
    CONCLUSION:

    There was a significantly higher frequency of serum ANA (23.2%) in Taiwanese OLP patients than in healthy control subjects. Treatment with levamisole for 2-38 months reduced the high serum ANA to an undetectable level, and significantly improved the signs and symptoms in all treated OLP patients.

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