Chronic Fatigue Syndrome, Genes and Infection: The early T-cell Activation-1/Osteopontin (Eta-1/Op) Paradigm

: The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

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The Reification of the Clinical Diagnosis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) as an Immune and Oxidative Stress Disorder: Construction of a Data-Driven Nomothethic Network and Exposure of ME/CFS Subgroups

10.20944/preprints202101.0623.v1 ◽

2021 ◽

Author(s):

Michael Maes ◽

Marta Kubera ◽

Kristina Stoyanova ◽

Jean–Claude Leunis

Keyword(s):

Chronic Fatigue Syndrome ◽

T Cell Activation ◽

Bacterial Translocation ◽

Coenzyme Q10 ◽

Cell Activation ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Data Driven ◽

Fatigue Syndrome ◽

Fierce Competition

The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35). The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO). Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome. We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely). Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely one with increased lysozyme, one with increased CMI + CD38 activation + depressive symptoms, and another with increased bacterial translocation + autoimmune responses to OSENO.

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Humoral and cellular immune response after influenza vaccination in patients with postcancer fatigue and patients with chronic fatigue syndrome.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.9070 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 9070-9070

Author(s):

Hetty Prinsen ◽

Jolanda de Vries ◽

Foekje Stelma ◽

Sasja Mulder ◽

Carla Van Herpen ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Chronic Fatigue Syndrome ◽

Cellular Immune Response ◽

Foxp3 Expression ◽

Chronic Fatigue ◽

Fatigue Syndrome ◽

Patient Groups ◽

Postcancer Fatigue ◽

Cellular Immune

9070 Background: Postcancer fatigue (PCF) is a frequently occurring problem, impairing quality of life. Patients with chronic fatigue syndrome (CFS) also suffer from severe fatigue symptoms. We hypothesized that in fatigued patients (PCF and CFS) alterations in immune response could explain fatigue symptoms. Therefore, we examined whether the humoral and/or cellular immune response after influenza vaccination differed between fatigued patients and non-fatigued individuals and between PCF and CFS patients. Methods: PCF (n=15) and CFS patients (n=22) were vaccinated against influenza. Age and gender matched non-fatigued cancer survivors (n=12) and healthy controls (n=23) were included for comparison. Antibody responses were measured at baseline and at day 21 by a hemagglutination inhibition test. T cell responses were measured at baseline and at day 7 by a lymphocyte proliferation and activation assay. Results: Both patient groups developed seroprotection rates comparable to the accompanying control groups. Functional T cell reactivity was observed in all groups. Proliferation at baseline was significantly lower in fatigued patients compared to non-fatigued individuals. A significant increase in proliferation from baseline to day 7 was observed in fatigued patients, but not in controls. At day 7, proliferation was not significantly different between fatigued patients and non-fatigued individuals. CD4+CD127-FoxP3+ expression was significantly higher in PCF patients compared to non-fatigued cancer survivors. Conclusions: We observed a lower T cell proliferation at baseline in fatigued patients compared to non-fatigued individuals, suggesting a difference in the baseline state of the immune system between fatigued patients and non-fatigued individuals. Furthermore, the difference in CD4+CD127-FoxP3+ expression between PCF and CFS patients suggests subtle differences in immune state between these two fatigued patient groups. However, since humoral and cellular immune responses after vaccination did not differ significantly between fatigued patients and non-fatigued individuals, vaccination of fatigued patients (PCF and CFS) can be effective.

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T Cell Dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Frontiers in Immunology ◽

10.3389/conf.fimmu.2013.02.01009 ◽

2013 ◽

Vol 4 ◽

Author(s):

Brenu Ekua ◽

Hardcastle Sharni ◽

Huth Teilah ◽

Cosgrave Liam ◽

Staines Don ◽

...

Keyword(s):

T Cell ◽

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Fatigue Syndrome

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Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

PLoS ONE ◽

10.1371/journal.pone.0085387 ◽

2014 ◽

Vol 9 (1) ◽

pp. e85387 ◽

Cited By ~ 42

Author(s):

Madlen Loebel ◽

Kristin Strohschein ◽

Carolin Giannini ◽

Uwe Koelsch ◽

Sandra Bauer ◽

...

Keyword(s):

T Cell ◽

Chronic Fatigue Syndrome ◽

Cell Response ◽

Chronic Fatigue ◽

T Cell Response ◽

Fatigue Syndrome

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Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome

Journal of Translational Medicine ◽

10.1186/1479-5876-11-68 ◽

2013 ◽

Vol 11 (1) ◽

pp. 68 ◽

Cited By ~ 53

Author(s):

Marta Curriu ◽

Jorge Carrillo ◽

Marta Massanella ◽

Josepa Rigau ◽

José Alegre ◽

...

Keyword(s):

T Cell ◽

Chronic Fatigue Syndrome ◽

Chronic Fatigue ◽

Cell Phenotype ◽

Fatigue Syndrome ◽

And Function

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Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Frontiers in Immunology ◽

10.3389/fimmu.2021.656797 ◽

2021 ◽

Vol 12 ◽

Author(s):

Manuel Ruiz-Pablos ◽

Bruno Paiva ◽

Rosario Montero-Mateo ◽

Nicolas Garcia ◽

Aintzane Zabaleta

Keyword(s):

T Cell ◽

Chronic Fatigue Syndrome ◽

Epstein Barr Virus ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

Th2 Response ◽

Barr Virus ◽

Fatigue Syndrome ◽

Cell Immunity ◽

Epstein Barr

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.

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

10.1101/2019.12.23.887505 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ece Karhan ◽

Courtney L Gunter ◽

Vida Ravanmehr ◽

Meghan Horne ◽

Lina Kozhaya ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Fatigue Syndrome ◽

Cell Subset ◽

Chronic Fatigue ◽

Myalgic Encephalomyelitis ◽

T Cell Subsets ◽

Unknown Etiology ◽

T Cell Subset ◽

Fatigue Syndrome

AbstractMyalgic 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.

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