This study does not tell us what exactly causes long COVID or ME/CFS, nor does it test clinical symptoms like PEM.
But it may tell us something just as important - what type of biological problem this likely is..🧵
But it may tell us something just as important - what type of biological problem this likely is..🧵
https://twitter.com/falsel_net/status/2019160024950698293
The authors isolated immunoglobulins (IgG) from people with post-infectious ME/CFS, including post-COVID ME/CFS, and tested what these antibodies do to healthy cells.
In a subset of patients, these IgG alter the behavior of endothelial cells and their mitochondria.
Not by killing the cells or shutting down ATP production.
Not by killing the cells or shutting down ATP production.
Instead, mitochondria shift into a stress-adaptive state.
At rest, things may look relatively normal.
Under exertion, the system fails - post-exertional malaise (PEM).
At rest, things may look relatively normal.
Under exertion, the system fails - post-exertional malaise (PEM).
A crucial detail.
The effect is Fab-dependent, not Fc-dependent.
That means antigen-specific binding, not random inflammation or generalized immune activation.
The effect is Fab-dependent, not Fc-dependent.
That means antigen-specific binding, not random inflammation or generalized immune activation.
What does that imply?
The antibody is recognizing a specific structure (an antigen).
Importantly, the study did not find viral proteins in immune complexes.
The antibody is recognizing a specific structure (an antigen).
Importantly, the study did not find viral proteins in immune complexes.
So this is not evidence of ongoing viral infection.
Rather, it points to post-infectious immune memory that can persist independently.
Rather, it points to post-infectious immune memory that can persist independently.
That antigen does not need to be viral.
It may involve self-structures, such as
the extracellular matrix or endothelial regulatory components.
It may involve self-structures, such as
the extracellular matrix or endothelial regulatory components.
The result is not classic autoimmunity and not tissue destruction.
It looks more like a maintained stress-regulatory state, especially in the endothelium.
It looks more like a maintained stress-regulatory state, especially in the endothelium.
This helps explain why symptoms can remain relatively stable at rest,
yet collapse under exertion - because physiological reserves are already consumed.
yet collapse under exertion - because physiological reserves are already consumed.
A key implication.
Once a memory B-cell clone is established,
the original trigger is no longer required.
Once a memory B-cell clone is established,
the original trigger is no longer required.
An acute infection may flip the system,
but the chronic condition is then maintained by immune memory and regulatory loops.
but the chronic condition is then maintained by immune memory and regulatory loops.
This may also explain why children and young people sometimes recover more easily.
Their immune system, endothelium, and tissues are more plastic
and better able to unlearn a maladaptive state.
Their immune system, endothelium, and tissues are more plastic
and better able to unlearn a maladaptive state.
In adults, the system is more stable.
Not because they are weaker,
but because adult biology is optimized for maintenance, not rewiring.
Not because they are weaker,
but because adult biology is optimized for maintenance, not rewiring.
So this study does not point to a single culprit.
It points to a mechanism of disease persistence.
It points to a mechanism of disease persistence.
And that may be why simple fixes are so elusive - we are not trying to switch something off,
but to shift a biological system out of chronic threat mode.
but to shift a biological system out of chronic threat mode.
Liu at al., Immunoglobulin G Complexes from Post-infectious ME/CFS, including post-COVID ME/CFS Disrupt Cellular Energetics and Alter Inflammatory Marker Secretion. sciencedirect.com/science/articl…
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