The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE

Scheibenbogen, Carmen; Freitag, Helma; Blanco, Julià; Capelli, Enrica; Lacerda, Eliana; Authier, J.; Castro-Marrero, Jesús; Nora-Krūkle, Zaiga; Oltra, Elisa; Strand, Elin Bolle; Shikova, Evelina; Sekulić, Slobodan; Murovska, Modra

doi:10.1186/s12967-017-1263-z

Cited by 41 publications

(47 citation statements)

References 45 publications

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“…These triggers include stress, chemical exposure, changes in the microbiome, and/or infections by virus or other microorganisms, commonly involving or leading to immune system dysfunction. 16e21 Particular immune cell subpopulation biases or molecular signatures with potential biomarker value by their association with disease status have been described 22,23 ; however, none of them has been yet been population validated. In addition to the paucity of basic research in the area, an issue contributing to the lack of biomarker validation is related to patient heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

Almenar-Pérez

Ovejero

Sánchez-Fito

et al. 2019

Clinical Therapeutics

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Purpose: Studies to determine epigenetic changes associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remain scarce; however, current evidence clearly shows that methylation patterns of genomic DNA and noncoding RNA profiles of immune cells differ between patients and healthy subjects, suggesting an active role of these epigenetic mechanisms in the disease. The present study compares and contrasts the available ME/CFS epigenetic data in an effort to evidence overlapping pathways capable of explaining at least some of the dysfunctional immune parameters linked to this disease. Methods: A systematic search of the literature evaluating the ME/CFS epigenome landscape was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Differential DNA methylation and noncoding RNA differential expression patterns associated with ME/CFS were used to screen for the presence of transposable elements using the Dfam browser, a search program nurtured with the Repbase repetitive sequence database and the RepeatMasker annotation tool. Findings: Unexpectedly, particular associations of transposable elements and ME/CFS epigenetic hallmarks were uncovered. A model for the disease emerged involving transcriptional induction of endogenous dormant transposons and structured cellular RNA interactions, triggering the activation of the innate immune system without a concomitant active infection. Implications: Repetitive sequence filters (ie, RepeatMasker) should be avoided when analyzing transcriptomic data to assess the potential participation of repetitive sequences ("junk repetitive DNA"), representing >45% of the human genome, in the onset and evolution of ME/CFS. In addition, transposable element screenings aimed at designing cost-effective, focused empirical assays that can confirm or disprove the suspected involvement of transposon transcriptional activation in this disease, following the pilot strategy presented here, will require databases gathering large ME/CFS epigenetic datasets.

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Section: Introductionmentioning

confidence: 99%

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

Almenar-Pérez

Ovejero

Sánchez-Fito

et al. 2019

Clinical Therapeutics

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“…ME/CFS has also been known by other names (Unger et al, 2016), most recently as systemic exertion intolerance disease (Monro and Puri, 2018). ME/CFS is a complex disease that involves the muscular, nervous, hormonal, and immune systems (Natelson, 2001;Georgiades et al, 2003;Brurberg et al, 2014;Brigden et al, 2017;Scheibenbogen et al, 2017). As the name implies, ME/CFS is characterized by debilitating fatigue lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms, such as sleep disturbances, muscle aches, flu-like malaise, gastrointestinal symptoms, orthostatic intolerance, chronic or intermittent pain, as well as cognitive impairment reflected as memory and concentration difficulties (Natelson et al, 2007;Holgate et al, 2011;Yancey and Thomas, 2012;Ganiats, 2015;Komaroff, 2015;Scheibenbogen et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

Hatziagelaki

Adamaki

Tsilioni

et al. 2018

J Pharmacol Exp Ther

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance, and cognitive impairment, which severely impacts quality of life. A significant percentage of ME/CFS patients remain undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown, preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, which are apparently due to mitochondrial dysfunction in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism. Such mitochondria may be further contributing to the ME/CFS symptomatology by extracellular secretion of mitochondrial DNA, which could act as an innate pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental, neuroimmune, pathogenic and stress triggers activates microglia, leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.

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“…The elucidation of the molecular mechanisms of CFS is urgently needed for the discovery of therapies, and many governments in the US and Europe have encouraged research for CFS by increasing funding [26,27]. To contribute to these efforts, we evaluated the features of the LPS, poly I:C, and ADX mouse models in comparison with the major pathophysiological features of CFS.…”

Section: Discussionmentioning

confidence: 99%

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome

et al. 2020

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Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required. We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity. In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions. Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

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The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE

Cited by 41 publications

References 45 publications

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome

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