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