Perturbation of effector & regulatory T cell subsets in ME/CFS

Posted on 01/09/2020 by wames

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), by Ece Karhan, Courtney Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzannne D Vernon, Lucinda Bateman, Derya Unutmaz in bioRxiv  2019.12.23. 887505

 

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 IFNgamma;, 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.

 

Press release: JAX Research on Immune Profiles in ME/CFS is now Available Online, 27 Dec 2019

…In this detailed study, we analyzed the immunological differences between ME/CFS patients and healthy controls within a large cohort and found several major differences in T cell subset frequencies and functions between the two groups.

… the ratio of two major subsets of T cells, namely the CD4+ to CD8+ T cell ratio, was increased in ME/CFS patients compared to healthy controls.

… There was also a major difference seen between healthy controls and ME/CFS patients in the Th17 cell subset, which is involved in responding to bacteria and is also a culprit in several autoimmune and chronic inflammatory conditions… we think this suggests a chronic activation of Th17 cells in ME/CFS which induces an ‘exhausted’ state where the cells are more dysfunctional due to their chronic stimulation.

…There was also a major difference seen in the mucosal-associated invariant T (MAIT) cells in ME/CFS patients compared to healthy controls…  It is possible that these changes in Th17 and MAIT cells are associated with differences in the composition of the microbiota of the ME/CFS patients, and that a disruption in the microbiota causes chronic activation of these subsets and an exhausted state in ME/CFS patients.

Interestingly, we also noted that regulatory T cells (Tregs) were increased in ME/CFS patients compared to controls. Tregs function to suppress excessive chronic immune responses, so this is consistent with our finding that there appears to be chronic activation of major T cell subsets in ME/CFS patients.

Finally and importantly, we utilized these immune profiling parameters in a machine learning classifier and were able to correctly identify ME/CFS patients from healthy controls with high sensitivity and accuracy. As patients often wait years to receive an ME/CFS diagnosis since there are currently no clear diagnostic tools to identify the disease, the development of an immune profile classier could aid as a biomarker to diagnose the disease.

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Autonomic markers, CFS & post-exertion states

Posted on 01/08/2020 by wames

Autonomic markers, chronic fatigue syndrome, and post-exertion states, by Fred Friedberg in Journal of Psychosomatic Research Vol 127, Dec 2019, [https://doi.org/10.1016/j.jpsychores.2019.109845]

 

Article extracts:

A large body of evidence suggests that autonomic imbalance, i.e., hyperactive sympathetic nervous system and hypoactive parasympathetic nervous system, is associated with a number of pathological conditions and diseases, and may be a final common pathway to increased morbidity and mortality [1].

Heart rate variability (HRV), a measure of inter-beat interval fluctuations and more broadly of parasympathetic (vagal) activity has been successfully used to index autonomic imbalances.

…In conclusion, reduced HRV may be a sensitive (and conveniently assessed) autonomic indicator of post-exertional worsening and a correlate of activity and fatigue that may differentiate CFS from healthy controls. If negative changes in HRV are uniquely associated with greater PEM and day-to-day illness fluctuations in CFS, then its potential as an illness marker can be productively tested in exertional challenge designs that amplify PEM-related symptom exacerbations.

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Patients with ME/CFS & chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation

Posted on 01/07/2020 by wames

Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation, by Martin A Jonsjö, Jenny Åström, Michael P Jones, Bianka Karshikoff, KarinLodin, Linda Holmström, Lars Agréus, Rikard K Wicksell, John Axelsson, Mats Lekander, Gunnar L Olsson, Mike Kemani, Anna Andreasson in Brain, Behavior, & Immunity – Health 17 December 2019 [https://doi.org/10.1016/j.bbih.2019.100028]

 

Highlights:

  • Investigation of the level of subjective sickness behavior, assessed with a validated questionnaire, in patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and in patients with chronic pain compared to clinical, non-clinical and experimental groups.
  • The level of sickness behavior is similarly high in ME/CFS and chronic pain, and equal to the level in experimentally induced inflammation via injection of bacterial endotoxin.
  • Higher levels of sickness behavior showed significant associations with lower levels of self-rated health and functioning.

Abstract:

Background:
Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain.

The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.

Methods:
Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n ​= ​38) and patients with chronic pain (n ​= ​190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n ​= ​29), primary care patients (n ​= ​163), individuals from the general population (n ​= ​155) and healthy subjects (n ​= ​48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population.

Results:
LPS-injected individuals (M ​= ​16.3), patients with ME/CFS (M ​= ​16.1), chronic pain (M ​= ​16.1) and primary care patients (M ​= ​10.7) reported significantly higher SicknessQ scores than individuals from the general population (M ​= ​5.4) and healthy subjects (M ​= ​3.6) all p’s ​< ​0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p’s ​< ​0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p’s ​< ​0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population.

Conclusions:
Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.

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Central sensitization: a pathogenic mechanism in complex undefined diseases

Posted on 01/07/2020 by wames

Central sensitization: A pathogenic mechanism in complex undefined diseases, by Joaquim Fernández-Solà, in Neuropsychiatry (London) 2019: 9(6), 2485–2490

 

Abstract:

There is a common perception that complex undefined diseases manifested with diverse combination of symptoms and a difficult clinical diagnosis have a possible common physiological mechanism of disease production.

Physical or cognitive fatigue, widespread pain without arthritis, sleep, mood and autonomic disturbances as well as multiple intolerance involving drug, food, chemical agents, electromagnetic fields or other environmental factors may be included in this category.

Along last three decades, the existence of central sensitivity as a well established common pathogenic mechanism involved in abnormal symptom development emerged in diverse areas as pain, fatigue, food and environmental intolerance, as well as in the global chronic disease epidemic. The common fact of all of these disorders is a deregulation of the central control mechanisms at the limbic brain system. This may relate to amplification of pain and fatigue perception and disturbance of environmental tolerance and control of circadian rhythms and mood.

This deregulation causes amplification of central somatosensory perception, but also a decrease of nociceptive inhibitory outputs. The final result is a chronic condition with central hyperexcitability and systemic disabling symptoms highly difficult to manage.

This article comments on the current significance to evaluate central sensitization symptoms and to consider these mechanisms in the development of complex diseases, as well as in the global chronic disease epidemic. We propose to include central sensitization to structuring a multidisciplinary concept addressed to improve scientific comprehension and clinical management of diseases, as well as future research directions on this field.

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An investigation into the modulation of T cell phenotypes by amitriptyline & nortriptyline

Posted on 12/28/2019 by wames

An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline, by JonathanRoyds, Melissa J Conroy, Margaret R Dunne, Connail McCrory, Joanne Lysaght in European Neuropsychopharmacology, Dec 2019[doi.org/10.1016/j.euroneuro.2019.12.106]

 

Research abstract:
Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry.

The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001).

The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05).

Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-β (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

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Register your interest today in taking part in ME/CFS genome-wide research!

Posted on 12/23/2019 by wames

The ME/CFS Biomedical Partnership Genome-wide association study

The ME/CFS Biomedical Partnership is working on a funding application to be made in early 2020 to the MRC/NIHR for a genome-wide association study.

 

How can we help?

They need to demonstrate to the funders that they can recruit 20,000 people to participate so they are asking people to sign up to a mailing list to keep updated on the application progress. Additionally, UK residents can log their potential interest in being involved in the research itself and they need as many people as possible to do this.

Sign up here: https://mebiomed.org.uk/get-involved/

What is a genome-wide association study?

A genome-wide association study (GWAS) is a very large genetic study that seeks to uncover some of the biological roots of ME/CFS. By probing small DNA differences among people, a GWAS can help to pinpoint the genetic causes of disease and then can help to guide drug development.

This design has previously provided helpful in identifying genes together with molecular and cellular pathways to contribute to disease risk. Read more about the science of GWAS.

The ME/CFS Biomedical Partnership website: https://mebiomed.org.uk/

More information: https://mecfsresearchreview.me/2020/01/08/sign-up-your-support-could-help-win-funding-for-a-game-changing-me-cfs-study/

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WAMES helpline holiday hours 2019-2020

Posted on 12/22/2019 by wames

WAMES helpline hours

The WAMES helpline is run by volunteers and will be closed over the festive period.

 

Support bricksWe apologise that due to extra pressures on the team in January, the closure will last longer than usual. Feel free to email queries and we will reply as soon as possible.

helpline@wames.org.uk  0290 2051 5061

  • 23 December – 12 January  closed
  • 13 January onwards 10-7pm

 

For emotional support, the Samaritans can be contacted 24 hours a day, 7 days a week.

English – 116 123 – free number (24 hours a day, 7 days a week)

Cymraeg – 0808 164 0123 – free number (check times on the website)

 

Children and young people up to age 25 can also contact Meic by phone, email, SMS text and instant messaging.

  • 8am to midnight, 7 days a week
  • FREEPHONE: 0808 80 23456
  • SMS TEXT: 84001
  • IM/Webchat: www.meic.cymru
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Minireview for CFS & its medical attention recently

Posted on 12/19/2019 by wames

Minireview for Chronic Fatigue Syndrome and its medical attention recently, by Chang-Gue Son in J Korean Med. 2019;40(4):84-90 [http://dx.doi.org/10.13048/jkm.19043]

 

Review abstract:

Objectives: Chronic fatigue syndrome (CFS) is a debilitating illness impairing seriously quality of life, while CFS would be an optimized target disorder of Korean medicine. This study aims to present the recent information especially in aspect of medical policy and new diagnosis criteria for CFS.

Methods: The literature survey was conducted using the terms of “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “fibromyalgia” in PubMed database and Google database in its entirety from January 2011 to February 2019. The in-depth review was made focusing on the changes in policy and medical perspective for CFS.

Results: Recently large medical attentions and researches for CFS have been existed worldwide. By supporting of USA government, IOM made a report which leaded to a turning point in clinical practices and research in 2015. This report recommended a new name of CFS to systemic exertion intolerance disease (SEID), and new diagnostic criteria focusing on post-exertional malaise, unrefreshing sleep, cognitive impairment and orthostatic intolerance. The medical perspective also was changed into “a serious, chronic, complex, systemic disease” from a psychological-like disorder, and then UAS and EU governments sharply increased the research grants.

Conclusions: This study provided practitioners in Korean medicine (KM) a core information about the recent changes in CFS-related perspectives. This review would be helpful for KM-derived researches or therapeutics development for CFS.

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

Posted on 12/18/2019 by wames

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

Posted on 12/17/2019 by wames

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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