Do MEs cause CFS?

[Bob]

Could someone expand the abbreviation 'ANA' for me please?

 

[Jonathan Edwards]

Of course that would just be by symptoms since most of us can't check for stuff like ANA:s.

@Jonathan Edwards Assuming your groups are correct, do you think there would be a big difference in symptoms between the groups? There are some quite obvious differences between us:

Onset: Symptoms started with infection or not
Infections: Impaired immune system (catches every cold there is) / Over active immune system (never gets a virus)
Course of illness: Relapsing form / non-relapsing form / gets worse over time / constant over time
Symptoms: Gut, sensory sensitivity, pain, developing new allergies, orthostatic problems -- Don't have it / smaller issue / huge issue

How relevant do you think these differences are for determining what subgroup someone belongs to? Are any of them more interesting than the others?

I am not sure I would want to assume my groups are correct! And I don't have the direct clinical experience to give an opinion on what is likely to distinguish groups. Interesting questions to mull over though. Maybe the people you should really ask are Oystein Fluge and Olav Mella. They are several jumps ahead of me on all this. But they like to be confident of something before they say it - unlike me maybe!

 

[Jonathan Edwards]

Loads of interesting queries - mostly beyond my capacity but I will pick up on a few things. An easy one first:

Could someone expand the abbreviation 'ANA' for me please?

ANA is anti-nucelar antibody. That means any antibody that shows up by fluorescence probing to bind to a nucleus on a tissue section or cell culture prep. That will include antibodies to DNA and all sorts of proteins that exist in the nucleus. What is a bit confusing is that when testing shifted to ELISA methods that look for antibodies bound to purified proteins extracted from the nucleus (extractable nuclear antigens or ENA) it turned out that some of the proteins giving the fluorescence in nuclei on slides are actually mostly in the cytoplasm. So although the Sjogren's antigens RO and La come under 'ENA' they are mostly cytoplasmic. But basically ANA means antibodies to anything in the nucleus.

 

[rosie26]

Great to hear your thoughts @Jonathan Edwards. I think I might be closer to ME5 maybe but I don't think it was a virus that sensitized me before the sensitization of the flu sudden severe onset. My ANA is negative. (only 1 test was mild low positive IGM but came right quickly with repeat test). CRP levels - normal.
I haven't got problems with my thyroid hmm.

 

[Jonathan Edwards]

@Jonathan Edwards,

I'm not sure how to say this respectfully, but I think you may have the cart before the horse. PEM is a defining feature of this illness and autonomic dysfunction in the form of POTS, etc. is prevalent in a very significant subset of patients. I think that if you are trying to discuss possible triggers or causes for this illness, at least some of the causes should taken to account autonomic dysfunction and probably all the causes should take into account PEM. I remember hearing Dr. Suzanne Vernon say that when they did in-depth surveys of CFS patients she was surprised to find how common significant muscular pain was also.

I personally think vascular dysfunction could take into account these three symptoms (PEM, autonomic dysfunction, muscular pain) and also "Fatigue", "brain fog", etc.. then the question is - What are the core causes that would trigger this vascular dysfunction?

No disrespect taken. No worries, I am very happy to get the cart before the horse and then find out why the horse comes first. I think maybe Alex has it right though - Its a connected spaghetti nest of causal loops. Then again, this could be a cop-out - we do want to know where the spaghetti starts.

I think I was agreeing that PEM needs to be explained by any theory (although I would not want to leave people with non-PEM problems out in the cold just to be tidy). My thought was that a primary vascular tone problem probably would not on its own explain PEM, although it could easily facilitate it. I suspect that people with, say, pure autonomic neuropathy, who get severe vascular tone issues, may not get PEM.

And then maybe we come back to the same question - what causes the vascular dysfunction? I had been thinking about this particular spaghetti loop and had come to think that at least for MEs the problem is unlikely to START in the autonomic nervous system. The reason for this is that we seem to be dealing with a re-setting of some complex regulatory system. The immune system and the brain are complex enough to reset themselves to a new level through confused internal loops. My guess is that the autonomic nervous system is not quite that complicated - it works like the control system on your central heating and is quite complicated but it may not be complicated enough to reprogramme itself - if that makes sense. Somebody else is re-programming it. You might say that hypertension is a resetting of the autonomic system but I am pretty sure that the real causes of hypertension lie outside and that the autonomic system just resets the way it usually does - although in this case unhelpfully. This may be a confused analysis but it is as far as I have got so far!

 

[Gijs]

Dear professor Edwards,

Is it possible that the ANS problems like 'overdirve' can be 'driven' by the immune system? I think the problems of ME can be due to the ANS. There is a kind of an abnormal 'stressrepsons' going on. This respons can be the cause or can be a sort of compensation like by diabetic. I won't rule the ANS out at this moment. I think there can be several reasons for the ANS dysfunction: 1. compensation (low bloodflow?), 2. defect of the parasympathetic nervous system, 3. autoimmunity against acetylcholine- or bèta receptor..... etc...

Kind regards,

Gijs

 

[Jonathan Edwards]

I have trouble running a fever. If I get an incidental infection I typically feel worse (e.g. aches, malaise, possibly trembles, chills, cough) but don't have all the signs and symptoms unless it's a flu, but still not even moderately high fever. I have low NK cell function like those with infections. Is all this explained by autoimmune (or other expected immune) problems?

How does muscle dysfunction fit into everything? I can't paste studies from this device and honestly some (all?) of the studies are very small, but Yves Jammes and Kieren Hollingsworth are finding a neurological muscle problem in both smooth and skeletal muscle. Could the body be attacking the ion channels (if I understand it correctly) that work the muscles in some cases? I have a test result that would support this kind of muscle problem in my case (but no MG, MS, etc.). Also, if I walk too far, particularly if I've not been getting enough rest in general, my legs drag.

If autoimmune disease similar to Sjogren's were attacking the GI system, would it necessarily look bad on various scopes and image testing? Could this cause severe problems like malabsorption and maldigestion while looking relatively unimpressive and unidentifiable to a thoughtful GI doctor, or would that be a different problem? Second thought, I searched and I see it's not uncommon for Sjogren's patients to be diagnosed with IBS. They have some similar and some opposite problems to me, but this is intriguing.

How do you find a new autoantibody?

My idea for ME5 is that what is in overdrive is a part of the response to virus that does not directly involve the fever mechanism. I am suggesting it involves gamma interferon but not TNF so much. Could well be wrong but that is the sort of angle. It might possibly 'pre-empt' viral symptoms by getting to work on the virus before there is a big enough burst of viraemia (virus in the blood) to trigger the usual fever signals. There might be a distant analogy here with the B27 class I allele. People with B27 get ankylosing spondylitis and Reiter's but I gather that they are the slowest to progress to AIDS if they are infected with HIV. This has led to the idea that B27 is an 'overenthusiastic' class I type.

Angela Vincent talked at the IiME conference about the ion channel antibodies that cause rare neurological diseases, some of which can look a bit like CFS. I would be very happy to put in an ME7 based on autoantibodies to muscle ion channels. I bet there is a disease like that but it might be very rare. And then of course there is the possibility that there is a functional cross talk between immune system and muscle of an unexpected kind. It is worth noting that myasthenia gravis is in a sense both a disease of muscle and a disease of thymus. It has a unique structural pathology in the thymus (with B cell follicles there) as well as making muscles weak - maybe because acetyl choline receptors are actually important in the thymus too. The body very often uses molecules for two (or more) completely different purposes - like using a screwdriver to open a paint tin.

Autoantibodies could alter gut function without there being anything to see on scoping. In scleroderma the autoantibodies interfere with gut motility so that you get malabsorption from bacterial overgrowth in the small bowel. The antibodies in Sjogren's affect the mucus glands and I am not sure there is anything to see in that situation either. Anything seems to be possible.

You find new autoantibodies either by luck (most of the early ones) or by intelligent searching with new techniques. That is how the new neurological autoantibodies have been found. People are looking with new methods for ME antibodies and they may be lucky. But there could easily be antibodies that nobody has yet thought of a way to demonstrate yet because there are so many aspects to antibody binding. For instance in RA we now know that anti-CCP antibodies do not recognise any particular antigen. They recognise any protein that has had an arginine changed to citrulline. If you do not test for that you get the wrong answer - which is why for a long time people thought wrongly that these were antibodies to keratin because keratin tends to get citrullinated in normal tissues.

 

[Jonathan Edwards]

Dear professor Edwards,

Is it possible that the ANS problems like 'overdirve' can be 'driven' by the immune system? I think the problems of ME can be due to the ANS. There is a kind of an abnormal 'stressrepsons' going on. This respons can be the cause or can be a sort of compensation like by diabetic. I won't rule the ANS out at this moment. I think there can be several reasons for the ANS dysfunction: 1. compensation (low bloodflow?), 2. defect of the parasympathetic nervous system, 3. autoimmunity against acetylcholine- or bèta receptor..... etc...

Kind regards,

Gijs

Yes, I agree that the autonomic nervous system is one arm of the spaghetti loop. It is definitely in there. My thought is just that its malfunction is secondary to some immune error - rather as you suggest.

 

[Bob]

@Jonathan Edwards, thanks so much for exploring your thoughts and hypotheses with us.
Our community really needs this sort of curious analytical thinking about the nature of the illness/subsets, esp coming from researchers.
Meaningful explorations of subsets are widely neglected in research settings, probably due to funding issues, but also because of a lack of interest and expertise coming from alternative fields of medicine.

I think your categories are very interesting. I hope you will be able to develop them further, possibly with a view to exploring them with your colleagues in research settings?

From a personal perspective, I'm very keen on the autoimmune angle. I have a history of autoimmunity in myself and my family. (During my life, I've had: eczema and asthma, and I developed clinical hypothyroidism about three years after developing ME. And members of my immediate family have other autoimmune things going on, such as hay-fever, arthritis, psoriasis, and Ehlers-Danlos syndrome-like symptoms.) So I wouldn't be surprised if my biology is such that I am primed to develop a new auto-immune disorder relatively easily.

One of my favourite theories is that I have an auto-antibody to a mitochondrial-related protein. (This could explain the exhaustion, the flu-like symptoms, and cognitive symptoms, and it could also explain why random viruses are persistently associated with ME seeing as the mitochondria has a central role to play in the immune system.)

However, I'm also convinced that ME can start with a trigger event, such as an infection. I got ill with sudden onset ME, with flu-like symptoms, when working in a hospital. The hospital was filthy, and I contracted my first ever cold-sore from a ward a month or two before becoming ill, and I'd also been receiving a series of Hep B booster vaccines.

My symptoms are very reactive to exertion and can be quite stable if I avoid exertion and exert myself within my safe limits (i.e. If I rest-up for very long periods, and employ pacing techniques, then I can sustain a degree of stability.)

I've never experienced POTS as a feature of my illness, although I used to experience something like it occasionally before I had ME. (i.e. almost passing out after standing up too quickly, very occasionally.)

BTW, although my (mild) clinical hypothyroidism caused fatigue/exhaustion, the symptoms and course of the illness were very different from the subjective experience of ME. There was an overlap in symptoms, but they felt like entirely different symptom patterns. I could distinguish the two concurrent illnesses quite easily even before I'd got a hypothyroidism diagnosis and knew what was going on.

 

[Marco]

Fascinating discussion. Just lately on another thread I'd posted some references to 'exercise intolerance' in post concussion syndrome (by definition occuring long after the acute inflammatory response to traumatic brain injury) where it's proposed that exercise intolerance (as evidenced by symptom exacerbation/new symptoms) results from an 'uncoupling' of the autonomic and cardiovascular systems.

Chronic neuroinflammation has been proposed as the 'cause' of post concussion syndrome which only (like ME/CFS) affects a minority of those exposed to concussion. Which makes you wonder of they were 'predisposed'?

 

[Jonathan Edwards]

BTW, although my (mild) clinical hypothyroidism caused fatigue/exhaustion, the symptoms and course of the illness were very different from the subjective experience of ME. There was an overlap in symptoms, but they felt like entirely different illnesses. I could distinguish the two concurrent illnesses quite easily even before I'd got a hypothyroidism diagnosis.

That is interesting. My thought is that for the usual autoimmune (Hashimoto) hypothyroidism, as opposed to hypothyroidism from other causes (which aren't that common), there are indeed two entirely different illnesses. One is the sleepiness and slowness due to low thyroxine. The other is widespread pain and feeling unwell that does not get better when you take thyroxine and which I suspect is directly due to the autoantibodies. The analogy is with the usual autoimmune (Grave's) hyPERthyroidism where you get palpitations and sweating because of the high thyroxine level but you also get protruding eyes and sometimes bumps on the shins and swollen fingers from the autoantibodies that do not go away with lowering the thyroxine. I just wonder whether your ME is based on autoantibodies, maybe a cluster, including ones that led to the thyroid underactivity, but which predominantly produce this other effect of 'CFS'.

 

[Bob]

I just wonder whether your ME is based on autoantibodies, maybe a cluster, including ones that led to the thyroid underactivity, but which predominantly produce this other effect of 'CFS'.

Is a 'cluster' of antibodies common for autoimmune disorders?

FYI, the symptoms of my hypothyroidism and the symptoms of ME did not wax and wane together. (i.e. the thyroid symptoms did not get worse when the ME symptoms got worse.)

 

[Nielk]

@Jonathan Edwards -

You mentioned at ME4

Anti-thyroid antibodies crop up in people with RA for no reason we can understand and RA itself seems to involve two processes that can feed off each other – one for anti-CCP antibodies and one for rheumatoid factor.

Are anti-CPP and RF positive RA different from each other? In what way?

In addition, if someone is positive for anti-thyroid antibodies, how is that treated?

Thank you.

 

[Jonathan Edwards]

Is a 'cluster' of antibodies common for autoimmune disorders?

FYI, the symptoms of my hypothyroidism and the symptoms of ME did not wax and wane together. (i.e. the thyroid symptoms did not get worse when the ME symptoms got worse.)

Interesting.

Most autoimmune disorders have traditionally been associated with one autoantibody. RA had rheumatoid factor. Hypothyroidism had anti-thyroglobulin, pernicious anaemia had anti-intrinsic factor etc. But in the last twenty years it has become increasingly clear that autoantibodies come in bunches. We have always known that lupus tends to have several autoantibodies, including quite often rheumatoid factor. We have also known that 40% of RA patients have anti-thyroid antibodies. Now we know that most RA patients have both rheumatoid factor and anti-citrullinated protein antibodies. In Graves' disease decades ago it was suggested that the thyroid antibodies were different from some other antibodies, sometimes called EPF (exophthalmos producing factor).

So there do seem to be clusters of autoantibodies. Interestingly, what you do not get is two antibodies that look as if they can do the same job. Thus in scleroderma anti-topoisomerase, anti-centromere and anti RNA polymerase all seem to be able to lead to much the same tissue pathology. But patients only ever have one or other of these.

In Graves' disease the course of the eye problem does not necessarily follow the course of the thyroid problem. Similarly, in lupus different antibodies come and go in different ways. Anti-DNA jumps up and down with acute episodes but anti-Sm just sits there for years unchanged. My idea is that the loop that keeps these antibodies going may in some cases be a bit like a Swiss watch. Some antibodies are more like the second hand, some more like the hour hand, but they all mesh together in those little cogwheels inside the back.

 

[Jonathan Edwards]

@Jonathan Edwards -

You mentioned at ME4

Are anti-CPP and RF positive RA different from each other? In what way?

In addition, if someone is positive for anti-thyroid antibodies, how is that treated?

I am not sure how much has been established in good epidemiological studies but RF has in the past been specifically associated with the non-joint features of RA, especially if in very high titre - things like pleurisy and skin nodules. That would make sense because of the sorts of immune complex formed by IgG RF.

If someone with RA has anti-thyroid antibodiies there is no need for any treatment unless the thyroid is showing malfunction, which usually it isn't in these cases. It may be that the anti-thyroid antibodies are still relevant to symptoms I guess but I don't think anyone has any information on that so treatment is for the joint pain and stiffness as usual.

 

[snowathlete]

Fascinating discussion. Just lately on another thread I'd posted some references to 'exercise intolerance' in post concussion syndrome (by definition occuring long after the acute inflammatory response to traumatic brain injury) where it's proposed that exercise intolerance (as evidenced by symptom exacerbation/new symptoms) results from an 'uncoupling' of the autonomic and cardiovascular systems.

Chronic neuroinflammation has been proposed as the 'cause' of post concussion syndrome which only (like ME/CFS) affects a minority of those exposed to concussion. Which makes you wonder of they were 'predisposed'?

My dad gets this (PCS) and I've noted that the cognitive dyfunction experiences appears to be very similar to mine..

 

[Marco]

My dad gets this (PCS) and I've noted that the cognitive dyfunction experiences appears to be very similar to mine..

Sorry to hear that. From the symptoms lists I've seen, without a history of mild traumatic brain injury, I'm sure many could have been diagnosed with ME/CFS or overtraining syndrome.

ETA - as per table 1 of this paper :

http://natajournals.org/doi/pdf/10.4085/1062-6050-48.5.02

 

[Ninan]

Interesting.

Most autoimmune disorders have traditionally been associated with one autoantibody. RA had rheumatoid factor. Hypothyroidism had anti-thyroglobulin, pernicious anaemia had anti-intrinsic factor etc. But in the last twenty years it has become increasingly clear that autoantibodies come in bunches. We have always known that lupus tends to have several autoantibodies, including quite often rheumatoid factor. We have also known that 40% of RA patients have anti-thyroid antibodies. Now we know that most RA patients have both rheumatoid factor and anti-citrullinated protein antibodies. In Graves' disease decades ago it was suggested that the thyroid antibodies were different from some other antibodies, sometimes called EPF (exophthalmos producing factor).

So there do seem to be clusters of autoantibodies. Interestingly, what you do not get is two antibodies that look as if they can do the same job. Thus in scleroderma anti-topoisomerase, anti-centromere and anti RNA polymerase all seem to be able to lead to much the same tissue pathology. But patients only ever have one or other of these.

In Graves' disease the course of the eye problem does not necessarily follow the course of the thyroid problem. Similarly, in lupus different antibodies come and go in different ways. Anti-DNA jumps up and down with acute episodes but anti-Sm just sits there for years unchanged. My idea is that the loop that keeps these antibodies going may in some cases be a bit like a Swiss watch. Some antibodies are more like the second hand, some more like the hour hand, but they all mesh together in those little cogwheels inside the back.

I don't know for sure if psoriasis is caused by antibodies or not and hence not if this is relevant, but, speaking of the connection between different autoimmune (?) diseases in the same person: As you probably know, the PWME:s who had preexisting psoriasis and responded to rituximab in the Fluge/Mella study experienced a worsening of their psoriasis symptoms as they got better. I know someone who got better from Remicade and experienced the same thing. It happens to me too: When I take LDN or Doxycycline (I think they are both immunomodulators, right? At least they both give me energy after 24 hours, that lasts for a couple of weeks.) I get a lot more energy but my usually pretty mild psoriasis gets much, much worse too. It seems that when ME gets better, PSO gets worse. Do you have any idea what that means?

 

[Jonathan Edwards]

I don't know for sure if psoriasis is caused by antibodies or not and hence not if this is relevant, but, speaking of the connection between different autoimmune (?) diseases in the same person: As you probably know, the PWME:s who had preexisting psoriasis and responded to rituximab in the Fluge/Mella study experienced a worsening of their psoriasis symptoms as they got better. I know someone who got better from Remicade and experienced the same thing. It happens to me too: When I take LDN or Doxycycline (I think they are both immunomodulators, right? At least they both give me energy after 24 hours, that lasts for a couple of weeks.) I get a lot more energy but my usually pretty mild psoriasis gets much, much worse too. It seems that when ME gets better, PSO gets worse. Do you have any idea what that means?

In simple terms psoriasis and ankylosing spondylitis look to belong to the 'other side' of the immune system. As far as we know they have nothing to do with antibodies or even any sort of specific 'immunity to self' but rather seem to be due to 'T cells being too busy in a non-specific way'. The easiest way to explain the worsening of psoriasis with rituximab is that helper T cells (CD4+) have the option of either talking to macrophages in a local 'cell mediated' response or talking to B cells to 'help' the B cells make antibody. IL-10 seems to push towards the B cell interaction. If there are no B cells the T cells may go and play with the macrophages - which may be exactly what you do not want in psoriasis. The situation for TNF inhibitors like remicade ought to be different. But TNF production tends to produce a 'balancing' IL-10 production so maybe if you block TNF, IL-10 goes to sleep as well and the T cells go off and play with macrophages again. There are probably other ways of explaining this one though.

 

[Jonathan Edwards]

And yes Bob, autoimmunity to mitochondrial proteins is an interesting idea. Jonas Blomberg is very interested in that.