Kings’s College finds overactive immune system in ME/CFS

Posted on 12/18/2018 by wames

Kings College London news post: Clues to CFS in overactive immune response

New research from King’s College London finds that an exaggerated immune response can trigger long-lasting fatigue, potentially explaining how chronic fatigue syndrome (CFS) begins. The study is the most in-depth biological investigation yet into the role of the immune system in lasting symptoms of fatigue.

CFS, also known as myalgic encephalomyelitis (ME), is a long-term illness which is characterised by extreme tiredness. The underlying biology of CFS has remained a mystery, hampering the search for treatments. There is some evidence that the immune system plays a role in triggering CFS and many patients report their illness starting with a challenge to the immune system such as a viral illness.

By the time patients are diagnosed it is too late to catch CFS in its earliest stages, and it is impossible to assess the biology of patients before the illness develops. To get around this problem, researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) used a model for CFS based on a treatment for hepatitis C called interferon-alpha.

IL-13 is a cytokine that plays a central regulator role in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis, It is a mediator of allergic inflammation and different diseases including asthma.

Interferon-alpha activates the immune system in the same way as a powerful infection. A lot of patients develop acute fatigue during treatment with interferon-alpha and a minority go on to have a CFS-like illness, where fatigue lasts for more than six months after the treatment ends. The researchers measured fatigue and immune system markers in 55 patients before, during and after treatment with interferon-alpha, tracking which people developed the persistent CFS-like illness.

 The team found differences in the immune systems of 18 patients who developed lasting fatigue compared to those who recovered as normal. During treatment with interferon-alpha there was a much bigger immune response among those who developed the CFS-like illness, with a doubling in the levels of immune system ‘messenger’ molecules interleukin-10 and interleukin-6.

Importantly, even before treatment started, levels of interleukin-10 were higher among those who went on to have lasting fatigue, suggesting the immune system may have been ‘primed’ to over-respond.

Lead researcher Dr Alice Russell from the IoPPN says:

‘For the first time, we have shown that people who are prone to develop a CFS-like illness have an overactive immune system, both before and during a challenge to the immune system. Our findings suggest that people who have an exaggerated immune response to a trigger may be more at risk of developing CFS.’

By the time the CFS-like illness developed, however, there was no longer any detectable difference in the immune system of patients compared to those who recovered as normal. As well as looking at people having interferon-alpha treatment, the researchers also found no difference in immune activation between 54 people with diagnosed CFS and 57 healthy controls.

Alongside the overactive immune response, those people who developed the CFS-like illness had more acute fatigue during treatment with interferon-alpha than people who recovered as normal. Yet before treatment there was no difference between the groups in their levels of fatigue or in any psychiatric symptoms like depression or recent stressful life-events.

Senior researcher Professor Carmine Pariante from the IoPPN says:

‘A better understanding of the biology underlying the development of CFS is needed to help patients suffering with this debilitating condition. Although screening tests are a long way off, our results are the first step in identifying those at risk and catching the illness in its crucial early stages.’

Confirmation is needed that the findings from people treated with interferon-alpha apply to people with CFS, and future work to better understand the factors that may be driving an exaggerated immune response is required.

Dr Neha Issar-Brown, Head of Population and Systems Medicine at the Medical Research Council, which funded the research, said:

‘CFS/ME is a serious condition and its underpinning biology is poorly understood. Encouragingly, this work sheds light on potential mechanisms of immune dysregulation underlying early stages of chronic fatigue syndrome. The MRC strongly encourages more research to better understand this condition in order to address an area of unmet clinical need.’

Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of Chronic Fatigue Syndrome, by Alice Russell, Nilay Hepgul, Naghmeh Nikkheslat, Alessandra Borsini, Zuzanna Zajkowska, Natalie Moll, Daniel Forton, Kosh Agarwal, Trudie Chalder, Valeria Mondelli, Matthew Hotopf, Anthony Cleare, Gabrielle Murphy, Graham Foster, Terry Wong, Gregor A. Schutzb, Markus J. Schwarzb, Neil Harrison, Patricia A. Zunszain, Carmine M. Pariante  in Psychoneuroendocrinology 17 Dec 2018

Highlights
• Baseline fatigue is not associated with the development of persistent fatigue after IFN-α.
• IFN-α-induced persistent fatigue is associated with increased baseline IL-10.
• Patients who develop persistent fatigue experience greater increases in IL-6 and 10 in response to IFN-α.
• Persistently fatigued patients recover at a similar rate, but from a more severe acute response to the initial trigger.
• Once established, neither the persistent fatigue phenotype, nor CFS, are associated with peripheral immune activation.

ME Action: Post-interferon fatigue study: a mixed bag

Nick’s blog: Have scientists found an explanation for the onset of ME/CFS? 

BBC Wales ‘Good Evening Wales’, 17 Dec 2018: news item starts at 44 mins. Dr Carmen Pariente & pwme John Peters from Swansea are interviewed.

Guardian: Chronic fatigue syndrome ‘could be triggered by overactive immune
system’

BBC: Overactive immune system ‘may trigger ME-like symptoms’

Reuters: Study finds chronic fatigue clues in overactive immune response

Telegraph: Chronic Fatigue Syndrome may be triggered by hyperactive immune system, study suggests

Mail online: ME is real and your body is to blame: Chronic fatigue condition that has mystified scientists for decades is caused by an over-active immune system, study claims

Science alert: Strongest Evidence Yet Links Chronic Fatigue Syndrome And an Overactive Immune System 

CNN: Chronic fatigue syndrome may be due to an overactive immune system, study finds

HuffPost: ‘Overactive Immune System’ May Be The Cause Of ME, Scientists Say
Proof it really is a “serious illness”.

Simmaron Research: Immune Factor May Jump Start Chronic Fatigue Syndrome (ME/CFS)

Posted in News | Comments Off on Kings’s College finds overactive immune system in ME/CFS

Adolescent’s descriptions of fatigue, fluctuation and payback in CFS/ME

Posted on 12/13/2018 by wames

Adolescent’s descriptions of fatigue, fluctuation and payback in chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): Interviews with  adolescents and parents, by Roxanne M Parslow, Nina Anderson, Danielle Byrne, Alison Shaw, Kirstie L Haywood, Esther Crawley in BMJ Paediatrics Open Vol 2, #1, December 4, 2018

What this study hopes to add?

  • All adolescents describe unique aspects of fatigue in CFS/ME; how it fluctuates naturally day to day but can also get worse following activity (payback).
  • The individual experience of fatigue varies in severity, frequency, the amount of activity taken to cause payback as well as the resulting impact on function.
  • The variation in the experience of fatigue needs to be taken into account in treatment.

Research abstract:

Objective:
As part of a larger qualitative study to explore outcomes important in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) and what improvements in fatigue and disability are key, interviews were undertaken with adolescents and their parents. This paper focuses on their descriptions of fatigue, fluctuation of symptoms and payback.

Design and setting:
Semistructured qualitative interviews were undertaken between December 2014 and February 2015. Adolescents and parents were interviewed separately. Participants were recruited from a single specialist paediatric chronic fatigue service. Interviews were audio recorded, transcribed verbatim and analysed using thematic analysis.

Participants:
We interviewed 21 adolescents and their parents (20 mothers and 2 fathers). The adolescents were aged between 12 and 17 years of age (mean age 14.4 years), mild to moderately affected by CFS/ME (not housebound) and the majority were female (16/21).

Results
All adolescents with CFS/ME reported fatigue, a natural fluctuation of the condition, with good days and bad days as well as an increase in symptoms after activity (payback). However, adolescent’s descriptions of fatigue, symptoms and the associated impact on their daily lives differed. The variations included: fatigue versus a collection of symptoms, constant versus variable symptoms and variable symptom severity. There were differences between participants in the amount of activity taken to cause payback. The impact of fatigue and symptoms on function ranged from: limiting the duration and amount of leisure activities, struggling with daily activities (eg, self-care) to no activity (sedentary).

Conclusions
Fatigue, fluctuation of the condition and payback after activity are described by all adolescents with CFS/ME in this study. However, the individual experience in terms of how they describe it and the degree and impact varies.

Posted in News | Tagged , , , , , , , , , , , | Comments Off on Adolescent’s descriptions of fatigue, fluctuation and payback in CFS/ME

Glial activation & expression of the serotonin transporter in CFS

Posted on 12/10/2018 by wames

Glial activation and expression of the serotonin transporter in Chronic Fatigue Syndrome, by Mami Noda, Masataka Ifuku, Md. Shamim Hossain and Toshihiko Katafuchi in Front. Psychiatry, 16 November 2018

Mini Review article abstract:

Fatigue is commonly reported in a variety of illnesses and has major impact on quality of life. Chronic fatigue syndrome (CFS) is a debilitating syndrome of unknown etiology. The clinical symptoms include problems in neuroendocrine, autonomic, and immune systems. It is becoming clear that the brain is the central regulator of CFS. For example, neuroinflammation, especially induced by activation of microglia and astrocytes, may play a prominent role in the development of CFS, though little is known about molecular mechanisms.

image description

Many possible causes of CFS have been proposed. However, in this mini-review, we summarize evidence for a role for microglia and astrocytes in the onset and the maintenance of immunologically induced CFS.

In a model using virus mimicking synthetic double-stranded RNA, infection causes sequential signaling such as increased blood brain barrier (BBB) permeability, microglia/macrophage activation through Toll-like receptor 3 (TLR3) signaling, secretion of IL-1β, upregulation of the serotonin transporter (5-HTT) in astrocytes, reducing extracellular serotonin (5-HT) levels and hence reduced activation of 5-HT1A receptor subtype.

Hopefully, drug discovery targeting these pathways may be effective for CFS therapy.

Posted in News | Tagged , , , , , , , , | Comments Off on Glial activation & expression of the serotonin transporter in CFS

IAFME sends an ‘agenda for change’ for ME to the WHO

Posted on 12/06/2018 by wames

IAFME contacts the WHO about ME

The International Alliance for Myalgic Encephalomyelitis (IAFME) has produced a trans-national consensus document covering Myalgic Encephalomyelitis (M.E.). Recognition, research and respect: An agenda for change in M.E. has the support of over 60 clinicians, researchers, and non-governmental organisations from 28 different countries.

As a member of IAFME, WAMES supports the sending of this document to the World Health Organisation by the Chair of the IAFME and Chief Executive of Action for M.E., Sonya Chowdhury, and the Executive Director of IAFME, Alexandra Heumber, requesting a meeting with representatives to discuss how they can work together to achieve the aims.

The IAFME is calling on the World Health Organisations (WHO) to take leadership for people living with ME worldwide who continue to face poor access to healthcare and support. Recognition, research and respect – an agenda for change in ME 25.11

WHO Headquarters in Geneva, Switzerland

This consensus document has three aims:

  1. To provide an overview of ME and the disease burden
  2. To highlight barriers to progressing research in the ME field
  3. To propose an agenda for change

Dr Heidi Nicholl, CEO Emerge Australia and Vice-Chair IAFME said,

“This consensus document is a result of collaborative work from international experts, academics and researchers. It represents an important step forward that will underpin the global advocacy led by the IAFME, and has the broad support from stakeholders around the world. We look forward to hearing from the World Health Organisation in response to the Alliance’s request that they co-ordinate a global public health response to ME”

For more information: Alexandra Heumber aheumber@iafme.org, Executive Director IAFME.

Facebook IAFME: https://www.facebook.com/IAforME/

 

Posted in News | Tagged , , , , , , | Comments Off on IAFME sends an ‘agenda for change’ for ME to the WHO

ME/CFS in the era of the human microbiome

Posted on 12/06/2018 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in the era of the human microbiome: persistent pathogens drive chronic symptoms by interfering with host metabolism, gene expression and immunity, by Amy D Proal and Trevor Marshall in Front. Pediatr. 4 Dec 2018

The illness ME/CFS has been repeatedly tied to infectious agents such as Epstein Barr Virus. Expanding research on the human microbiome now allows ME/CFS-associated pathogens to be studied as interacting members of human microbiome communities.

Humans harbor these vast ecosystems of bacteria, viruses and fungi in nearly all tissue and blood. Most well-studied inflammatory conditions are tied to dysbiosis or imbalance of the human microbiome. While gut microbiome dysbiosis has been identified in ME/CFS, microbes and viruses outside the gut can also contribute to the illness. Pathobionts, and their associated proteins/metabolites, often control human metabolism and gene expression in a manner that pushes the body towards a state of illness.

Intracellular pathogens, including many associated with ME/CFS, drive microbiome dysbiosis by directly interfering with human transcription, translation, and DNA repair processes. Molecular mimicry between host and pathogen proteins/metabolites further complicates this interference. Other human pathogens disable mitochondria or dysregulate host nervous system signaling. Antibodies and/or clonal T cells identified in patients with ME/CFS are likely activated in response to these persistent microbiome pathogens.

Different human pathogens have evolved similar survival mechanisms to disable the host immune response and host metabolic pathways. The metabolic dysfunction driven by these organisms can result in similar clusters of inflammatory symptoms. ME/CFS may be driven by this pathogen-induced dysfunction, with the nature of dysbiosis and symptom presentation varying based on a patient’s unique infectious and environmental history. Under such conditions, patients would benefit from treatments that support the human immune system in an effort to reverse the infectious disease process.

Excerpt from Discussion:

…It often takes patients years to receive a diagnosis of ME/CFS. This delay wastes a valuable period during which the immune system is most responsive to immunostimulatory treatment. Patients treated during earlier stage disease are also less likely to experience severe or long-lasting immunopathology. This suggests that immunostimulative therapies should be administered in a predictive and even preventative fashion. In addition, interventions or treatments that might help patients better manage the byproducts of immunopathology (bacterial LPS etc.) should become a priority for the research community.

The overall success of ME/CFS research also hinges on the scientific community’s willingness to embrace the concept of the human holobiont. In ME/CFS, the immune response, metabolism, central nervous system, and human gene expression are all linked by the activity of the microbiome and its associated proteins/metabolites. A greater focus on these interconnected systems is necessary, which will require increased collaboration between separate research teams.

Posted in News | Tagged , , , , , , , , | Comments Off on ME/CFS in the era of the human microbiome

The UK ME/CFS Biobank

Posted on 12/06/2018 by wames

The UK ME/CFS Biobank: A disease-specific biobank for advancing clinical research into myalgic encephalomyelitis/ chronic fatigue syndrome, by Eliana M. Lacerda, Kathleen Mudie, Caroline C. Kingdon, Jack D. Butterworth, Shennae O’Boyle, Luis Nacul in Frontiers in Neurology, 14 Nov 2018 [preprint

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and
pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis.

This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique
research infrastructure specifically designed to expedite biomedical research into  ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants.

The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A
longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points.

As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analysed within our research team but have also been shared with researchers across Europe, America and the Middle East. We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.

Keywords: ME/CFS, Biobank, Research infrastructure, Partnership, Patient
engagement (PE)

——–

Posted in News | Tagged , , , , , , , | Comments Off on The UK ME/CFS Biobank

Brain abnormalities in ME/CFS

Posted on 12/06/2018 by wames

Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging, by Kimura Y, Sato N, Ota M, Shigemoto Y, Morimoto E, Enokizono M, Matsuda H, Shin I, Amano K, Ono H, Sato W, Yamamura T in Journal of Magnetic Resonance Imaging, 14 Nov 2018

Research abstract:

Background:
Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI).

Purpose:
To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics.

Study Type:
Prospective.

Population:
Twenty ME/CFS patients and 23 healthy controls were recruited.

Field Strength/Sequence:
Three-b value DWI (b-values = 0, 1000, and 2000 sec/mm2 ) and 3D T1 -weighted images were at 3.0T.

Assessment:
Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated.

Statistical Testing: 
The two-sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups.

Results:
In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05). Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05).

Data Conclusion:
Right SLF abnormalities may be a diagnostic marker for ME/CFS.

Level of Evidence:
1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

Read the full article

Posted in News | Tagged , , , , , , , , , | Comments Off on Brain abnormalities in ME/CFS

miRNA profiling of circulating EVs in ME/CFS

Posted on 12/03/2018 by wames

miRNA profiling of circulating EVs in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) by Eloy Almenar-Pérez, Lubov Nathanson, Teresa Sánchez-Fito, Leonor Sarria, Germán Cerdá-Olmedo, Elisa Oltra  in Journal of Extracellular Vesicles, suppl. Supplement 1; Abingdon Vol. 7,  (2018): 139.

 

Research abstract:

Background:

ME/CFS (ICD-10; G93.3) is a complex multisystem disease of unknown origin with characteristic clinical features that include postexertional malaise, cognitive dysfunction, orthostatic intolerance, ongoing flu-like symptoms and unrefreshing sleep in conjunction with other. Its worldwide prevalence is 0.4%–1% with a female to male ratio of 6:1. Current treatments rely on the management of symptoms due to a lack of understanding of the underlying mechanisms of disease onset and progression. The aim of this work was to identify biomarkers of ME/CFS by analysing miRNA profiles of patient plasma EVs and comparing them to those of their PBMCs. This information should improve our knowledge of ME/CFS and allow the development of unbiased quantitative diagnostic methods.

Methods:

miRNA profiles of PBMCs or EVs isolated from plasma (Invitrogen cat.4484450) of  ME/CFS patients and population, sex, age and BMI-matched healthy participants (N = 15 per group) from the ME UK Biobank (London, UK) were determined using Nanostring technology (nCounter Human v3 miRNA Expression Assay Kit).

Gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) were used to determine disrupted cellular functions in ME/CFS. The study was approved by the DGSP-CSISP CEIC (ref. UCV201701), Spain. Signed informed consent was required for inclusion of samples.

Results:

miRNA profiles evidenced a global trend for miRNA downregulation in patients with respect to healthy controls (76% and 64% of the miRNAs presented inhibition, by at least 50%, in PBMCs and EVs respectively; while only one miRNA in PBMCs and 6% of them in EVs showed upregulation to this level). Qualitatively, miRNA profiles in PBMCs did not match those obtained from EVs indicating active packaging of miRNAs in EVs. The functions to be affected by the deregulated miRNAs support a model of immune, mitochondrial and neural defects for this disorder.

Summary/Conclusion:

This is the first report of paired PBMCs and EV miRNA profiles of ME/CFS patients by enzyme-free array technology. The results confirm previous proposals that this epigenetic mechanism is linked to the pathophysiology of ME/CFS. Validation studies with expanded cohorts are needed before particular miRNA profiles can be used as biomarkers of ME/CFS in a clinical setting.

Funding: The study was funded by the ME Association’s Ramsay Research Fund (RRF) (UK).

Posted in News | Tagged , , , , , , , , , , | Comments Off on miRNA profiling of circulating EVs in ME/CFS

Online pacing tutorial begins January 2019

Posted on 11/30/2018 by wames

Online Pacing Tutorial

US based ME/CFS & Fibromyalgia Self-help program hold quarterly online tutorials to teach the basics of pacing.

  • Open to to all English language speakers
  • 7 week course
  • Offered quarterly and conducted via email list server, the class is a structured discussion group
  • It is led by trained volunteer moderators, all of whom have ME/CFS and/or FM
  • Register now for classes that begin on Wed 21 Jan 2019. Registration closes on Jan 14.
  • Cost: $20.00 for course alone or $30 / $34 for course and book

The Three Parts of Pacing:

  1. Define Your Current Limits (Energy Envelope)
    The foundation for pacing is understanding your current limits. This includes limits on physical activity, and also mental activity, socializing, sense data, and stress.
  2. Adapt Using Pacing Strategies
    The second part of pacing is adjusting your life so you live within your limits. This is a gradual process, usually involving the use of multiple strategies.
  3. Expand Your Limits
    If you pace consistently, you may be able to expand your limits, doing more without increasing your symptoms.

The effects of pacing can be transformative, but progress is gradual. Learning to pace requires discipline, patience, and time, but you can see benefits immediately from even a small change such as those you’ll find in the tutorial.

NB   People with ME in Wales have found this course helpful, but please check that it is right for you. Ensure you have enough time and energy to make the most of it.

The ME/CFS and Fibromyalgia Self-Help Program is a non-profit organization offering a suite of low-cost and free online self-help courses, plus other resources for people affected by ME/CFS and fibromyalgia.

Posted in News | Tagged , , | Comments Off on Online pacing tutorial begins January 2019

Dr Anne McIntyre RIP

Posted on 11/27/2018 by wames

A long time advocate and sufferer of ME, Dr Anne McIntyre, died on Saturday 24th November 2018.  She had been living with rheumatoid arthritis for many years and developed pulmonary fibrosis as a complication of that.

Her book M.E. Chronic Fatigue Syndrome: a practical guide was written in the 1990s but is still considered by many to be one of the most helpful.

She will be remembered for her compassion and willingness to help, and for her work as advisor to the ME Association, and writing and speaking about ME.

 

Read tributes by Dr Charles Shepherd and her friend Jenny Wilson.

Watch Frontline documentary, presented by Dr McIntyre and featuring the Gilderdale family and Ean Proctor.

Posted in News | Tagged | Comments Off on Dr Anne McIntyre RIP