Thesis Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome, 2023, Maya

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Free fulltext:
https://ecommons.cornell.edu/items/242f8723-6f87-47cc-b36d-bf51a21f4255

Author(s)
Maya, Jessica

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic and incapacitating multisystem condition with unknown etiology, no cure, and no FDA- approved treatments, all of which can be attributed to historical underfunding, widespread misinformation, and the complexity of the disease.

Many patients encounter several immune-related symptoms, extreme fatigue, post-exertional malaise, and a flu-like onset.

Studies have documented changes in ME/CFS immune cell populations and decreased natural killer (NK) cell performance, along with aberrant cytokine production, reduced glycolysis in T cells, and altered metabolites relevant to fatty acid oxidation, implicating potential intracellular metabolic dysregulation.

This knowledge prompted me to investigate fatty acid oxidation and immune cell functional states in isolated ME/CFS lymphocytes.

Using extracellular flux analysis and flow cytometry, I observed elevated fatty acid oxidation levels in ME/CFS immune cells, including NK cells, CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells compared to healthy controls, particularly during high energy demands and activation.

My findings suggest a metabolic dysfunction in ME/CFS immune cells, consistent with T cell exhaustion - a state that hinders immune cell proliferation, survival, and cytokine production following persistent antigen stimulation.

Building upon these results, I further investigated immune cell exhaustion and dysfunction in isolated CD8+ and CD4+ T cells from ME/CFS and healthy samples.

I analyzed T cell sub-populations, including naïve, effector, memory, regulatory, and helper T cells, for frequencies of inhibitory receptors and transcription factors associated with dysfunctional immune cell states.

I detected distinct transcription factor dynamics and elevated exhausted T cell phenotype proportions in ME/CFS CD8+ T cell populations compared to healthy controls.

In ME/CFS CD4+ T cells, I also observed altered inhibitory receptor population frequencies compared to healthy control samples.

Moreover, dysfunctional T cell features correlated with ME/CFS health status and symptom presentation.

Overall, my findings detect dysfunctional T cell states in specific ME/CFS cell populations, which can lead to reduced effector function that may contribute to ME/CFS symptom presentation.

This work highlights the significance of assessing both metabolic components and immune cell dysfunction-associated targets in the development of potential therapeutic interventions for individuals with ME/CFS.

Date Issued
2023-05
;
Committee Chair
Hanson, Maureen
Degree Discipline
Genetics, Genomics and Development
Degree Name
Ph. D., Genetics, Genomics and Development
Degree Level
Doctor of Philosophy


Files
Maya_cornellgrad_0058F_13614.pdf (7.28 MB)
Permanent Link(s)
https://doi.org/10.7298/6r2r-3p30
https://hdl.handle.net/1813/114098
Collections
Cornell Theses and Dissertations

Cornell University Graduate School
  • Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome
  • This was embargoed until 2024-06-13
https://twitter.com/user/status/1809970672082334166
Click to expand...
 
This thesis seems to be part of the evidence base for Hanson's swing to believing there's persistent infection.


I observed a population of T cells that were positive for both CD4 and CD8
markers in both cohorts, as well as differences in the proportion of Tox+ cells within
this population between the two groups. These CD8+CD4+ T cells are specialized T
cells with strong antiviral activity, and an increased frequency of this population could
suggest a higher degree of viral reactivation (Bernal et al., 2022).

... I noted a significant increase in Tox
expression in the naïve population of ME/CFS patients. This finding further supports
the hypothesis that ME/CFS could be a chronic viral infection, as Tox+ naïve T cells
have been previously identified in other chronic viral infections like HBV and EBV,
and at higher frequencies than in naïve populations with acute viral infections...

Future research in ME/CFS should continue to search for the
specific virus or viruses involved in the disease, which will facilitate the isolation and
analysis of virus-specific CD8+ T cells and improve the characterization of exhausted
T cells.


I find a viral persistence hypothesis plausible. Especially if it is hijacking some sub-cellular infrastructure (peroxisomes?) that can explain energy and immune effects.

If there is viral infection we're going to have to learn a lot about how it keeps evidence of itself out of the blood stream!! Could be implications for viral persistence in all sorts of tissue.
 
Murph said:
If there is viral infection we're going to have to learn a lot about how it keeps evidence of itself out of the blood stream!! Could be implications for viral persistence in all sorts of tissue.
Click to expand...

Not that we know enough yet but I have favoured a post-infection (or equivalent) immune dysregulation, without requiring persistent antigen or replicating pathogen. However, I am keeping a close eye on the French team's findings in LC in megakaryocytes, as the marrow might be quite a good hiding place. I don't know if the sorts of T cell changes above could be mimicked by immune dysregulation without implicating persistently triggering viral antigen. They do say "could" tho.
 
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