Do MEs cause CFS?

[catly]

How about the contribution of the sex hormones, perhaps menopause since this disease (s) affects women quite predominantly ? Case or effects?

And I will repeat my question for @Jonathan Edwards can ANA pattern switch from speckled to homogenous?

First thanks to @Jonathan Edwards for engaging with us here on PR. I look forward to your posts on the possible auto-immune correlation with ME and the pending research.

Regarding @Kati's comment above. I believe that my ME was triggered by menopause.

What started as "normal menopause" type symptoms (e.g. typical hot flashes/night sweats, pounding heart rate at night, fleeting anxiety) which 80% of my friends had, somehow culminated in extreme neuro type symptoms (CNS, ANS, SNS), overwhelming and incapacitating fatigue and PEM and brainfog which have left me able to do only about 25% of what I could do before hand.

I had no viral trigger, stress or any other explainable cause. I was very active and very fit and rarely got any kind of colds or other viruses. In fact, I hadn't missed a day of work in 25 years due to illness and was throughly enjoying the mild winter we had in the Northeast US when MECFS struck suddently in Feb of 2012.

Clinically, I have:

• +ANA (first speckled and then switched to both speckled and homogenous), neg auto-antibodies for Lupus
• Low +CCP, boardline RF but only mild joint pain without swelling or evidence of RA. Although with my intial onset of ME symptoms I had overnight appearance of tendonitis (trigger finger) in 3 fingers. This lasted for a year or so and eventually just disappeared
• "sub-clinical" hypothyroidism with TSH going up steadily over the course of a year, corrected by thyroid meds, which definately didn't help help my fatigue and especially not PEM/PENE
• + anti-TPO antibodies with hashimotos confirmed on tissue sample from the partial thyroidectomy I had for a nodule that turned out to be CA,

• SICCA syndrome but no auto-antibodies for Sjögrens
• antibodies suggesting reactivation of EBV (though I never had mono) and HHV-6 and,
• very low NK function (which is maybe why I got thyroid CA?)

I'm not sure what category I would put myself into. I had both PEM and possible "auto-immune" type fatigue which could have been impacted by high auto-antibodies when I was at my worst last year. But my initial symptoms were and continue to be more neurological. I have to kind of agree with @Alex's comments about a nervous system, and cosequently an imune system in chaos. Possibly in my case either triggered by auto-immune diseae and/or hormonal changes seconday to menopause.

 

[taniaaust1]

Thanks Jonathan Edwards for being here and starting up such interesting discussions. (thou I cant figure out in all the groups I fit. I have severe autonomic issues thou with this illness. My orthostatic hypertension is now going up over 190! but I have low BP when laying, I also have severe POTS.. all as part of the ME I have in which I get over 90 different symptoms too. This illness recently caused me to have to be ambulanced to hospital 3 times for a drip in 6 weeks as I collapsed and couldnt get back up (they actually had to give me 2L, 2 bags of saline each time to bring my BP down!. Im going hypertensive in response to low blood volume).

This illness has now started to affect my kidneys due to my low blood volume. (the experienced blood nurse who came to my home to get some blood from me last week, couldnt even get enough blood from me to do 3 small tubed lots of blood tests, she tried from not just my arms but my feet too so has to come back and try again.

I have another angle to add to twin studies. We have M.E in three generations of females in my family: My mother, a maternal cousin, myself and my daughter with an M.E like illness. The point being that I was adopted at 6 weeks and my brith mother with an M.E diagnosis never saw me, or even held me after birth, and yet the genetic susceptibility seems to exist within our family.

My birth mother also has the hypothyroid issues and I now have positive ANA (speckled) my presentation was gradual and I have had onle long remiison for several years to near normal. My daughters presentation was sudden onset.

Anyway, very interesting discussion, so much I would like to say about the science, rather than just personal anecdote, but i'm afraid that my brain does not work in the way it used to and I find it very hard to take part. But I thank @Jonathan Edwards very much for being here to take part in and initiate these discussions.

I wish they'd study families too. Out of my nannas 5 sons (4 of them are celiacs, one has Aspergers, one has severe systemic mastocytosis), 3 of these sons (my father and uncles) have children with ME/CFS, there are now 4 of us with ME/CFS (all females) as my sister has it now too (its having a 25% hit rate on us and none of us are past mid 40s yet. We all have grown up and live in different states of the country).

With my nannas illnesses, Im certain this illness or genetic suseptability came down from my nanna and not my grandfather as she's got FM, rheumatoid arthritis, ostero arthritis, IBS, lactose intollerance, migraines/headaches, insomina etc. (she hasnt got ME/CFS thou, no post exertional issue)

What is interesting is that there was ME outbreaks here (In Sth Australia in the 1950s) close to where she lived. So did she get something and is a carrier so passed it on two generations later (she didnt have any daughters only sons).

 

[mellster]

Interesting write-up, though I could not categorize my 3-4 year stint in any of those. ME5 sounds interesting, but most patients exhibit low NK cell numbers/activity and thus very likely low gamma interferon, which may also explain problems with degranulization in lymph nodes and other tissue. ME6 is interesting, too, but very vague. While there are likely many causes and forms I maintain my skepticism towards auto-immune classification or immune-system overreaction. In fact gamma interferon is likely underexpressed in patients with chronic viral loads, so I would vote for including a reverse ME5 thesis. Many pathogens (viruses, bacteria, parasites) can exhibit immunosuppressive effects and some may feed off each other.

 

[Marco]

By 'prodromal' (i.e. the use of inverted commas) and the fact that you state 'not necessarily related', do you mean coincidental?

Not necessarily related to autoimmunity but I was thinking of any 'predispositions' perhaps showing up in different ways prior to what we would call onset. In my case I recall things like despite swimming everyday it always felt like a struggle, I always ended the session overheated and flushed and I never seemed to increase my stamina - it just plateaued. I was also thinking of other perhaps personality related things even when fully physically well. In my case social anxiety plus I'm pretty sure I would have scored highly on an Aspergers checklist (even more so these days).

Of course its very easy to read too much into things in hindsight and it may just be me. I'm also loathe to give too much credence to the accuracy of a diagnosis of ME/CFS.

 

[Jonathan Edwards]

And I will repeat my question for @Jonathan Edwards can ANA pattern switch from speckled to homogenous?

Sorry, I missed this one. Yes patterns of ANA can change. But remember that the 'pattern' may depend on the cells used by the lab and the opinion of the technician. There are a huge number of slightly different patterns. Sometimes they are mixed. So the technician one day might think 'that's pretty homogeneous' and another day 'I guess that's a bit speckly'. And of course it may be a different technician. To be sure there is a change you really need ELISA results on individual antigens.

 

[Jonathan Edwards]

@ Jonathan Edwards,

Is it possible for you to direct us to some references (preferably not behind a pay wall) that show graphical show the steps in the RA system, feedback loops etc? I think it might be helpful (to at least me and probably others) to be able to visually see some of these interactions and loops, etc.

It is all rather complicated but you might find our 1999 Immunology article gives an idea of the general mechanism. It is called 'Do self-perpetuating B lymphocytes drive human autoimmune disease?' If you look up the ResearchGate website and type my name in hopefully you will pull up my RG page which has that and some other papers available at a click. You might have to sign up to RG to get that but I hope not.

 

[thegodofpleasure]

It is all rather complicated but you might find our 1999 Immunology article gives an idea of the general mechanism. It is called 'Do self-perpetuating B lymphocytes drive human autoimmune disease?' If you look up the ResearchGate website and type my name in hopefully you will pull up my RG page which has that and some other papers available at a click. You might have to sign up to RG to get that but I hope not.

Thanks Prof. Edwards. FYI, your paper is freely available here: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2567.1999.00772.x/full

 

[MeSci]

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.

We must be in different subgroups then! I have had fewer respiratory infections since becoming ill, and the only change is that is has gone from very few to none. Like others, I felt much better when I appeared to have a proper cold or flu.

The only possible infections I can recall since getting ME have been in the ears and/or urinary tract, other than gut problems that might be better described as dysbiosis than infection.

 

[voner]

Continued from the thread: Who tried immunosuppressive treatment/drugs.

Do MEs cause CFS?

......

5. ME5 is a speculation rather than something I have evidence for, but the specific autoimmune types I have given so far will not cover the majority. There is at least one more type needed and this is my guess. ME5 involves a sensitisation of the immune signalling mechanisms triggered by viruses. As part of an immune response to a virus the system produces antibodies that sensitise the ‘virus alarm system’ to the extent that even when there is no virus around it may trigger, just with exercise or stress. Two molecules might be particularly important here: gamma interferon and the immunoglobulin receptor FcRI (CD64) which is used to ‘pre-arm’ phagocytes with antibody even before any foreign pathogens have arrived.

.....lll

@ Jonathan Edwards,

Any speculation on The possibility of a gut virus attack kicking off bacteria population inbalances in the gut, leading to long-term gut issues and possible autoimmunity?

Here is a blog (by Cort Johnson, the founder of this website) on a presentation by Dr. Maddie Horning on Dr. Lipkin goup's investigation into viruses, gut related issues and ME/CFS.

http://simmaronresearch.com/2013/03/hornig/

I'm especially interested in seeing the results of The Shukla CFIDS Association gut metagenome study that is mentioned...

 

[Jonathan Edwards]

@ Jonathan Edwards,

Any speculation on The possibility of a gut virus attack kicking off bacteria population inbalances in the gut, leading to long-term gut issues and possible autoimmunity?

Here is a blog (by Cort Johnson, the founder of this website) on a presentation by Dr. Maddie Horning on Dr. Lipkin goup's investigation into viruses, gut related issues and ME/CFS.

http://simmaronresearch.com/2013/03/hornig/

I'm especially interested in seeing the results of The Shukla CFIDS Association gut metagenome study that is mentioned...

I don't really have any thoughts about viruses altering bacterial populations in the gut, although gut infections of various sorts can lead to long term gut dysfunction and malabsorption. In general I do not think infections lead to autoimmunity much, although I am prepared to believe that some MEs are exceptions. My description of ME5 may not have been very clear. I am not sure that I wanted to imply that a virus triggered the antibodies in the first place, merely that an antibody response evolved that over-sensitised the response to any future virus. But, as discussed before, it would be hard to distinguish.

My understanding from Mady Hornig's presentation in May was that they had not really found much in the way of viruses.

 

[MeSci]

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!

Apologies if this has already been said (I'm still ploughing through the thread), but could not the vascular tone problem be caused by solute diuresis that leaves us with both low blood volume and low electrolytes? Both of these phenomena seem to be common in ME.

I've been worrying at this issue myself, and there seems to be a pattern:

• Exertion leads to increase in pro-inflammatory cytokines
• Increase in pro-inflammatory cytokines leads to solute diuresis
• Solute diuresis leads to hypovolaemia/dehydration and electrolyte deficiency.

Some of us have remarked on a similarity between PEM and hangovers, which also result from dehydration and electrolyte deficiency.

I've done a quick blogpost on this, consisting mostly of abstracts from PubMed.

Further circumstantial evidence for the theory is that a number of people here have reported feeling much better after IV saline.

 

[Scarecrow]

I wish they'd study families too.

Probably not exactly what you are looking for but it's a start: http://phoenixrising.me/archives/24522

Go to Searcher 11.08

 

[rosie26]

I don't really have any thoughts about viruses altering bacterial populations in the gut, although gut infections of various sorts can lead to long term gut dysfunction and malabsorption. In general I do not think infections lead to autoimmunity much, although I am prepared to believe that some MEs are exceptions. My description of ME5 may not have been very clear. I am not sure that I wanted to imply that a virus triggered the antibodies in the first place, merely that an antibody response evolved that over-sensitised the response to any future virus. But, as discussed before, it would be hard to distinguish.

My understanding from Mady Hornig's presentation in May was that they had not really found much in the way of viruses.

That is my feeling, in my case, you said " I am not sure that I wanted to imply that a virus triggered the antibodies in the first place, merely that an antibody response evolved that over-sensitized the response to any future virus."
I guess that's why I am not personally interested in viruses as others are.
I wonder if some bacteria can act like viruses setting up alarm signals - even after infection has been cleared. I don't know enough to know if that can happen as well.

 

[alex3619]

@rosie26, I think that is indeed the case, that bacteria can send alarm signals to a sensitized immune system, and clearance or non-clearance might be only part of it. We have inbuilt sensors for things like bacterial lipopolysaccharide (LPS). We have learned responses too. It is often the case that high levels of LPS are found in ME patient blood. LPS is a what is called a superantigen, it has the capacity to massively induce an immune response. Immune cells called gamma delta T cells can migrate to sites of high LPS, and there they can induce or suppress the immune response. Yet LPS is only one common bacterial substance, there are others. It is also the case that we carry billions of bacteria in our body. If detox fails, particularly in the gut lining and liver, then products from these bacteria can make it to the blood and general immune system. I have speculated about this before, and always wanted to write a blog on it, but it still sits half finished several years later.

 

[thegodofpleasure]

@rosie26, I think that is indeed the case, that bacteria can send alarm signals to a sensitized immune system, and clearance or non-clearance might be only part of it. We have inbuilt sensors for things like bacterial lipopolysaccharide (LPS). We have learned responses too. It is often the case that high levels of LPS are found in ME patient blood. LPS is a what is called a superantigen, it has the capacity to massively induce an immune response. Immune cells called gamma delta T cells can migrate to sites of high LPS, and there they can induce or suppress the immune response. Yet LPS is only one common bacterial substance, there are others. It is also the case that we carry billions of bacteria in our body. If detox fails, particularly in the gut lining and liver, then products from these bacteria can make it to the blood and general immune system. I have speculated about this before, and always wanted to write a blog on it, but it still sits half finished several years later.

@alex3619 Do you have any thoughts on how that scenario would lead to the initial creation of the kind of auto-reactive B cells which appear to be crucial to perpetuating the illness process ?
To me, the answer to that question is probably a big part of the puzzle in (at least) ME1 & ME2

 

[alex3619]

@thegodofpleasure That was the point of my blog. I have forgotten much of what i was going to write, but I have hundreds of pages of relevant papers and material I collected in a desktop folder. It induces multiple things. The first is it causes cytokine shifts (with more TNF alpha if I recall correctly), and migration of immune cells. If the gamma delta T cells are strongly drawn to the gut to deal with LPS, then they may be less active elsewhere. That is something I wanted to explore. Gamma delta T cells are part of the inflammatory suppression response, and if they are not doing what they should it could lead to increased risk of inflammation and autoimmunity ... perhaps. Then I broke my ankle, wound up in hospital for two months after surgery, then never really recovered my thinking capacity. So the blog is on hold.

 

[Marco]

@Jonathan Edwards @alex3619 (or anyone else for that matter).

You might be interested in Cort's latest blog covering the systems approach to a complex problem like ME/CFS taken by Broderick, Younger and others which is similar to some of what we've been discussing here, although perhaps at a more macro level :

http://www.cortjohnson.org/blog/201...ome-amenable-intervention-dr-broderick-talks/

Younger's finding that individual ME/CFS patients' fatigue days closely correlate with fluctuations (within normal parameters) in leptin levels interests me. Although not to my knowledge currently classed as an 'alarmin' (its an emerging field) leptin is the the kind of signal of metabolic/cellular 'stress' that sensitised glial cells might theoretically over-react to (ATP is another via purinergic pathways). Leptin also has the interesting property that it can not only prime microglia but also modulate how they react to subsequent immune challenge.

 

[thegodofpleasure]

@Jonathan Edwards Whilst I think that nowhere near sufficient attention is focussed on mitochondrial impairment as a crucial component of fatiguing illnesses, is it really such a distinct entity in ME as to merit a separate ME sub-group?

Were you perhaps thinking that there may be a specific internal structural / genetic mitochondrial defect when speculating about the existence of ME6 ?

As I understand it, Dr Myhill & colleagues believe that (amongst other things) oxidative and nitrosative stress (due to multiple causes/factors) does damage to mitochondrial membranes, resulting in low anaerobic threshold in the majority of PwME - which certainly fits with the "energy envelope" and "pacing" theories for managing the illness.
Their work seems to show that mitochondrial dysfunction is pretty ubiquitous within ME and hence is involved (to some extent at least) in all ME subgroups.

You have already mentioned the work of Prof. Jonas Blomberg's group in Sweden, which discovered antibodies to epitopes of HSP60 in a large proportion of PwME. This discovery would seem to have (structural membrane & ATP transport) implications for mitochondrial function (and ties in nicely with the benefits of Rituximab & the work of Fluge & Mella), but until their work has progressed further, we won't know for certain, to what extent anti-HSP60 antibodies play a role in mitochondrial impairment. I'm sure that if it comes, independent confirmation of their work would represent a major step towards understanding many ME subgroups.

On reflection, do you really think that there is a need for a separate mitochondrial subgroup - ME6 ?

 

[thegodofpleasure]

@thegodofpleasure That was the point of my blog. I have forgotten much of what i was going to write, but I have hundreds of pages of relevant papers and material I collected in a desktop folder. It induces multiple things. The first is it causes cytokine shifts (with more TNF alpha if I recall correctly), and migration of immune cells. If the gamma delta T cells are strongly drawn to the gut to deal with LPS, then they may be less active elsewhere. That is something I wanted to explore. Gamma delta T cells are part of the inflammatory suppression response, and if they are not doing what they should it could lead to increased risk of inflammation and autoimmunity ... perhaps. Then I broke my ankle, wound up in hospital for two months after surgery, then never really recovered my thinking capacity. So the blog is on hold.

@alex3619 That's a very interesting theory and, on the face of it, quite a plausible one. Perhaps Prof. Simon Carding's group at the Institute of Food Research in Norwich could be encouraged to have a look into it ?
http://www.ifr.ac.uk/research/scientists/simon-carding/

To move things forward, you really need to write that blog !

 

[alex3619]

The Leptin finding was discussed at the Stanford conference, and I think there is a thread on this here. It fits with the microglial theory of ME I think. My current understanding is that this is connected to fluctuations in leptin, not high leptin, which might point to either sensitivity or leptin being a surrogate marker for something else.