Transient receptor potential melastatin 2 channels are overexpressed in ME/CFS patients

Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients, by Cassandra Balinas, Helene Cabanas, Donald Staines, Sonya Marshall-Gradisnik in Journal of Translational Medicine Vol 17, #1, p 401, December 3, 2019

 

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells.

This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.

Methods:
Ten ME/CFS patients (43.45  p/m  12.36) and 10 HCs (43  p/m  12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.

Results:
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.

Conclusion:
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.

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Paediatric CFS patients’ & parents’ perceptions of recovery

Paediatric chronic fatigue syndrome patients’ and parents’ perceptions of recovery, by Matthew Robert Harland, Roxanne Morin Parslow, Nina Anderson, Danielle Byrne, Esther Crawley in BMJ Paediatrics Open Vol 3, #1, Dec 2, 2019

 

Research abstract:

What is known about the subject?

  • Little is known about how to define recovery in the paediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) population.

What this study adds?

  • Children and their parents struggle to define what would constitute a complete recovery as CFS/ME has become a ‘new normal’.
  • There is wide variation in definitions of recovery between individuals.
  • Recovery definitions go beyond symptom reduction and focus on returning to or achieving the same activity as peers, without payback and with flexibility in routine.

Objectives:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is common in children and adolescents; however, little is known about how we should define recovery. This study aims to explore perceptions of recovery held by paediatric patients with CFS/ME and their parents.

Methods:
Children with CFS/ME and their parents were recruited through a single specialist paediatric CFS/ME service. Data were collected through semistructured interviews with children and parents. The interview questions explored how participants would know if they/their child had recovered from CFS/ME. Thematic analysis was used to identify patterns within the data.

Results:
Twenty-one children with CFS/ME, twenty mothers and two fathers were interviewed. Some children found it hard to define recovery as the illness had become a ‘new normal’. Others thought recovery would indicate returning to pre-morbid levels of activity or achieving the same activity level as peers (socialising, education and leisure activities). Increased flexibility in routines and the absence of payback after activities were important. The interviews highlighted the concept of recovery as highly individual with wide variation in symptoms experienced, type and level of activity that would signify recovery. Parents describe how changes in mood and motivation would signify their child’s recovery, but children did not reflect on this.

Conclusion:
Some parents and children struggle to define what would constitute complete recovery. However, signs of recovery were more easily identifiable. Definitions of recovery went far beyond symptom reduction and were focused towards rebuilding lives.

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A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us?

A laboratory approach for characterizing chronic fatigue: What does metabolomics tell us? by Elardus Erasmus, Shayne Mason, Mari van Reenen, Francois E
Steffens, B Chris Vorster, Carolus J Reinecke in Metabolomics Vol 15, p 158, November 27, 2019

 

Research abstract:

Introduction:
Manifestations of fatigue range from chronic fatigue up to a severe syndrome and myalgic encephalomyelitis. Fatigue grossly affects the functional status and quality of life of affected individuals, prompting the World Health Organization to recognize it as a chronic non-communicable condition.

Objectives:
Here, we explore the potential of urinary metabolite information to complement clinical criteria of fatigue, providing an avenue towards an objective measure of fatigue in patients presenting with the full spectrum of fatigue levels.

Methods:
The experimental group consisted of 578 chronic fatigue female patients. The measurement design was composed of (1) existing clinical fatigue scales, (2) a hepatic detoxification challenge test, and (3) untargeted proton nuclear magnetic resonance (1H-NMR) procedure to generate metabolomics data. Data analysed via an in-house Matlab script that combines functions from a Statistics and a PLS Toolbox.

Results:
Multivariate analysis of the original 459 profiled 1H-NMR bins for the low (control) and high (patient) fatigue groups indicated complete separation following the detoxification experimental challenge. Important bins identified from the 1H-NMR spectra provided quantitative metabolite information on the detoxification challenge for the fatigue groups.

Conclusions:
Untargeted 1H-NMR metabolomics proved its applicability as a global profiling tool to reveal the impact of toxicological interventions in chronic fatigue patients. No clear potential biomarker emerged from this study, but the quantitative profile of the phase II biotransformation products provide a practical visible effect directing to up-regulation of crucial phase II enzyme systems in the high fatigue group in response to a high xenobiotic-load.

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Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with ME/CFS

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome by Alaa Ghali, Carole Lacout, Maria Ghali, Aline Gury, Anne-Berengere Beucher, Pierre Lozac’h, Christian Lavigne & Geoffrey Urbanski (France) in Nature Scientific Reports vol 9, Article number: 18817 (2019) Published Dec 11, 2019

 

Research abstract:

Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate.

Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group.

The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55).

ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.

From the conclusion:

At the best of our knowledge, this is the first study that reports elevated blood lactate in resting conditions in a significant proportion of patients with ME/CFS. Patients who showed abnormal elevation of blood lactate at rest displayed more frequent severe PEM than those with normal lactate concentrations.

This finding brings supplementary evidence for mitochondrial dysfunction in ME/CFS patients, and may contribute to a better understanding the illness.

Subtyping ME/CFS patients adds to the growing body of evidence that ME/CFS is heterogeneous, and allows identifying patients with more risk for severe PEM who must adhere more closely to pacing strategies in order to avoid PEM occurrence and prevent disease exacerbation.

Furthermore, our study allowed describing clinical and biological characteristics of a French population with MPE/CFS. Shedding light on these characteristics may improve knowledge and raise awareness of this public health issue.

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ME/CFS patients exhibit altered T cell metabolism & cytokine associations

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations, by Alexandra H Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L Peterson, Marco Maynard, C Gunnar Gottschalk, and Maureen R Hanson in J Clin Invest. 2019. [First published December 12, 2019] https://doi.org/10.1172/JCI132185

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease.

ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients.

To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines.

We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects.

Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

 

Video: Dr Alexandra Mandarano explains the research in this paper.

NIH press release: Study finds differences in energy use by immune
cells in ME/CFS

Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.

“Our work demonstrates the importance of looking at particular types of immune cells that have different jobs to do, rather than looking at them all mixed together, which can hide problems specific to particular cells,” said Dr. Hanson. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS.”

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Investigating the role of tgf-b & fatigue in CFS

Investigating the role of tgf-b and fatigue in chronic fatigue syndrome, by Beth Dibnah, Emmanuella Traianos, Jessica Tarn, Dennis Lendrem, Wan Fai Ng in Annals of the Rheumatic Diseases Volume 78, Issue Suppl 2:1495 2019 [http://dx.doi.org/10.1136/annrheumdis-2019-eular.4690]

 

Research abstract:

Background:

Chronic fatigue syndrome (CFS) is estimated to affect up to 5% of people in Europe and is more common in women than men. It is characterised by unexplained fatigue, post-exertional malaise and a range of other symptoms. Recent studies indicate potential immune dysfunction in CFS, specifically regarding cytokines and the adaptive behavioural response.

Objectives:

This study aims to investigate serum transforming growth factor-beta (TGF-β) and the expression of the TGF-β Receptor 1 (TGFBR1) and TGF-β Receptor 2 (TGFBR2) genes, in relation to the fatigue associated with CFS.

Methods:

Serum active and total TGF-β concentrations were measured in 117 CFS patients and 40 HCs using a TGF-β responsive luciferase bioassay. Expression levels of TGFBR1 and TGFBR2 were analysed using quantitative PCR. Fatigue was measured using the fatigue impact scale (FIS)1. FIS was categorised into three groups; ‘mild’ (0-80), ‘moderate’ (81-120) and ‘severe’ (121-160). Linear and ordinal regressions were performed on the continuous FIS and FIS categories respectively.

Results:

Serum TGF-β concentrations in the CFS group did not differ significantly compared with the HC group (p=0.58). TGF-β concentrations showed no correlation with disease duration but there was a trend towards decreased TGF-β with increasing symptom duration. There were no significant differences between the levels of TGFBR1 and TGFBR2 in any of the fatigue groups, or between HCs. Active TGF-β concentrations were significantly elevated in the ‘severe’ FIS group compared to the ‘mild’ FIS group (p=0.04). Active/total TGF-β levels were significantly higher in the ‘severe’ FIS group than the ‘mild’ and ‘moderate’ FIS groups (p=0.02, p=0.03 respectively).

Conclusion:

These data suggest no differences in serum concentrations of TGF-β or expression of TGFBR1 and TGFBR2, between the HC and CFS groups. It also suggests no differences in expression levels of TGFBR1/2 between any of the CFS fatigue groups. However, active/total TGF-β levels were increased in more severely fatigued patients based on FIS. This finding could be due to higher levels of circulating TGF-β, or increased amounts of TGF-β activation. Further work is necessary to confirm this finding in a larger cohort of CFS patients, and to explore how this increase in TGF-β relates to fatigue.

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Intimate partner violence & the risk of developing FM & CFS

Intimate partner violence and the risk of developing Fibromyalgia and Chronic Fatigue Syndrome, by Joht Singh Chandan, Tom Thomas, Karim Raza, Caroline Bradbury-Jones, Julie Taylor, Siddhartha Bandyopadhyay, Krishnarajah Nirantharakumar in Journal of Interpersonal Violence, December 6, 2019 [https://doi.org/10.1177/0886260519888515]

 

Research abstract:

Intimate partner violence (IPV) is a global public health issue with a variety of ill health consequences associated with exposure.

Due to the stimulation of chronic stress and inflammatory pathways, childhood abuse has been associated with the subsequent development of functional syndromes such as fibromyalgia and chronic fatigue syndrome (CFS). Although IPV in women appears to elicit similar biochemical responses, this association has not been tested thoroughly in IPV survivors. These functional syndromes are complex in etiology and any indication of their risk factors would benefit health care professionals managing this population. Therefore, we aimed to investigate the association between exposure to IPV with functional syndromes: fibromyalgia and CFS.

We conducted a retrospective open cohort study using “The Heath Improvement Network” database between January 1, 1995 and December 1, 2017. A total of 18,547 women who were exposed to IPV were each matched by age to four controls who were not exposed (n = 74,188). The main outcome measures were the risk of developing fibromyalgia and CFS.

These were presented as adjusted incidence rate ratios (aIRR) with 95% confidence intervals (CIs). We found that 97 women in the exposed group developed fibromyalgia (incidence rate [IR] = 1.63 per 1,000 person-years) compared to 239 women in the unexposed group (IR = 0.83 per 1,000 person-years). Following adjustment, this translated to an IRR of 1.73 (95% CI = [1.36, 2.22]).

Similarly, 19 women developed CFS in the exposed group (IR = 0.32 per 1,000 person-years), compared to 53 in the unexposed group (0.18 per 1,000 person-years), which translates to an aIRR of 1.92 (95% CI = [1.11, 3.33]).

Therefore, we have identified an association between a history of IPV in women and the development of these functional syndromes, which may provide more information to inform the biopsychosocial pathway precipitating the development of fibromyalgia and CFS.

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Press release: Domestic abuse survivors twice at risk of long-term illnesses

…the research shows that women who have experienced domestic abuse are almost twice as likely to develop fibromyalgia and chronic fatigue syndrome (CFS) than those who have not.

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Circulating levels of GDF15 in patients with ME/CFS

Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, by A Melvin, E Lacerda, H M Dockrell, S O’Rahilly & L Nacul in Journal of Translational Medicine vol 17, no. 409 (2019)

 

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

Methods:
GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50).

Results:
Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7–8.8) apart, 720 pg/ml (95% CI 625–816) vs 670 pg/ml (95% CI 598–796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429–553), 546 pg/ml (95% CI 478–614) in MS patients, 560 pg/ml (95% CI 502–617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531–674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

Conclusions:
Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

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ME/CFS: investigating care practices pointed out to disparities in diagnosis & treatment across European Union

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union
Elin B Strand, Luis Nacul, Anne Marit Mengshoel, Ingrid B Helland, Patricia Grabowski, Angelika Krumina, Jose Alegre-Martin, Magdalena Efrim-Budisteanu, Slobodan Sekulic, Derek Pheby, Giorgos K Sakkas, Carmen Adella Sirbu, F Jerome Authier, on behalf of the European Network on ME/CFS (EUROMENE) in PLoS ONE 14(12): e0225995, Dec 2019[https://doi.org/10.1371/journal.pone.0225995]

 

Research abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients.

A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research.

We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches. For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines.

Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

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Identification of actin network proteins, talin-1 & filamin-A, in circulating extracellular vesicles as blood biomarkers for human ME/CFS

Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/ chronic fatigue syndrome, by Akiko Eguchi, Sanae Fukuda, Hirohiko Kuratsune, Junzo Nojima, Yasuhito Nakatomi, Yasuyoshi Watanabe, Ariel E Feldstein, in Brain, Behavior, and Immunity November 2019 [ https://doi.org/10.1016/j.bbi.2019.11.015]

 

Highlights

  • Circulating EV number was increased in ME/CFS patients correlating to CRP and BAP.
  • AUROC for circulating EVs was 0.802 allowing correct diagnosis in 90–94% of ME/CFS.
  • Proteins in actin skeletal regulation and EB virus infection were identified in ME/CFS patients.
  • Talin-1, filamin-A and 14-3-3 proteins were the most abundant proteins representing highly specific ME/CFS.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years.

Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS.

We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases.

From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers.

Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

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