Are Infections Just a Trigger of ME/CFS, or an Ongoing Cause of ME/CFS?

[halcyon]

Any idea if the ME/CFS outbreaks that appeared in these locations were just one or two cases, or were they a major outbreak like in Incline Village? Checking on the map, these places are fairly distant from Lake Tahoe (20 miles or further), so you would not expect them to be hit with algae toxins from the lake (unless people from those places were working near Lake Tahoe).

It looks like Yerington was 100 cases. Truckee and Incline Village combined was 200 cases. Not sure about Placerville, but it's listed as being due to contamination of the local water supply, so I imagine it affected a number of people.

 

[Hip]

As far as I know there is no evidence whatever for a 'balance' between TH1 and TH2. More TH1 does not imply less TH2, just as more vegetables does not imply less meat. You might want lots of both. The systems dynamics of the immune system are much more complex and like a high class kitchen. Broderick is on to this sort of thing with his mathematical models but I am not clear that he has enough data to validate them.

Just to be clear, can I ask, are you saying that the immune system is more complex than this Th1/Th2 balance model assumes, meaning that the model is an oversimplification, but there may be some truth to the model, ie, an approximation to the truth?

Or are you saying that there is no evidence whatsoever for this Th1/Th2 balance model, ie, for the idea that if Th0 cells go down the Th1 route, then there can be a deficiency and suppression of Th2 cells, and vice versa?



In any case, do any ideas or interpretations spring to mind when looking at the cytokine data from Chia's oxymatrine work, or Montoya's Valcyte study?

How can we interpret the increase in Th1 cytokines (IL-12, IL-2, IFN-γ) that appeared alongside improved ME/CFS symptoms and reduced viral load when these two immunomodulators were used?

The usual interpretation by ME/CFS doctors like Dr Chia is that the immunomodulators induce an increase in Th1 cytokines, which then ramp up the intracellular immune response, which helps clear out viral infection, leading to improved ME/CFS symptoms. And I think the assumption by these doctors is that the Th1 response is stuck or under par because the Th2 response is overactivated.

But if this Th1/Th2 balance model is not valid, then we would need to find another explanation for why the intracellular immune system in ME/CFS patients seems weak or stuck, but can be coaxed back into action by immunomodulators.

Perhaps another interpretation is that the immunomodulator has done something which makes the immune system "more aware" of the presence of these intracellular infections (ie, improves the ability of the immune system to detect these infections), and the Th1 cytokines then just appear as a natural consequence of the immune system gearing up to fight the infection, rather than anything to do with the Th1/Th2 balance.

It would be good to attempt to understand what is going on when these immunomodulators improve ME/CFS symptoms and reduce viral loads, because it does seem that in some sense the immune system has got stuck in ME/CFS patients, and is not fully responding to and eradicating the viral infections.

If we can figure out exactly why ME/CFS patients appear to be stuck when it comes to intracellular immunity, we might be able to develop a treatment that rectifies the situation.

 

[Hip]

It looks like Yerington was 100 cases. Truckee and Incline Village combined was 200 cases. Not sure about Placerville, but it's listed as being due to contamination of the local water supply, so I imagine it affected a number of people.

That would make sense if all the locations that the Lake Tahoe ME/CFS outbreak hit were supplied by the same contaminated drinking water source. Do we know if this is the case?

 

[Valentijn]

That would make sense if all the locations that the Lake Tahoe ME/CFS outbreak hit were supplied by the same contaminated drinking water source. Do we know if this is the case?

In the case of Truckee, the new ventilation system in the high school was implicated, due to mold or something in the system combined with sealed windows. Apparently the faculty lounge was particularly hard hit.

 

[halcyon]

That would make sense if all the locations that the Lake Tahoe ME/CFS outbreak hit were supplied by the same contaminated drinking water source. Do we know if this is the case?

No idea. They may all share an upstream source at some point, but I imagine they all have different local storage and treatment facilities.

 

[Hip]

No idea. They may all share an upstream source at some point, but I imagine they all have different local storage and treatment facilities.

I found a map of the local water supply in the Lake Tahoe area, which seems to indicate the drinking water in the area comes from Lake Tahoe.

 

[Jonathan Edwards]

Just to be clear, can I ask, are you saying that the immune system is more complex than this Th1/Th2 balance model assumes, meaning that the model is an oversimplification, but there may be some truth to the model?

Or are you saying that there is no evidence whatsoever for this Th1/Th2 balance model, ie, for the idea that if Th0 cells go down the Th1 route, then there can be a deficiency and suppression of Th2 cells, and vice versa?

I don't know of any evidence whatsoever for a Th1/Th2 balance model in human disease. I would be interested to hear of evidence but I never heard of any yet.

I do not see why T cells going down a Th1 route would reduce them also going down a Th2 route. Presumably we are talking of a proliferation response in which a Th0 cell gives rise to a Th1 cell and a Th0 cell that retains the memory potential for producing more cells later or either sort. So next time round the remaining Th0 cell can bud off a Th2 cell. I am not aware of any competition between the two pathways although there is relative expansion of either type at different stages of responses to different microbes.

My problem with all the work with so called anti-viral immunomodulators in ME is that we do not have any reliable evidence for them having any effect. People may get better while using them but the trials have not so far shown clearly that the drug produces the improvement. There are so many steps not validated in these stories. But even if these drugs do increase Th1 cytokines I know of no good reason to think that the problem is due to poor Th1 cells secondary to too much Th2. (And in the Montoya study Th2 cytokines did not go down!) My understanding of immunological disease is that the problems are much more specific than that and nothing to do with 'imbalance'.

We would only need to find another explanation for a weak intracellular immune response in ME if there actually is a weak or stuck response and I see no clear evidence for that so far. Across the spectrum of researchers the is fairly little enthusiasm for such a theory.

 

[halcyon]

I do not see why T cells going down a Th1 route would reduce them also going down a Th2 route.

I thought the main idea with the th1/th2 polarization model is that the th1 cytokines downregulate expression of th2 cytokines, and vice versa.

 

[Jonathan Edwards]

I thought the main idea with the th1/th2 polarization model is that the th1 cytokines downregulate expression of th2 cytokines, and vice versa.

They do, but it is a very large and dubious step to extrapolate to the idea that somehow they are competing with each other for 'dominance'. What seems much more likely to me is that the mutual inhibition is a way of the lymph node arranging that Th1 cells get together and do their job in one place and Th2 cells get together and do their job in another place - which makes sense since they do different jobs. A standard immune response to a microbe will evolve through phases where Th1 cells or Th2 cells are the main focus of expansion but they both have a job to do. If there is a thumping great load of antigen about both are likely to get a bit stimulus. A teeny bit of antigen and not much of either. In both cases the mutual inhibition will make sure there is effective division of tasks.

I am most familiar with people talking about the balance as 'scene setting' for risk for autoimmune or autoinflammatory disease and in the diseases I have studied it just seems irrelevant. The scene setting for RA is HLA-DR4 (and PTPN22 which is involved in B cell receptor editing). The scene setting for ank spond is HLA-B27 and the common cytokine receptor that picks up IL-17.

 

[lansbergen]

@Jonathan Edwards

What would you think when an immune modulator makes the difference between live and death in young animals and the sooner it is started the sooner the symptoms disappear?

 

[Hip]

What would you think when an immune modulator makes the difference between live and death in young animals and the sooner it is started the sooner the symptoms disappear?

What are you talking about?

 

[Hip]

But even if these drugs do increase Th1 cytokines I know of no good reason to think that the problem is due to poor Th1 cells secondary to too much Th2. (And in the Montoya study Th2 cytokines did not go down!) My understanding of immunological disease is that the problems are much more specific than that and nothing to do with 'imbalance'.

So you are saying that that immunomodulators like oxymatrine and Valcyte may be increasing the intracellular immune response by increasing Th1 cytokines, but that has nothing to do with Th2. They may just induce an increase in Th1 cytokines independent of Th2.

 

[heapsreal]

So you are saying that that immunomodulators like oxymatrine and Valcyte may be increasing the intracellular immune response by increasing Th1 cytokines, but that has nothing to do with Th2. They may just induce an increase in Th1 cytokines independent of Th2.

My thoughts were that immune mods that have evidence to work like immunovir are actually interferon inducers or stimulators and this increase in interferon has antiviral properties itself but also increases nk function.

i think it was dr lerner who mentioned that herpes viruses have a way of avoiding the immune system by somehow turning down interferon production. I guess its possible with other viruses or if some other mechanism lowered interferon than this could allow infections like EV and herpes viruses that are so common to reactivate in those with low interferon??

i can recall dr lerner mentioning th1/th2 responses but could be wrong. Th balancing theory was pushed alot by dr cheney back in the day . Dr chia seems to mention alot about th1 and th2 response .

 

[minkeygirl]

Is there a way to test for low Interferon?

 

[heapsreal]

Is there a way to test for low Interferon?

Not sure but low nk function would be an indication its low i guess ?

 

[Eeyore]

NK function can be low for quite a few reasons - so no, you cannot deduce much about interferon levels from NK function alone, although conceivably there could be a correlation.

Interferons can be quantitatively measured and you can look at the results of doing so in many ME patients in the recent Hornig/Lipkin study. It is either in the main article or the supplementary material (the latter includes all the measured cytokines).

There is more than one interferon too, and they do different things and have different medical applications. Type 1 interferons include alpha and beta, and they work somewhat similarly, but not identically. Type 2 would be gamma interferon. These have different (and in some cases opposite) effects on immune function and cellular vs humoral immunity. Hep C is often treated with interferon alpha and MS with interferon beta. Interferon gamma is used to treat granulomatous disease.

When talking about interferons you do need to be specific as they are not the same.

I used to think Dr. Edwards and I differed more on our views on th1/th2, but I think it's really more about precision of speech and semantics - although we may still differ some. It is not like a scale where adding one reduces the other, and vice versa - and the 2 do not act independently. An infection gives you both cellular and humoral immune responses, but at different levels at different stages of the infection and for different infections.

One point where I would differ is that induction of the transcription factor GATA3 (which is the master transcriptional regulator for th2 cells) does shut down th1 activity, even in the presence of signals that would normally stimulate a cytotoxic response (ifn-gamma, il-12, etc.) I think it is likely that in the early stages of infection you want more inflammation, but over time, you need to quiet the inflammation, and so you want to eventually shut it down and move to a th2-type response. This is, however, all oversimplified - but I find it to sometimes be a useful model to conceptualize what is happening. It can be very hard to see the big picture in immunology, and miss the forest for the trees, if you focus too much on detail - or maybe it's just that my brain can hold as much at once as it used to.

I think rather than thinking of th1 and th2 cell populations or competition for dominance, I think of them as representing immune states, groups of cytokines that tend to be expressed together and reinforce each other, along with other immune cells. I do not believe there is actually a defect in CD4 cell function at the root of ME. It is easier to remember and associate certain cytokines with certain types of immune function.

Human biology regulates the production of genes in bunches rather than individually (for many things at least). A given transcription factor (this is a protein or other molecule that affects whether genes are transcribed or not) will usually trigger the transcription of multiple genes at once, and may also have a negative effect on the transcription of other genes. The result is that you tend to have things expressed together, in patterns, rather than uncorrelated individual gene expression. A given transcription factor will produce an array of gene products that all have a cohesive, logical function.

It's possible to stimulate more th1 or th2 alone or together, or to suppress both - so the word balance may not adequately capture the complexity of the situation. To some degree there do appear to be discrete populations of CD4 cells that make certain cytokines and become committed to a particular function, but it's not clear exactly how much plasticity there is in that polarization.

 

[Mel9]

Just to be clear, can I ask, are you saying that the immune system is more complex than this Th1/Th2 balance model assumes, meaning that the model is an oversimplification, but there may be some truth to the model, ie, an approximation to the truth?

Or are you saying that there is no evidence whatsoever for this Th1/Th2 balance model, ie, for the idea that if Th0 cells go down the Th1 route, then there can be a deficiency and suppression of Th2 cells, and vice versa?



In any case, do any ideas or interpretations spring to mind when looking at the cytokine data from Chia's oxymatrine work, or Montoya's Valcyte study?

How can we interpret the increase in Th1 cytokines (IL-12, IL-2, IFN-γ) that appeared alongside improved ME/CFS symptoms and reduced viral load when these two immunomodulators were used?

The usual interpretation by ME/CFS doctors like Dr Chia is that the immunomodulators induce an increase in Th1 cytokines, which then ramp up the intracellular immune response, which helps clear out viral infection, leading to improved ME/CFS symptoms. And I think the assumption by these doctors is that the Th1 response is stuck or under par because the Th2 response is overactivated.

But if this Th1/Th2 balance model is not valid, then we would need to find another explanation for why the intracellular immune system in ME/CFS patients seems weak or stuck, but can be coaxed back into action by immunomodulators.

Perhaps another interpretation is that the immunomodulator has done something which makes the immune system "more aware" of the presence of these intracellular infections (ie, improves the ability of the immune system to detect these infections), and the Th1 cytokines then just appear as a natural consequence of the immune system gearing up to fight the infection, rather than anything to do with the Th1/Th2 balance.

It would be good to attempt to understand what is going on when these immunomodulators improve ME/CFS symptoms and reduce viral loads, because it does seem that in some sense the immune system has got stuck in ME/CFS patients, and is not fully responding to and eradicating the viral infections.

If we can figure out exactly why ME/CFS patients appear to be stuck when it comes to intracellular immunity, we might be able to develop a treatment that rectifies the situation.

I have a question for those with immunology expertise - important as it is getting into the 'flu' season in southern hemisphere. If the immune system is weak in people with ME CFS, should they avoid the flu vaccine?

 

[Eeyore]

This is a difficult question. One ME specialist told me that if I had had vaccines previously, and not had a bad reaction, then I should get the vaccine. If I had had a bad reaction or had no experience, I should avoid it. Other ME specialists have suggested that one should get it as the flu is much worse and could cause more serious issues.

It is my personal opinion, but not medical advice (which you should seek from your physician, not a forum) that the live attenuated vaccines are much safer than the heat killed versions. These are usually nasal sprays or something similar.

 

[Hip]

My understanding of immunological disease is that the problems are much more specific than that and nothing to do with 'imbalance'.

We would only need to find another explanation for a weak intracellular immune response in ME if there actually is a weak or stuck response and I see no clear evidence for that so far. Across the spectrum of researchers the is fairly little enthusiasm for such a theory.

One area of the immune system that has been considered as an explanation for why ME/CFS patients do not clear intracellular infections is STAT-1 deficiency.

One study found there was a STAT-1 deficiency in a subset of ME/CFS patients (refs: here and here). As I understand it, STAT-1 relays the interferon signal into the cell, and so if STAT-1 levels are low, the intracellular immune response triggered by interferon will be weak.


Interestingly, in this paper it notes that un-methylated STAT-1 is less active than methylated STAT-1 :

Unmethylated STAT1 is less active since it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). The treatment of cells with S-adenosyl-L-methionine (AdoMet [aka: SAM-e]) and betaine could restore STAT1 methylation and improve IFN alpha signaling.

It occurred to me that this might provide an alternative explanation as to why the methylation protocol can improve ME/CFS symptoms: the methylation protocol may be of benefit for ME/CFS because may boost interferon activity, as a result of methylating STAT-1 and thereby making STAT-1 more active.

 

[duncan]

I'm not sure of the relevance, but has anybody seen the new Parkinsons Disease study speaking to the infectious burden in Parkinsons patients? A Chinese effort published May of this year? The conclusion supports the role of infection in the eitiology of PD?

For the life of me, I cannot figure out the journal's name. Sorry. But its findings may have some cross-elasticities with ME/CFS.