In another thread I reiterated how my physically-induced PEM was not triggered by overall exertion, but rather by activity that would damage muscle cells. A 40 km bike ride might not trigger my PEM, but less than a minute of washing a window would, since that was an activity my muscles weren't used to. Thus my hypothesis that my PEM was triggered by the immune response to damaged cells. This fits the well-known rise in IFN-g 24 hrs after exertion, which matched my PEM delay. Also, my physically-induced PEM seemed very similar to the symptoms I got from viral infections (although I only had a couple of viral infections in 20+ years of ME).
The new addition to the hypothesis is dysfunction of the immune system's response to damaged muscle cells (and connective tissue cells?). In some people, this might be a relatively extreme abnormal response, resulting in severe PEM, and possibly lasting a long time. For others, such as me, it's only mild PEM, typically lasting less than 24 hrs. It might not just be a simple case of one or more cytokines being elevated in ME, but some more subtle changes in the immune response.
I believe that the immune system response to cell damage triggers activation of glial cells, which in turn influence other brain cells which results in PEM. A good question is whether the problem in the body's immune response, the glial response, or both.
Lots of people, researchers included, seem to jump to the "exertion = elevated mitochondrial demands, therefore that's the cause of PEM" theories. However, that same exertion also typically results in immune system activation, so that's also a valid correlation and thus potentially valid theory. I think that perspective should be more widely spread to the research community, so they can consider that when thinking "Why is x happening in ME?", and also so they can think of ways of testing that hypothesis. Is the immune system response in/around the muscles different in PWME vs similarly physically limited people without ME? Is there an abnormal autoimmunity response to the debris from damaged cells?
This study ( https://www.mdpi.com/1422-0067/24/3/2698 ), posted in another thread, found significant transcriptomic changes in PWME following exertion, which caused "dysregulated immune signaling pathways". That supports the theory that PEM is triggered by immune response to exertion, rather than mitochondrial dysfunction. I would like to see that study improved by a larger group, longer times (at least 24 hrs), and taking samples from within the brain, rather than just CSF.
The new addition to the hypothesis is dysfunction of the immune system's response to damaged muscle cells (and connective tissue cells?). In some people, this might be a relatively extreme abnormal response, resulting in severe PEM, and possibly lasting a long time. For others, such as me, it's only mild PEM, typically lasting less than 24 hrs. It might not just be a simple case of one or more cytokines being elevated in ME, but some more subtle changes in the immune response.
I believe that the immune system response to cell damage triggers activation of glial cells, which in turn influence other brain cells which results in PEM. A good question is whether the problem in the body's immune response, the glial response, or both.
Lots of people, researchers included, seem to jump to the "exertion = elevated mitochondrial demands, therefore that's the cause of PEM" theories. However, that same exertion also typically results in immune system activation, so that's also a valid correlation and thus potentially valid theory. I think that perspective should be more widely spread to the research community, so they can consider that when thinking "Why is x happening in ME?", and also so they can think of ways of testing that hypothesis. Is the immune system response in/around the muscles different in PWME vs similarly physically limited people without ME? Is there an abnormal autoimmunity response to the debris from damaged cells?
This study ( https://www.mdpi.com/1422-0067/24/3/2698 ), posted in another thread, found significant transcriptomic changes in PWME following exertion, which caused "dysregulated immune signaling pathways". That supports the theory that PEM is triggered by immune response to exertion, rather than mitochondrial dysfunction. I would like to see that study improved by a larger group, longer times (at least 24 hrs), and taking samples from within the brain, rather than just CSF.