Do MEs cause CFS?

[lansbergen]

Autoantibodies could in theory target anything but the common autoimmune disorders do not go for periosteum. What does go for periosteum is spondarthropathy - which includes Reiter's syndrome, psoriatic arthropathy and colitic arthropathy.

On first sight does not fit well enough.

 

[Isabelle]

@Jonathan Edwards

Hi Professor Edwards,
As you probably know the development of signs suggestive of autoimmunity (see below) seem to be related to a response to immunotherapy in the treatment of melanoma.

I keep getting the feeling that there is something important here that I am missing, like two sides of the same coin. It is hard to see through brain fog so I’m hoping you can see ‘it’ for me.

(FWIW I developed patches of Vitiligo quite early in the course of ME/CFS.)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517185/

As discussed above in the sections regarding IL-2 and vaccine therapy, stimulation of anti-melanoma responses is associated in some cases with appearance of autoimmunity. A study by Gogas et al210 reported a correlation between the response to HDI therapy and various manifestations of autoimmunity, including antithyroid, antinuclear, anti-DNA, and anticardiolipin autoantibodies, and vitiligo. Development of autoimmunity represented an independent prognostic factor for relapse-free and overall survival (P<0.001).

 

[lansbergen]

(FWIW I developed patches of Vitiligo quite early in the course of ME/CFS.)

That reminds me of my pigmenation symptoms. That happened before I started levamisole. I was not only unpigmented patches but also overpigmentated patches and as I recall it, it did not develp slow but fast. Once there were unpigmentared and overpigementated patches at the same arm at the same time. As it is not live threatening I did not take much notice. For me it was just another weird symptom.

 

[Jonathan Edwards]

@Jonathan Edwards

Hi Professor Edwards,
As you probably know the development of signs suggestive of autoimmunity (see below) seem to be related to a response to immunotherapy in the treatment of melanoma.

I keep getting the feeling that there is something important here that I am missing, like two sides of the same coin. It is hard to see through brain fog so I’m hoping you can see ‘it’ for me..

I am not sure quite what this tells us. Therapies that reset the thresholds for the immune system, like bone marrow ablation and transplant, IL-2 and anti-CTLA-4 can be followed by higher rates of autoimmunity, although this is often temporary. That is not particularly surprising if control systems are reset. Whether it has any direct relation to effectiveness of anti-tumour therapy I am not sure, especially since tumour immunotherapy seems to be very unpredictable in results.

 

[A.B.]

I have a hard question for @Jonathan Edwards.

I'm trying to understand why the medical community tends to act like it does when confronted with symptoms that are difficult to explain.

I'm sure doctors are well aware that in the past, many illnesses were considered psychosomatic, to be treated by psychotherapy. This includes very serious conditions such as multiple sclerosis, rheumatoid arthritis, diabetes, Graves' disease, asthma, and so on. Psychotherapists claimed to see personality flaws in their patients that were causing the illness. They also claimed success in treating these conditions with psychotherapy.

Today these conditions are generally no longer considered to be psychogenic in origin. The existence of psychogenic illness cannot even be demonstrated. The psychogenic illness model has repeatedly failed.

Yet somehow the concept lives on and doctors continue to diagnose psychogenic disorders with great confidence (and questionable results as far as I know). The absence of evidence is taken to be evidence of absence, which is seen as evidence for the presence of a psychogenic disorder.

Where does this thinking come from? Medical school? Does this approach actually ever work? Do doctors really believe this, or is it just something they do when overworked and stressed? Are doctors allowed to say that they don't know or can't diagnose something?

 

[Jonathan Edwards]

I'm trying to understand why the medical community tends to act like it does when confronted with symptoms that are difficult to explain.

I'm sure doctors are well aware that in the past, many illnesses were considered psychosomatic, to be treated by psychotherapy. This includes very serious conditions such as multiple sclerosis, rheumatoid arthritis, diabetes, Graves' disease, asthma, and so on. Psychotherapists claimed to see personality flaws in their patients that were causing the illness. They also claimed success in treating these conditions with psychotherapy.

Today these conditions are generally no longer considered to be psychogenic in origin. The existence of psychogenic illness cannot even be demonstrated. The psychogenic illness model has repeatedly failed.

Yet somehow the concept lives on and doctors continue to diagnose psychogenic disorders with great confidence (and questionable results as far as I know). The absence of evidence is taken to be evidence of absence, which is seen as evidence for the presence of a psychogenic disorder.

Where does this thinking come from? Medical school? Does this approach actually ever work? Do doctors really believe this, or is it just something they do when overworked and stressed? Are doctors allowed to say that they don't know or can't diagnose something?

At the end of the day I think the sentence at the bottom of your post sums it up
Psychosomatic explanations for illness exist to give the reassuring illusion that the problem is understood.

 

[Snow Leopard]

@Jonathan Edwards

I have a question as to how some autoimmune disorders can be non-inflammatory, eg do not form produce granulomata or notable amounts of ANA, CRP and so on? I'm not sure how to be more specific, but what are the differences in either the antibody targets or immune loops that lead to an inflammatory profile? What are some notable examples?

Is it possible for non-antibody mediated immunological loops, whether involving B-Cells or not could explain the disease and are there any notable examples worth looking at?

Another speculative idea I've had is whether the body uses any particular kinases as a gauge for certain fatigue signals, given that kinases are used for phosphorylation and therefore their activity would depend on the levels of energy available in the cell. Sunitinib for example targets RTK and has been noted to directly induce fatigue. In addition, TKIs have been associated with hypothyroidism, something that is also associated with ME/CFS http://www.ncbi.nlm.nih.gov/pubmed/19333228

Lastly, does the increased rate of Non-Hodkin's lymphoma in the large NIH study give any clues into which receptors or other proteins such as kinases may be involved?

 

[Jonathan Edwards]

I have a question as to how some autoimmune disorders can be non-inflammatory,

Is it possible for non-antibody mediated immunological loops, whether involving B-Cells or not could explain the disease and are there any notable examples worth looking at?

Another speculative idea I've had is whether the body uses any particular kinases as a gauge for certain fatigue signals, given that kinases are used for phosphorylation and therefore their activity would depend on the levels of energy available in the cell. Sunitinib for example targets RTK and has been noted to directly induce fatigue. In addition, TKIs have been associated with hypothyroidism, something that is also associated with ME/CFS http://www.ncbi.nlm.nih.gov/pubmed/19333228

Lastly, does the increased rate of Non-Hodkin's lymphoma in the large NIH study give any clues into which receptors or other proteins such as kinases may be involved?

An autoantibody will only cause inflammation if it binds to something outside the circulation and in doing so engages either complement or Fc receptors, with macrophage activation and cytokine release. Inflammation is the calling out of cells and fluid from the circulation into the tissues. If an antibody binds to something in the circulation it cannot produce inflammation because that cannot call cells to go somewhere else - the signals stay in the circulation, as do the cells. An example is immune thrombocytopenia. Antibodies bind to platelets which are then engulfed by macrophages still in the circulation and so platelets disappear but there is no inflammation.

In myasthenia gravis the antibody binds to a receptor hidden in a muscle end plate cleft. This can engage complement but the cleft is so small that cells cannot get in. As a result there is no real inflammation. Also if the antigen is inside a cell then an antibody may bind to it inside the cell and not generate either a complement or Fc receptor mediated signal. Another situation is that antibodies bind to circulating proteins to form complexes that block the filter in the renal glomerulus without binding inflammatory mediators - so called membranous nephropathy, often found in lupus.

In fact a high proportion of autoimmune diseases do not involve much cytokine production and CRP rise - scleroderma, lupus, pernicious anaemia, thryoid disease, Addison's etc etc.

Non-antibody non-B cell loops occur in psoriasis and Reiter's syndrome and some ME may be related to Reiter's syndrome (my ME2). These are loops in which there is overactivity of a T cell population belonging to one of the four T cell traffic domains (skin domain for psoriasis, gut/GALT domain for Crohn's, mucosa/MALT domain for Reiter's and 'everything else' domain for ankylosing spondylitis).

I think it is reasonable to think that kinases may be involved in signalling the sense of fatigue. I would be cautious about linking a level of phosphate availability in the form of ATP with 'lack of energy' in the fatigue sense but there may be an indirect relation.

I think if there is an increased incidence of NHL that may simply be a sign that a lot of NHL exists undiagnosed for years in a form that may be associated with ME type symptoms. Alternatively, NHL are often associated with abnormal antibodies and these might be producing MEs long before the tumour was detectable. Since antibodies can bind to anything the mechanism of fatigue may be different in each case.

 

[MeSci]

I love your short biochemistry lectures, @Jonathan Edwards! I'm saving some of them for future reference. Really useful in helping to understand this illness and others.

 

[chipmunk1]

I'm sure doctors are well aware that in the past, many illnesses were considered psychosomatic, to be treated by psychotherapy. This includes very serious conditions such as multiple sclerosis, rheumatoid arthritis, diabetes, Graves' disease, asthma, and so on. Psychotherapists claimed to see personality flaws in their patients that were causing the illness. They also claimed success in treating these conditions with psychotherapy.

The problem with these theories is that usually the therapist decides if the therapy was successful or not. What the patient believes doesn't matter since their thinking and cognition is distorted and they lack insight(and psychological or medical training)

Since they don't have to live with the condition themselves it's very easy to proclaim you cured someone since you don't have to deal with the consequences of a poorly treated chronic condition.

Does this approach actually ever work?

Patients are nothing but riff-raff. The only useful purposes they serve are to help us earn a living and to provide learning material. In any case, we cannot help them. Sigmund Freud1

 

[Gemini]

The question is why the immune system fails to switch off for those with ME...some viruses may have a particular ability to reset the immune system maybe without autoimmunity...coxsackie viruses also have a reputation for doing odd things.

Professor Edwards thank you for defining ME/CFS subsets. Sorry for jumping back to the middle of this fast-moving thread. Information in the coxsackie literature caught my attention as it fits Mady Hornig's idea of multiple factors at play, i.e., people with pre-existing immunoglobulin deficiencies who contract a coxsackie infection may go on to develop chronic encephalitis and the virus may activate pre-existing antibodies. Interestingly there are ME/CFS patients with such deficiencies who would have been excluded from ME/CFS studies in the past because of them. Do you think with the "Personalized Medicine" approach such patients will now be included in research and perhaps constitute a subset?

Article describes how coxsackie interacts with the immune system:

http://www.wjgnet.com/2220-3249/full/v1/i3/91.htm

It would be nice to have a coxsackie researcher speak at a future conference.

 

[Hip]

@Jonathan Edwards

Here is another question on autoimmunity, if I may:

The question is about the significance of autoantibodies that target receptors in the central or peripheral nervous systems.

One study found 53.3% of ME/CFS patients had autoantibodies that target the muscarinic M1 cholinergic receptor, 15.2% had mu-opioid receptor autoantibodies, 1.7% had 5-HT1A receptor autoantibodies, and 5.0% had dopamine D2 receptor autoantibodies.

And a recent study on postural orthostatic tachycardia syndrome (POTS), a dysautonomia condition that is a common comorbidity in ME/CFS, found autoantibodies that target the alpha 1 adrenergic receptor, the beta 1 adrenergic receptor, and the beta 2 adrenergic receptor. I understand that this POTS study is being viewed as groundbreaking, because these autoantibodies may explain why there is a dysfunction in the autonomic nervous system (ANS) that leads to POTS: these autoantibodies may interfere with the transmission of nerve impulses through the ANS receptors. POTS, incidentally, has symptoms very similar to ME/CFS symptoms.

Why do quite a few neuronal receptors become targets for antibodies?

The only other autoantibody I am aware of in ME/CFS is anticardiolipin antibodies, which this study found in 95% of patients.

 

[Jonathan Edwards]

One study found 53.3% of ME/CFS patients had autoantibodies that target the muscarinic M1 cholinergic receptor, 15.2% had mu-opioid receptor autoantibodies, 1.7% had 5-HT1A receptor autoantibodies, and 5.0% had dopamine D2 receptor autoantibodies.

And a recent study on postural orthostatic tachycardia syndrome (POTS), a dysautonomia condition that is a common comorbidity in ME/CFS, found autoantibodies that target the alpha 1 adrenergic receptor, the beta 1 adrenergic receptor, and the beta 2 adrenergic receptor. I understand that this POTS study is being viewed as groundbreaking, because these autoantibodies may explain why there is a dysfunction in the autonomic nervous system (ANS) that leads to POTS: these autoantibodies may interfere with the transmission of nerve impulses through the ANS receptors. POTS, incidentally, has symptoms very similar to ME/CFS symptoms.

Why do quite a few neuronal receptors become targets for antibodies?

The only other autoantibody I am aware of in ME/CFS is anticardiolipin antibodies, which this study found in 95% of patients.

I think we need to see replication of these studies. Unfortunately it is all too easy to 'find autoantibodies' to something you want to find them to. The muscarinic receptor study was from 2003, so I wonder why we do not have a follow up on a bigger series ten years later? Everybody has anticardiolipin antibodies if you do the test a certain way.

 

[Hip]

I think we need to see replication of these studies. Unfortunately it is all too easy to 'find autoantibodies' to something you want to find them to. The muscarinic receptor study was from 2003, so I wonder why we do not have a follow up on a bigger series ten years later? Everybody has anticardiolipin antibodies if you do the test a certain way.

There was one replication study on the muscarinic receptor antibodies, performed in 2005 by David S. Bell et al, which unfortunately was not published but presented at a conference:

Antibodies to the Muscarinic Acetylcholine Receptor in CFS.

Presented In: International Conference on Fatigue Science 2005; Karuizawa, Japan, 2005. David E. Bell, BS, Aristo Vojdani, PhD, David S. Bell, MD

Patients with chronic fatigue syndrome experience severe fatigue, orthostatic intolerance and numerous other symptoms that are similar to known illnesses of the autonomic nervous system. Because of these similarities it is possible that disruption of autonomic nervous system nerve transmission may play a role in the symptoms of the illness. In a recent paper, researchers noted that 50% of patients with CFS had antibodies to the muscarinic acetylcholine receptor (Tanaka S, et al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med 2003;12:225-230.) The presence of an autoimmune dysautonomia with autoantibodies to the muscarinic acetylcholine receptor is a theoretical etiology for some patients with CFS. If autoimmune dysautonomia exists and can be effectively recognized, therapeutic implications for this group of patients may be developed.
Objective: The present study was designed to examine IgG, IgM, and IgA antibodies to the neuromuscular acetylcholine receptors (AR) and to muscarinic receptors (MR) in patients with chronic fatigue syndrome (CFS) and healthy matched controls.
Methods: Twenty five adults with CFS were matched with healthy community controls for age and sex. After informed consent, venous blood samples were drawn and sent to Immunosciences Laboratory in a blinded manner. The testing procedure was the same as previously described.
Results: Five of the antibodies studies (IgA_AR; IgM_AR; IgG_AR; IgM_MR; and IgG_MR) showed no differences between patients and controls. However the IgA_MR was statistically higher in patients than in controls (0.43 vs. 0.33, p = 0.031).
Conclusions: Our studies are in agreement with the studies of Tanaka et al (1) that autoantibodies against muscarinic receptors may be an important marker in a group of patients with CFS. Further studies should be undertaken to further characterize these autoantibodies and to determine specifics of the subgroup to which they may apply. If this proves to be a consistent finding, therapy directed toward the acetylcholine neurotransmitter system may be of benefit in this group of patients.

 

[JalapenoLuv]

Dr. Edwards,

Here is the pepper theory of CFS:

As a CFSME patient with a medical background I suspect that for at least the subtype I have we are dealing with two infections-a new form of bartonella spp that, like all bartonella, is transmitted by cats, and epstein barr virus. Both agents are potent apoptosis blockers at different intracellular pathways so you end up with a mass of persistent colonized cells. Epstein barr virus, like other viruses, secretes nagalase which nullifies the critical immune signaling molecule Gcmaf. Without this molecule T cells can't attach to infected tissues to trigger apoptosis and clear them. Normally bartonella colonizes nerve tissue, macrophages and the peripheral vascular endothelium. However, I theorize that when EBV is present the bartonella is able to infect EBV persistent tissues and increase its mass, colonizing muscles, tendon and ligament insertions, skin the throat and prostate. Bartonella blood vessel inflammation is the cause of chronic headaches and the inflammation in the soft tissues causes pain inhibition. Infected, persistent tissue damages mitochrondria causing an energy deficit and the methylation problems. Generally the immune dysfunction prevents antibodies from being generated. I have lab studies where I was positive for ebv in 2008 but negative on all subsequent tests. This is due to the EBV inhibition. However, if there is any immune function left we would expect autoantibodies because they are necessary to attack the infected self tissue.

JP

 

[MeSci]

@Jonathan Edwards, apologies if you have covered this before, but I couldn't find reference to it from about 5 minutes searching here, after trying general internet searches and looking at scientific papers. It may be somewhere in my science text books but you probably know the answer!

I'm going through my medical records typing up test results, etc., that appear potentially relevant, and have come across a high lymphocyte count - 6.3 x 10^9 per litre - which was found a little over 3 months after I was attacked by a dog, and almost 3 months after I had a tetanus booster, which I don't think was overdue.

This was the year that I consider my IBS to have morphed into ME.

Do you think the high lymphocyte count could have been due to either of these events?

 

[Jonathan Edwards]

@Jonathan Edwards, apologies if you have covered this before, but I couldn't find reference to it from about 5 minutes searching here, after trying general internet searches and looking at scientific papers. It may be somewhere in my science text books but you probably know the answer!

I'm going through my medical records typing up test results, etc., that appear potentially relevant, and have come across a high lymphocyte count - 6.3 x 10^9 per litre - which was found a little over 3 months after I was attacked by a dog, and almost 3 months after I had a tetanus booster, which I don't think was overdue.

This was the year that I consider my IBS to have morphed into ME.

Do you think the high lymphocyte count could have been due to either of these events?

I doubt it. The immune response matures and completes over a period of about four weeks normally. A temporary high lymphocyte count occurs early on in a viral infection and for longer in EBV infection. Counts vary a lot so I would not pay much notice to a single reading to be honest.

 

[MeSci]

I doubt it. The immune response matures and completes over a period of about four weeks normally. A temporary high lymphocyte count occurs early on in a viral infection and for longer in EBV infection. Counts vary a lot so I would not pay much notice to a single reading to be honest.

Thanks. Just realised that I made a mistake - it was leukocytes/WBC, not lymphocytes, so the value was normal after all.

Oh, my ME brain!

 

[Kati]

I am afraid to say that I am sceptical about this sort of biochemical discussion. Do we have data from blinded trials of B12 and folate in ME? I think not. Without that my instinct is to think that PWME feel better after taking vitamins for the same reason that millions of other people feel better after taking vitamins - probably nothing to do with needing vitamins. And the various changes you suggest might relate to glutathione I cannot think will actually make any significant difference to basic metabolic pathways, except pregnancy which changes everything so we could blame anything else just as much.

I fear all the talk of B12 sounds like using scientific language without any true grasp of what would actually happen in reality. Long ago I learnt only to believe an effect where you had a quantitative 'dose-response' type relation. A theory that predicts something goes up is pretty useless. A theory that predicts something will go up somewhere between 0.35 and 0.45 units with a dose of 60mg and 0.75-0.85 units with 90mg is worth testing. Show me a glutathione dose response curve in a blinded trial of vitamins in ME patients and I will take note.

I hate to sound a spoilsport in regard to suggestions from patients, particularly as so many insightful comments come up on PR. But I have to stick to Spock mode and be dispassionate about all the theories around. We want the right answer. Methylation does not add up to me, at least so far.

@Jonathan Edwards I really appreciate your skepticism.

In my opinion, patients are desperate and will experiement a lot and will also subscibe to theories or anedoctal reports of improvements. We are all different and what one reports as helpful could be due to so many different things, or could be just temporary or represent the placebo effect.

We need to realize that if the majority of us is still on the furums, we haven't been cured of what ails us.

Regarding methylation protocol and generitc data. Have you ever looked at MTHFR gene mutation apparently is supposed to be the cause of a wide array of diseases? It's too good to be true. The other aspect that makes me skeptical is that apparently if it's not working, it's because you haven't done it right. give me a break.

i will see it when there is good research showing proofs of that. Personally I tested homozygous for one gene, have been on methyl B-12 and folate for 6 months, and there is absolutely no change in my condition. i am not going to discuss this further in case someone is wanting to tell me to try another brand or asking whether I did not 'methyl trap.' Avd I will not pay the 30$ a months it take for methylfolate, I bet it all goes in the sewage in the end.

We need sound research out there, and of course funding for our researchers.
Thank you @Jonathan Edwards

 

[JalapenoLuv]

Kati,
The methylation protocol doesn't address the underlying CFS factors. After all, CFS patinets only get sick after they get some sort of infection. So it stands to reason that prior to the infection they were methylating fine. Granted that genetic mutations occur that can make people more stressed with this disease but it isn't the cause and so taking these supplements isn't going to cure you. That said, if they help use them.