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Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, View ORCID ProfilePeter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz
doi: https://doi.org/10.1101/2019.12.23.887505
Ece Karhan
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Courtney L Gunter
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Vida Ravanmehr
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Meghan Horne
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Lina Kozhaya
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Stephanie Renzullo
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Lindsey Placek
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Joshy George
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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Peter N Robinson
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
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  • ORCID record for Peter N Robinson
Suzanne D Vernon
2Bateman Horne Center, Salt Lake City, Utah, USA
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Lucinda Bateman
2Bateman Horne Center, Salt Lake City, Utah, USA
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Derya Unutmaz
1Unutmaz Laboratory, Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
3Department of Immunology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
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  • For correspondence: derya@mac.com
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Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

  • Abbreviations

    ME/CFS
    myalgic encephalomyelitis/chronic fatigue syndrome
    PBMC
    peripheral blood mononuclear cells
    DN
    double negative; CD4-CD8-
    NK
    natural killer
    MAIT
    mucosal-associated invariant T
    Treg
    T regulatory cells
    N
    naive
    CM
    central memory
    EM
    effector memory
    EMRA
    effector memory RA
    PMA
    phorbol 12-myristate 13-acetate
    p
    probability value
    rs
    Spearman’s Rank Correlation Coefficient
    K
    number of folds in cross validation
    k
    number of features
    RF
    random forest
    TPR
    true positive rate
    FPR
    false positive rate
    ROC
    receiver operating characteristic
    AUC
    area under the curve
    F1
    F score; measure of a test’s accuracy
    EBV
    Epstein-Barr virus
    CMV
    cytomegalovirus
    HIV
    human immunodeficiency virus
  • Copyright 
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    Posted December 26, 2019.
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    Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
    Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz
    bioRxiv 2019.12.23.887505; doi: https://doi.org/10.1101/2019.12.23.887505
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    Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
    Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz
    bioRxiv 2019.12.23.887505; doi: https://doi.org/10.1101/2019.12.23.887505

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