Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome
| dc.contributor.author | Maya, Jessica | |
| dc.contributor.chair | Hanson, Maureen | en_US |
| dc.contributor.committeeMember | Grimson, Andrew | en_US |
| dc.contributor.committeeMember | Leifer, Cynthia | en_US |
| dc.date.accessioned | 2024-01-31T21:19:30Z | |
| dc.date.issued | 2023-05 | |
| dc.description.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. | en_US |
| dc.identifier.doi | https://doi.org/10.7298/6r2r-3p30 | |
| dc.identifier.other | Maya_cornellgrad_0058F_13614 | |
| dc.identifier.other | http://dissertations.umi.com/cornellgrad:13614 | |
| dc.identifier.uri | https://hdl.handle.net/1813/114098 | |
| dc.language.iso | en | |
| dc.rights | Attribution 4.0 International | * |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | * |
| dc.subject | Chronic fatigue syndrome | en_US |
| dc.subject | ME/CFS | en_US |
| dc.subject | Myalgic encephalomyelitis | en_US |
| dc.subject | NK cells | en_US |
| dc.subject | T cell exhaustion | en_US |
| dc.subject | T cells | en_US |
| dc.title | Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome | en_US |
| dc.type | dissertation or thesis | en_US |
| dcterms.license | https://hdl.handle.net/1813/59810.2 | |
| thesis.degree.discipline | Genetics, Genomics and Development | |
| thesis.degree.grantor | Cornell University | |
| thesis.degree.level | Doctor of Philosophy | |
| thesis.degree.name | Ph. D., Genetics, Genomics and Development |
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