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...?
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.
