Do MEs cause CFS?

[DanME]

@Valentijn What the Dutch group does is so cynical, I don't know what to say to that.

 

[heapsreal]

My thoughts are maybe to put together a list of biomarkers which unit all the sub groups possibly, the old regulars nk function, low cd8 function and the 2 day exercise test, L rnase test maybe, particular cytokine pattern?? or something of this nature that gives the ME diagnosis.

Then after this tease out the sub groups. I dont know if this is possible that all the sub groups have some common biomarker though. But i think when looking at the bond/griffith uni research it seems that a few of the biomarkers mentioned above are quite common in ME, although im unsure of the percentages but it must be quite high if they were looking at this test as a possible diagnostic test??

Then i guess when in the sub groups, do they have their own particular biomarker to place them in??

 

[Jonathan Edwards]

@Jonathan Edwards

If I understand you correctly, you think ME1 is an autoimmune disorder like Lupus and Sjögrens, in which ENAs are attacked. Do you think an unknown ENA is involved or do you think it is more of an overlap with known diseases. As far as I am aware, patients with other ANA diseases are not exercise intolerant. Or are they?

In ME5, do you think the B-Cells are sensitised and constantly arm the immune system to kill the long gone (or latent) viruses? And this is why Rituximab could break the cycle of an over stimulus?

Have you any idea, why so many of us suffer from severe OI and POTS like symptoms? The regulation of the vascular tone seems to be severely impaired. In which category would you put these symptoms?

As I have described ME1 it covers people in whom you can find an ANA, which may be one of the recognised ENAs or an unknown one. People with ANAs with recognised syndromes like Sjogren's can have severe fatigue although I am not sure they get post-exercise malaise. My memory is that they do describe 'crash' type episodes though.

Yes, in ME5 there would be continued antibody production and the target, rather than being a tissue like thyroid or stomach, would be a protein within the immune system itself - so if anywhere in the lymph nodes and tonsils. But aggravating the lymphocytes there would release signals that made you feel fluey in the brain and muscles as well as having a sore throat. And I agree with Alex that this could overlap with targeting microglia directly. Rituximab removes any B cell clones around at the time. As described on the thread with my name on some time back I think in autoimmune disease the cycle is p assed from one B cell clone to another over time by a process of 'miseducation'. In some autoimmune diseases it seems that rituximab can get rid of enough clones to block a furhter cycle of miseducation, although in RA this does not normally occur. The Norwegian data suggest that a proportion of ME responders may get free of a cycle, but it is too early to be sure.

I don't have a good grip on the orthostatic intolerance angle. I hear a lot about it but I am not sure where I think it comes in. I am fairly sure it is going to be secondary to immune or CNS signals in most cases. Of course it occurs acutely in the acute stages of viral illness and it will occur in what is called 'cytokine storm syndrome' which people most often used to experience in a mild form as a reaction to the endotoxin (?or adjuvant) in typhoid vaccine. There might be a different route to orthostatic intolerance through a primary disorder of vascular tone control but I don't understand why you should get all the other features of CFS like brain fog and PEM in that case.

 

[snowathlete]

The Dutch biopsychosocial (BPS) group does something similar, in dividing ME/CFS into two distinct disease processes, while still claiming they are the same psychosomatic disorder.

Because some patients push themselves too hard and constantly crash as a result, they don't fit the usual stereotype of ME/CFS patients having a presumed exercise phobia. Hence this BPS group suggests that one group of patients has kinesiophobia (an absurdity in itself compared to real phobias), and the rest have unrealistic expectations of their own capabilities as they age, etc, and exceed their normal limitations.

So somehow they conclude that people with completely different causative psychological and behavioral issues, resulting in either inactivity or overactivity, are suffering from the same illness. And these vastly different psychological and behavioral disorders then produce identical symptoms

This made me laugh, it's so stupid. These people (the BPS) belong in a nut-house. Oh, wait...

 

[Jonathan Edwards]

It might be difficult to separate the hen from the egg here, ME could have made me more prone to infections the same day it started. Even though I've hardly ever had an infection since. But I don't think so, I'm pretty sure the infection was the trigger. Together with lousy genes and a stressful period in my life. That "three strike theory" Horning talks about fits my experience perfectly.

I understand that that is what it feels like. It is just that for the autoimmune diseases we understand it looks as if the old trigger theory is back to front. In RA the antibodies are there before something sparks off the symptoms. And for my ME5 thought it would be impossible for the person to tell which way around it was. Mady Hornig's experimental work is brilliant but I do tend to disagree with her on the old infectious trigger chestnut - it has been around for so long and the evidence for it is so hard to find. It works for rheumatic fever, but then the immune reaction is over with once the infection is treated with penicillin - you are just left with scarring. But, as I said, I am prepared to believe for ME it might be either way around or both because of the history of epidemics (like Reiter's) and the very common link to a documented infection at onset.

 

[snowathlete]

Very interesting. Thank you for posting your thoughts about this and starting a very good discussion.

From my personal experience of the disease, I think model 5, which may have multiple triggers, make up at least two thirds of people with the disease, with your other models, and others, as well as misdiagnosis, making up the rest in varying proportions.

Model 5, I think, would account for a key symptom in my illness (which I know many others have too) which is practical immunity to cold and flu. It's like some part of my immune system is already on high alert when it should be relaxing, and it jumps on any respitory virus at full force as soon as it turns up, so the virus never gets going. Strangely, I still get stomach viruses. (Maybe there is some clue there about which part of the immune system is on high alert).

Best
Joel

 

[DanME]

Very interesting. Thank you for posting your thoughts about this and starting a very good discussion.

From my personal experience of the disease, I think model 5, which may have multiple triggers, make up at least two thirds of people with the disease, with your other models, and others, as well as misdiagnosis, making up the rest in varying proportions.

Model 5, I think, would account for a key symptom in my illness (which I know many others have too) which is practical immunity to cold and flu. It's like some part of my immune system is already on high alert when it should be relaxing, and it jumps on any respitory virus at full force as soon as it turns up, so the virus never gets going. Strangely, I still get stomach viruses. (Maybe there is some clue there about which part of the immune system is on high alert).

Best
Joel

I am practical immune to the cold and flu, too. But rarely (every 1 1/2 years) an infection comes through and I get a little fever. In these short episodes, I feel great relief of all my symptoms and my OI disappears. Do you have that as well? It seems to me the immune system gets distracted by actually killing some real viruses and leaves me alone.

 

[Ninan]

I understand that that is what it feels like. It is just that for the autoimmune diseases we understand it looks as if the old trigger theory is back to front. In RA the antibodies are there before something sparks off the symptoms. And for my ME5 thought it would be impossible for the person to tell which way around it was. Mady Hornig's experimental work is brilliant but I do tend to disagree with her on the old infectious trigger chestnut - it has been around for so long and the evidence for it is so hard to find. It works for rheumatic fever, but then the immune reaction is over with once the infection is treated with penicillin - you are just left with scarring. But, as I said, I am prepared to believe for ME it might be either way around or both because of the history of epidemics (like Reiter's) and the very common link to a documented infection at onset.

Good point. Most of us probably take or mistake the phenomenon, whatever it is, that seems to cause the first symptoms for the trigger of the disease itself. But of course it can already have broken out without showing, maybe triggered by something completely different. In my case there are a few things (moldy apartment in a rainy Lyon giving me joint pain and having my ears pierced in the wrong way so they got infected) the year before. My parents were just waiting for me to come down with RA. I guess it could have happened then. If outside triggers are even needed, which of course doesn't have to be the case.

Very interesting with the sub groups, btw. I'm exactly like you, @DanielBR Whenever my immune system seems to have something to do -- fight infections (doesn't even happen anymore), allergies, is busy cleansing out my cells with Doxycycline (or maybe that's just modulation) -- I feel much better. It's the same for my father, who has Bechterews disease: He has less pain and more energy when he's hit by a virus. I don't know, maybe that's a common thing for autoimmune diseases?

(I have a pretty severe case of OI too, just like you @DanielBR Maybe if we all found our symptoms buddies here and teamed up we could form a couple of potential sub groups? )

 

[snowathlete]

I am practical immune to the cold and flu, too. But rarely (every 1 1/2 years) an infection comes through and I get a little fever. In these short episodes, I feel great relief of all my symptoms and my OI disappears. Do you have that as well? It seems to me the immune system gets distracted by actually killing some real viruses and leaves me alone.

Once. Early on about a year into ME I got a pretty mild cold, and that was the best I have felt since I got ME. I would decribe my experience with that cold exactly the same as you did. There was a very very definite change and despite having a cold, I felt comparitively fantastic. I would gladly live with that cold constantly if it meant having that relief from the ME. I live in hope of catching a cold and it somehow reseting my immune system.

 

[snowathlete]

(I have a pretty severe case of OI too, just like you @DanielBR Maybe if we all found our symptoms buddies here and teamed up we could form a couple of potential sub groups? )

That seems like a great idea. No idea if that's been done before, but closely nit patients may be in a uniquely strong position to cluster together as 'same' and put themselves forward for some kind of study. I wonder if a group of say 100 patients could pull themselves into different groups and then if tests were performed could be told apart reliably.

 

[Sushi]

@Jonathan Edwards

This poll on whether patients get more or fewer colds and flu might interest you. 99 out of 122 members who voted said that they got fewer incidences of colds and flu since their ME/CFS onset.

I have not had a cold or flu in about 10 years.

Sushi

 

[deleder2k]

I'm not sure which of the MEs this falls into, but I watched a presentation by Fluge. He said that one part of the M.E patients had a lot of regular infections, while the other part had practically none at all. Those who experienced a full recovery after Rituximab, got their regular infection cycle back after treatment. I.e, they are now back to their normal cycle of flu, cold, fever and other infections. I have been ill for 4 years now, but I havent had fever one time. Usually I had fever at least once a year. Maybe my immune system is overactive, while others are not?

 

[Ninan]

That seems like a great idea. No idea if that's been done before, but closely nit patients may be in a uniquely strong position to cluster together as 'same' and put themselves forward for some kind of study. I wonder if a group of say 100 patients could pull themselves into different groups and then if tests were performed could be told apart reliably.

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?

 

[ukxmrv]

@Jonathan Edwards

This poll on whether patients get more or fewer colds and flu might interest you. 99 out of 122 members who voted said that they got fewer incidences of colds and flu since their ME/CFS onset.

I have not had a cold or flu in about 10 years.

Sushi

I wonder if this would change if we followed patients over time? My first 15 years (approx) were of less colds, flus etc and then my next 15 (approx) were of more.

 

[voner]

I don't have a good grip on the orthostatic intolerance angle. I hear a lot about it but I am not sure where I think it comes in. I am fairly sure it is going to be secondary to immune or CNS signals in most cases. Of course it occurs acutely in the acute stages of viral illness and it will occur in what is called 'cytokine storm syndrome' which people most often used to experience in a mild form as a reaction to the endotoxin (?or adjuvant) in typhoid vaccine. There might be a different route to orthostatic intolerance through a primary disorder of vascular tone control but I don't understand why you should get all the other features of CFS like brain fog and PEM in that case.

@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?

 

[alex3619]

@voner, yet vascular dysfunction in the brain has the similar effects to brain hypometabolism and brain inflammation. We need to separate these issues out, not in discussion, but in clear research finding. I suspect there are subgroups.

All of these things can effect the others. Its a connected spaghetti nest of causal loops.

 

[Hip]

Orthostatic intolerance and autonomic dysfunction may well be explained by autoimmune processes too: there are autoantibodies involved in POTS and orthostatic hypotension:

In orthostatic hypotension, autoantibodies that target the M2 muscarinic receptors, the M3 muscarinic receptors, the beta 1 adrenergic receptors, and the beta 2 adrenergic receptors have been found (ref: here).

And in POTS, a recent and groundbreaking 2014 study found autoantibodies to adrenergic receptors in the 14 POTS patients tested, with no autoantibodies found in the healthy controls (ref: here).

With these autoantibodies in POTS and orthostatic hypotension targeting the neuronal receptors in the autonomic nervous system, one presumes this will throw a spanner into the works of autonomic nerve signal transmission, thus leading to autonomic dysfunction.


ME/CFS patients have been shown to have autoantibodies to autonomic nervous system receptors too, in this case the M1 muscarinic receptors (ref: here). And interestingly, Sjögren's syndrome (a common comorbidity of ME/CFS) has been shown to involve autoantibodies that target the M3 muscarinic receptors (ref: here); furthermore, this study neatly demonstrates that these M3 autoantibodies reduce saliva production.

 

[WillowJ]

@Jonathan Edwards thank you for thinking this through so clearly and taking the time to share/discuss it with us. That is so encouraging.

I have ANA (speckled as you said, increasing over some time into indisputably significant level, but no other markers for particular diseases; several have been checked... [edited to remove some individual specifics]

I didn't notice it in the early days but I now have PEM. In addition to that, I have fatigue. I did not find a lot of infections when we checked. [edited some individual specifics] My questions are:

I have trouble running a fever (seldom do, and if I seem to really need to, it is not consistent and not high, which confuses ER, for example). 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 (& for others, not much by way of specific S&S of cold, noravirus, etc.). I have low NK cell function like those with infections. Is all this explained by autoimmune (or other expected immune) problems? (I have not had cytokine testing.) My temp is most often low.

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?

Apologies if some of this has already been asked; I got too sick to follow the long thread.

Thanks again; this is a very interesting thread. I have always thought it most likely there would be at least two groups, possibly many, because as Alex said it's common to find a similar proportion split. Also because we have different groups finding disparate things.

 

[thegodofpleasure]

Model 5, I think, would account for a key symptom in my illness (which I know many others have too) which is practical immunity to cold and flu. It's like some part of my immune system is already on high alert when it should be relaxing, and it jumps on any respitory virus at full force as soon as it turns up, so the virus never gets going. Strangely, I still get stomach viruses. (Maybe there is some clue there about which part of the immune system is on high alert).

I tend to agree with you that Model 5 of the illness would explain the experience of many PwME (myself included) who report a heightened level of immunity to colds and flu. Most of the time, this is assymptomatic (viruses are fended off unnoticed) but occasionally you really know when you're fighting off a cold / flu - the immune response is far greater than that experienced by other family members who have been exposed to the same virus. However, there are also still occasions when this heightened level of immunity is overcome by a particular strain of cold or flu virus and full-blown infection develops. The consequent illness seems to be much worse (greater severity of symptoms and more prolonged) than that experienced by otherwise healthy people.

De Meirlier and others talk about PwME experiencing a shift towards Th2 dominant immunity, whereby the numbers of the different types of T helper cells (which help to regulate the immune system) are out of balance - Th2 dominant = hyper-vigilant against viral infection (but also consequently Th1 depleted, hence macrophages are under-stimulated). Notably, GcMaf (Gc Macrophage Activating Factor) helps some PwME to feel better.

Of course, we don't routinely get tested in order to characterise our Th phenotypes, so this potential sub-grouping biomarker gets overlooked by our doctors.

Non of the above helps to explain what is causing any of this to happen, although the existence of a persistently aggravating / chronic viral infection (such as EBV) would seem to me to be a likely candidate.

However, overall, I think that this explanation fits well with the Prof. Edward's Model 5 M.E.

 

[chipmunk1]

Because some patients push themselves too hard and constantly crash as a result, they don't fit the usual stereotype of ME/CFS patients having a presumed exercise phobia. Hence this BPS group suggests that one group of patients has kinesiophobia (an absurdity in itself compared to real phobias), and the rest have unrealistic expectations of their own capabilities as they age, etc, and exceed their normal limitations.

we have already understood that it's always, ALWAYS! the patient's fault:

If they don't follow the suggestions it's their fault that they aren't getting better because they didn't try hard enough
If they do follow them it's their fault that they aren't getting better because they tried too hard.
If they get better on their own they never were ill in the first place which means it was it was their fault.
If they get better while doing a therapy, it means that it was psychosomatic and therefore the patient's fault.
If the patient disagrees with a crazy theory it proves that it is psychosomatic and therefore it's the patients fault.
If the patient agrees with a crazy theory: We told you so. it was your fault.