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Hornig/Lipkin cytokine study out now - press release

halcyon

Senior Member
Messages
2,482
Can someone point me to which part of the study suggested it could be a hit and run disease? I'm highly skeptical of the hit and run hypothesis. I'll admit that my understanding of the immune system is basic at best, and probably wrong at worst, but from what I understand, the immune system is primarily driven by antigen detection (especially in the situation where a large number of diverse cytokines would be released by diverse immune cells responding in a cascade as they do). With all of the evidence that we have for persistent infections in ME, does it make more sense that the immune system is chronically activated because there is a chronic infection present, or that the immune system is freaking out responding to thin air?
 

SOC

Senior Member
Messages
7,849
Can someone point me to which part of the study suggested it could be a hit and run disease? I'm highly skeptical of the hit and run hypothesis. I'll admit that my understanding of the immune system is basic at best, and probably wrong at worst, but from what I understand, the immune system is primarily driven by antigen detection (especially in the situation where a large number of diverse cytokines would be released by diverse immune cells responding in a cascade as they do). With all of the evidence that we have for persistent infections in ME, does it make more sense that the immune system is chronically activated because there is a chronic infection present, or that the immune system is freaking out responding to thin air?
I wonder the same thing. Is the hit-and-run theory driven only by the fact that they can't find a single pathogen in all of us? That seems unlikely since it could obviously be an as-yet-unknown, or not-sufficiently-studied pathogen.

Perhaps the theory is not rejecting the notion that once immune dysfunction is initiated, we become susceptible to multiple opportunistic infections continuing to drive immune activation. Maybe they are only hypothesizing that the pathogen that initiated the immune dysfunction is no longer driving the immune activation...? :confused: Even so, that seems to ignore the clear possibility that the pathogen is currently undetectable rather than non-existent. Thoughts?
 

halcyon

Senior Member
Messages
2,482
It appears they're not giving up on the chronic infection idea at least. From the Columbia CII blog:

In separate ongoing studies, they are looking for “molecular footprints” of the specific agents behind the disease—be they viral, bacterial, or fungal—as well as the longitudinal look at how plasma cytokine patterns change within ME/CFS patients and controls across a one-year period, as noted above.

I hope they're not just looking at plasma again.
 

Kati

Patient in training
Messages
5,497
Can someone point me to which part of the study suggested it could be a hit and run disease? I'm highly skeptical of the hit and run hypothesis. I'll admit that my understanding of the immune system is basic at best, and probably wrong at worst, but from what I understand, the immune system is primarily driven by antigen detection (especially in the situation where a large number of diverse cytokines would be released by diverse immune cells responding in a cascade as they do). With all of the evidence that we have for persistent infections in ME, does it make more sense that the immune system is chronically activated because there is a chronic infection present, or that the immune system is freaking out responding to thin air?

I believe a previous publication from CII could not find pathogens, only a couple of cases of HHV-6A but also present in healthy controls.
 

zzz

Senior Member
Messages
675
Location
Oregon
Can someone point me to which part of the study suggested it could be a hit and run disease? I'm highly skeptical of the hit and run hypothesis. I'll admit that my understanding of the immune system is basic at best, and probably wrong at worst, but from what I understand, the immune system is primarily driven by antigen detection (especially in the situation where a large number of diverse cytokines would be released by diverse immune cells responding in a cascade as they do). With all of the evidence that we have for persistent infections in ME, does it make more sense that the immune system is chronically activated because there is a chronic infection present, or that the immune system is freaking out responding to thin air?

From my reading of the study, and based on the material I referenced in my previous post, I would say that the answer to your last question is "Neither." Instead, whatever triggers this illness triggers a type of immune dysfunction that has not been seen before; hence the reference to "the presence of a specific immune profile early in the course of ME/CFS" in the paper. As there are known to be many different triggers for ME/CFS, there does not seem to be a single cause for this immune dysfunction. But although in some cases of ME/CFS (such as those triggered by EBV), the triggering pathogen often sticks around, in a large proportion of the cases, if not the great majority, the trigger (which may or may not be viral or bacterial) typically disappears shortly after the onset of illness. Hence, hit-and-run.

But what causes this immune system activation in the early years? Again, the email from Jarred Younger seems to clarify this:
He suggested systemic inflammation may drive ME/CFS early on but sensitized microglia and astrocytes in the central nervous system drive it in its later stages. Because we don’t have good ways to test central nervous system inflammation at that point the disease mostly becomes invisible to testing afterwards.

Support for this statement can be found in the second paragraph of the Discussion section of the paper:
Our study has limitations... Third, our assays were conducted using only blood samples. Although blood is more easily obtained than cerebrospinal fluid, analysis of the latter may enable unique insights into immune activation in the central nervous system. This is important because many signs and symptoms of ME/CFS are consistent with central nervous system dysfunction (55).

This excerpt is particularly important because many of the symptoms of ME/CFS that are found from the beginning are neurological (e.g., cognitive dysfunction). The neurological symptoms don't wait for three years until the immune system calms down before they arise.

Note the word "systemic" at the beginning of Younger's quote. The implication is clear: The authors are not concluding that the immune system is the driving force behind this disease in its early stages; it is merely that immune dysfunction is the part that they can currently see. The quote immediately above from the paper supports the "systemic" part of Younger's quote.

If the central nervous system is the driver of this disease in its later stages, as Younger suggests, is it possible that it is the driver in the earlier stages as well? The paper certainly leaves that possibility open. In the above quote, the statement that "we don’t have good ways to test central nervous system inflammation" is the admission that the role the central nervous system plays in the early stages of this illness is not well understood.

In other places, I have related how I came down with full-blown ME/CFS in 1990, but (accidentally) managed to drive it into almost an eight-year remission with a neurological treatment, namely a single dose of Isordil (isosorbide dinitrate). I had a classic, sudden onset of the disease that appeared to be virally caused, and yet Isordil has no known antiviral effect, especially in a matter of hours. Nor does it have any known immune-modulating effects. This and many other reports of similar or even less complete remissions in the early years by drugs that act on the central nervous system lead me to believe that the CNS is the driver of this illness from the beginning. This is not to contradict the paper's conclusion that early immunomodulatory intervention may prevent long-term, recalcitrant illness. For we have seen in many cases that this illness is much more amenable to treatment in its early stages, and fixing any major part of the dysfunction may be able to eliminate the illness as a whole.

Perhaps the theory is not rejecting the notion that once immune dysfunction is initiated, we become susceptible to multiple opportunistic infections continuing to drive immune activation.

I certainly see nothing to indicate that multiple opportunistic infections may not continue to drive immune activation. In fact, once the initial dysfunction of the immune system and central nervous system occurs, opportunistic infections may very well come into play and make things worse, as too many of us know all too well.
Maybe they are only hypothesizing that the pathogen that initiated the immune dysfunction is no longer driving the immune activation...? :confused:

That is definitely how I read the paper.
Even so, that seems to ignore the clear possibility that the pathogen is currently undetectable rather than non-existent. Thoughts?

I don't think so. There are so many pathogens that can end up triggering ME/CFS, and yet the disease that they trigger has certain well-defined characteristics that are independent of the original pathogen. Sometimes we know the pathogen disappears, as in the case of a flu vaccine, yet the ME/CFS generated by that vaccine has no unique characteristics that allow us to say, "This is a vaccine-generated case of ME/CFS!" Similarly, giardia and HHV-6 have precious little in common, yet they can generate cases of ME/CFS that look very much the same. Once again, we come back to "the presence of a specific immune profile early in the course of ME/CFS," one that is independent of the originating pathogen.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I wonder the same thing. Is the hit-and-run theory driven only by the fact that they can't find a single pathogen in all of us? That seems unlikely since it could obviously be an as-yet-unknown, or not-sufficiently-studied pathogen.
They have not just failed to find a single pathogen, there are many patients who have no detectable active infection. This could be a failure to detect, or ignoring non cytopathic viruses, but the autoantibody part of immune disorders is only one subtype of immune disorder.

While the science is not as well established for autoinflammatory states, its looking reasonable. In this case the hypothesis suggests the problem might be, just might be, an increase of sensitivity in immune cells in the brain. No pathogen is then necessary. Food, chance viruses, chance mold contact, chemicals etc etc etc might then trigger it. Maybe even on a daily or an hourly basis.

None of the causation is at all nailed down. This study is about pathophysiology, not causation.

PS They have also failed to find an autoantibody situation strong enough to explain our symptoms, though there are probably individuals for whom there is indeed a strong autoantibody response.
 

halcyon

Senior Member
Messages
2,482
Instead, whatever triggers this illness triggers a type of immune dysfunction that has not been seen before; hence the reference to "the presence of a specific immune profile early in the course of ME/CFS" in the paper.
They don't refer to the early immune profile as dysfunctional though do they? Is there any evidence that this profile is actually dysfunctional? The elevated cytokines found in the early immune profile are most of the ones you would expect to see in response to a viral infection. I would argue that the late immune profile is dysfunctional however. Not being able to produce the same cytokine levels as a healthy person is a clear dysfunction.

He suggested systemic inflammation may drive ME/CFS early on but sensitized microglia and astrocytes in the central nervous system drive it in its later stages. Because we don’t have good ways to test central nervous system inflammation at that point the disease mostly becomes invisible to testing afterwards.
We don't have a good way to test for CNS pathogens either, but postmortem studies have shown the presence of (apparently persistent) neurotropic pathogens. This sure could account for increased/sensitized immune surveillance in the brain.

Our study has limitations... Third, our assays were conducted using only blood samples. Although blood is more easily obtained than cerebrospinal fluid, analysis of the latter may enable unique insights into immune activation in the central nervous system. This is important because many signs and symptoms of ME/CFS are consistent with central nervous system dysfunction
It's going to be interesting to see the upcoming CSF study results.
 

msf

Senior Member
Messages
3,650
Re: hit and run, the researchers didn't use this term, and someone posted a quote which seemed to be from them that suggested that the cytokine exhaustion might either result from something like the mechanism found in diabetes, or from chronic infection.
 

msf

Senior Member
Messages
3,650
This was in the quote that Scarecrow posted - they also mentioned the previous finding that CD57 is decreased in patients as possible evidence of chronic viral infection. It's interesting that they didn't mention Lyme, since this has also been associated with low CD57.
 

msf

Senior Member
Messages
3,650
I would also point out that a hit-and-run that takes 3 years is not the same thing as one that takes a couple of weeks, and it doesn't excuse doctors and researchers from trying to find the cause.
 

adreno

PR activist
Messages
4,841
I wont know without doing some investigating. I suspect this might include biological drugs, that is things like antibodies, but there are lots of drugs that have been discussed over the years for this kind of thing. There are a wide range of cytokines involved, and this means we have many targets. With many targets comes many drugs, and potential drugs, and drugs overllooked by pharma because they didn't see a need for them.
It might also be treatable through the gut (i.e., probiotic/antibiotic treatments), as the micro biome regulates cytokine expression. This is what the Microbiome Discovery Project is all about.
 

Kati

Patient in training
Messages
5,497
Remember what Montoya said a few days ago, there might be a few more Herpes viruses getting discovered in the next few years.

That is music to my ears. We need earmarked, federal research funding. over 100,000,000$ a year for the next little while.
 

msf

Senior Member
Messages
3,650
Prof. Stephen Lawrie, Head of the Division of Psychiatry, University of Edinburgh, said:“This field – the biology and especially immunology of ME/CFS – has been bedeviled by false dawns for at least 20 years. This is a small study and the fact that the ‘biomarker’ does not internally replicate is a concern. Yes, it could be that there is a different immune profile in acute and chronic ME/CFS but it is at least as likely that the finding in acute patients is down to chance and hence a false positive signal.”

So it's a small study, despite the fact that it's the largest study ever done in ME? Are psychiatrists ever tempted to live in the real world?



 

halcyon

Senior Member
Messages
2,482
Sometimes we know the pathogen disappears, as in the case of a flu vaccine, yet the ME/CFS generated by that vaccine has no unique characteristics that allow us to say, "This is a vaccine-generated case of ME/CFS!" Similarly, giardia and HHV-6 have precious little in common, yet they can generate cases of ME/CFS that look very much the same.
There's no way to know if it's the vaccine itself that triggers it, or if it's another ME related pathogen caught during the period of immune suppression caused by the vaccine. Giardiasis can become persistent, as can HHV6.
 

lansbergen

Senior Member
Messages
2,512
With all of the evidence that we have for persistent infections in ME, does it make more sense that the immune system is chronically activated because there is a chronic infection present, or that the immune system is freaking out responding to thin air?

I go for the former .
 

nandixon

Senior Member
Messages
1,092
Perhaps the results from the gene expression study that Dr Montoya mentioned on the recent conference call might be used to validate, to some extent, the results of the present study (assuming the cohorts are different).

That study looked at the m-RNA from 200 ME/CFS patients and 400 controls. (See this post.)

If the expression of the genes from the Montoya study, corresponding to the cytokines measured in the present study, show the same relative differences between: patients at less than 3 years, more than 3 years, and controls, then the present study might (effectively) be considered at least partially validated in a different set of patients (and likewise Montoya's study similarly cross-validated).

On the other hand, if the gene expression for those same cytokines is different, then that wouldn't necessarily prove things one way or the other, since the levels of the cytokines measured in the present study could be affected after gene expression (i.e., post-transcriptionally).
 

August59

Daughters High School Graduation
Messages
1,617
Location
Upstate SC, USA
“It appears that ME/CFS patients are flush with cytokines until around the three-year mark, at which point the immune system shows evidence of exhaustion and cytokine levels drop,” says Dr. Hornig.

I hope this particular phrase leads to further studies! The phrase "immune system shows evidence of exhaustion" is pretty broad. Wouldn't severe immune system exhaustion have a major impact on ones ability to even make antibodies to some pathogens/infections. I we are not making enough antibodies then many methods of testing are mostly useless. Wouldn't that possibly lead to some viruses/bacterial infections easily replicating and further infecting more and more tissue/cells? If this proves to be true, then at some point there will have to studies done directly on tissue samples. They can have all of mine that they want!!!

I also hope the soon to be released CSF study either expounds upon this study and/or presents its own distinctive findings. Funding for studies to specifically replicate these should be made available immediately

I really hope that the NIH/HHS gets an ear full about not funding the "Microbiome Study" and wasting funding on some of the other useless studies that were funded. Hopefully, the NIH will get their head out of their posterior orifice and fund the microbiome study.

If the NIH/HHS can't see the shear quality of this study they need to be fired, being that the author list could very well be "The ME/CFS Researcher Hall of Fame" (among others!) plus the stringent selection of cohort and controls in relatively large numbers which is a rarity for the ME/CFS study.

We need a method of extending our gratitude to the authors of the study!

A sincere "Thank You" to The Hutchin's Family Foundation for making this study possible! Anyone know the best way to do this?

In the grand scheme of things (to me anyway) the patient community has been losing the ball game for a long time, but we are not behind as far as we once were and may be getting close to moving ahead. Either way, the momentum is in our favor now. Momentum is a great, especially if we can keep it and we need to take it and run with it! The dark side has lost any momentum it had which is great, especially if they keep losing it!
 
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