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Could ME/CFS be next?

T-cell

T-cells fight off pathogens. Even after 2 years they were surprisingly activated in both recovered and long-COVID patients.

There’s nothing like a pandemic to open new doors on post-infectious diseases, and it’s no surprise that the Henrich/Peluso team at the University of California at San Francisco would be the ones to do that. With their LIINC project, they have embraced long COVID like no other group.

Leave it to them to do the first whole-body positron emission imagining (PET) study in long COVID. In a preprint, “Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19“, Henrich and Peluso et al. keyed a radio-tracer on activated T-cells to see what happened with one of the big guns of the immune response.

THE GIST

  • Once again, long COVID prompts investigations that researchers in ME/CFS have wanted to do for years but lacked the funding for.
  • In this study, UCSF combined a whole-body PET scan with a radio-tracer keyed on activated T-cells to see what happened with the T-cells – one of the big guns of the immune response, over two years.
  • Theoretically, the T-cells should have ramped up to knock down the virus and once they did that, quieted down – but that’s not what happened at all.
  • Even in the recovered group, the T-cells remained abnormally activated in a whole slew of tissues. Finding so much T-cell activation suggested that the coronavirus infection had resulted in “a new immunologic steady state”.
  • T-cells were particularly activated in in the long-COVID cohort just where you might expect it to be – the brainstem, spinal cord, gut, and lungs (in people with pulmonary symptoms).
  • The brainstem stood out. Located at the bottom of the brain, the brainstem regulates very basic functions – like breathing, heart rate, blood pressure, digestion, alertness, and sleep – the fundamental stuff you really don’t want to go wrong – and much of which has gone haywire in ME/CFS.
  • Henrich, the senior author of the study, reported, “You really shouldn’t have activated T cells in the spinal cord or the brainstem. We are seeing evidence of this immune response in areas we don’t typically see in the setting of an acute viral infection.”
  • The study also zeroes in on activated immune cells called macrophages which have recently been of interest in ME/CFS, and found evidence of pieces of the coronavirus in gut cells.
  • All in all, the study suggested that a widespread attempt to continue to fight off the infection, or an autoimmune response, was present. It provided more weight to the idea that pathogen persistence may be driving post-infectious diseases.
  • Because it focused on immune activation instead of targeting a specific pathogen, this is the kind of study that could easily be done in ME/CFS.

The T-cells are one of the real killers of the immune system; cytotoxic T-cells zero in on pathogen-infected cells and wipe them out. As they’re doing that, T-helper cells are managing and forming the immune response.

The Study

The question was – what was happening to the T-cells over 2 years in long-COVID and recovered COVID patients? Theoretically, the T-cells should have ramped up to knock down the virus, and once they did that, quieted down – but that’s not what happened at all – not even in the recovered group.

Even in the recovered group, the T-cells remained abnormally activated in a whole slew of tissues – the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary vasculature, lung parenchyma, and gut wall. Finding so much remaining T-cell activation in the recovered patients suggested that the coronavirus infection had resulted in “a new immunologic steady state”.

The T-cells could still be trying to cleanse the body of the coronavirus or they could reflect an autoimmune response. Whatever is happening it’s clear that infections – even infections that seem to have been fought off – have consequences. It will be interesting to see what happens to the recovered patients over time given the unexpectedly high rate of T-cell activation still present.

While T-cell activation was increased in tissues across the body in the recovered patients, it was particularly increased in the long-COVID cohort just where you might expect it to be – the brainstem, spinal cord, gut, and lungs (in people with pulmonary symptoms).

Back to the Brainstem

The brainstem stood out. Located at the bottom of the brain, the brainstem regulates very basic functions – like breathing, heart rate, blood pressure, digestion, alertness, sleep – the fundamental stuff you really don’t want to go wrong – and much of which has gone wrong in ME/CFS. Because it also filters the sensory and “motor” signals from the spinal cord, it also seems like a good place to produce problems with stimuli. It’s also densely packed with mast cells – a clear problem in ME/CFS.

Problems in the brainstem would be a darn good way to dysregulate a bunch of systems. We know that, in part, from Jeff and Jen Brea’s experiences with craniocervical instability, which caused their skull to contact their brainstem – producing virtually all the symptoms of ME/CFS. Down in Australia, Barnden has been charting brainstem dysfunction in ME/CFS for years.

Has the “Reptilian Brain” Gone Haywire in ME/CFS? Back to the Brainstem We Go.

Stating “We saw some very unexpected findings”, Henrich, the senior author of the study, told National Public Radio (NPR) “You really shouldn’t have activated T cells in the spinal cord or the brainstem. We are seeing evidence of this immune response in areas we don’t typically see in the setting of an acute viral infection.”

Pathogen Persistence

The question was what was causing the T-cells to go off? Since cytotoxic T-cells are pathogen hunters – the obvious answer was that either a lingering virus, or parts of a virus, were still present. Of all the tissues, the colon was apparently the easiest to biopsy and search for the virus, and so they did – and there it was – SARS-CoV-2 RNA was found in virtually all of the long haulers’ gut samples – providing more evidence that pathogen persistence – whether as a whole virus or as bits of it – could be driving the disease.

Next, the UCSF group examined different cells in an attempt to determine where the SARS-CoV-2 virus (the coronavirus), or pieces of it, might still be hanging out two years later, and found them in another immune cell pathogen hunter – the macrophages. Macrophages get rid of pathogens by ingesting them and breaking them up.

Infected macrophages nestled in the tissues could draw more immune cells after them, potentially causing chronic inflammation. The macrophage finding is particularly interesting given Andrew Grimson’s fascinating gene expression finding pegging monocytes (which turn into macrophages when activated) as the center of the immune dysfunction in ME/CFS.

Move Over NK, T and B-cells. Are Monocytes the Real Problem in ME/CFS?

Avindra Nath also found macrophages in the brain tissue of long-COVID patients and Bruce Patterson’s long-COVID protocol focuses on stopping monocytes from reaching the blood vessels.

Not everything was clear. Perhaps because the study was small they did not find correlations between the T-cell activation and symptoms. Still, the study was novel in is ability to find evidence  – the authors called it “provocative evidence” – of long-term immune system activation in the tissues.

The tissues have been like a black box in ME/CFS, but then again we’ve never had studies like this. The big question has been whether bits of enterovirus, or other viruses that we don’t see evidence of in the blood, are tweaking the immune system and causing symptoms.

Takeaways

There were several takeaways from the study. Whether you have long COVID or not, the coronavirus appears to be having a dramatic long-term effect on the immune system. Even recovered patients still exhibited a striking immune activation several years after they’ve recovered from the virus.

Secondly, immune activation is particularly increased in long-COVID patients in some intriguing areas. The brainstem, the spinal cord (cerebral spinal fluid leaks, spinal fluid hypertension), and the gut (IBS) are all areas of interest in ME/CFS.

Thirdly, the pathogen persistence hypothesis – which seems to get stronger and stronger as time goes on – was strengthened by finding activated pathogen hunters – the T-cells – in areas across the body – and by finding pieces of the coronavirus in gut tissues. With the pathogen findings ratcheting up, and the Long COVID Research Initiative plowing money into pathogen persistence, we should be hearing much more about this vital issue.

Lighting a Spark: Major New Long-COVID Initiative Promises Rapid Movement

Finally, the whole body PET scan /T-cell study is yet another example of long-COVID sparking research into potentially important areas that the small ME/CFS field always wanted to explore but never got a chance to do so. Because it focused in immune activation, and not on a specific pathogen, this is the kind of study that could be easily done in ME/CFS if the funds were present.

On that note, we should hopefully soon know from Jarred Younger and his fascinating MERUK-funded study whether immune cells from the body are invading the brain in ME/CFS.

Questions remain. The study was small (24 people). We don’t know if the T-cell activation is a real problem or is it a kind of add-on. Is the immune system targeting coronavirus RNA across the body or is an autoimmune reaction present? Whatever is causing it, another door has been opened. The finding is striking enough that it will surely lead to more studies.

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