CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation.

In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM).

In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation.

There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells.

In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

Source: Mensah FFK, Armstrong CW, Reddy V, Bansal AS, Berkovitz S, Leandro MJ, Cambridge G. CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Immunol. 2018 Oct 22;9:2421. doi: 10.3389/fimmu.2018.02421. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204382/ (Full article)

Individual Community Symposium Talks Now Available on OMF YouTube Channel

The individual talks from the Second Annual Community Symposium on the Molecular Basis of ME/CFS are now available as separate videos in a playlist on OMF’s YouTube channel.

Check out the speakers you are interested in hearing from, the panel discussions where they answer questions.

To watch the recordings, click here.

Visit OMF’s website to learn more about the Symposium and the research OMF is funding.

Discovery Forum 2017: Presentation of Dr. Nancy Klimas

Solve ME/CFS Initiative’s 2nd Annual Discovery Forum, held on October 14th in Washington DC, brings together leaders from across industry, academia, federal agencies, and biotech companies to tackle the most pressing issues confronting ME/CFS today. This recording is the full presentation of Dr. Nancy Klimas, Director of the Institute for Neuro Immune Medicine at Nova Southeastern University in Fort Lauderdale, FL.

Feedback on underperformance in patients with Chronic Fatigue Syndrome: The impact on subsequent neuropsychological test performance

Abstract:

Performance Validity Tests (PVTs) are used to measure the credibility of neuropsychological test results. Until now, however, a minimal amount is known about the effects of feedback upon noncredible results (i.e., underperformance) on subsequent neuropsychological test performance.

The purpose of this study was to investigate the effects of feedback on underperformance in Chronic Fatigue Syndrome (CFS) patients. A subset of these patients received feedback on Amsterdam Short-Term Memory (ASTM) failure (i.e., feedback [FB] group). After matching, the final sample consisted of two comparable groups (i.e., FB and No FB; both n = 33). At baseline and follow-up assessment, the patients completed the ASTM and two measurements of information processing speed (Complex Reaction Time [CRT] and Symbol Digit Test [SDT]).

Results indicated that the patients in the FB group improved significantly on the CRT, compared to the No FB group. Although not significant, a comparable trend-like effect was observed for the SDT. Independent of the feedback intervention there was a substantial improvement on ASTM performance at re-administration. A limited feedback intervention upon underperformance in CFS patients may result in improvement on information processing speed performance. This implies that such an intervention might be clinically relevant, since it maximizes the potential of examining the patients’ actual level of cognitive abilities.

Source: Roor JJ, Knoop H, Dandachi-FitzGerald B, Peters MJV, Bleijenberg G, Ponds RWHM. Feedback on underperformance in patients with Chronic Fatigue Syndrome: The impact on subsequent neuropsychological test performance. Appl Neuropsychol Adult. 2018 Oct 31:1-9. doi: 10.1080/23279095.2018.1519509. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30380922

The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome

Abstract:

Post-exertional malaise, or a variation of this term, is a key symptom of myalgic encephalomyelitis and chronic fatigue syndrome, as this symptom is mentioned in almost all myalgic encephalomyelitis and chronic fatigue syndrome case definitions. Until now there has not been a comprehensive questionnaire to assess post-exertional malaise. To rectify this situation, in this article we describe the development of a new questionnaire, called the DePaul Post-Exertional Malaise Questionnaire, which was based on input from hundreds of patients. Preliminary validation was provided by the findings of significant and predictable relationships between different domains of this post-exertional malaise questionnaire and physical functioning.

Source: Jason LA, Holtzman CS, Sunnquist M, Cotler J. The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Health Psychol. 2018 Oct 24:1359105318805819. doi: 10.1177/1359105318805819. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30354489

Defining the minimally clinically important difference of the SF-36 physical function subscale for paediatric CFS/ME: triangulation using three different methods

Abstract:

BACKGROUND: Defining the minimally clinically important difference (MCID) is important for the design and analysis of clinical trials and ensures that findings are clinically meaningful. Studies in adult populations have investigated the MCID of The Short Form 36 physical function sub-scale (SF-36-PFS). However, to our knowledge no studies have defined the MCID of the SF-36-PFS in a paediatric population. We aimed to triangulate findings from distribution, anchor and qualitative methods to identify the MCID of the SF-36-PFS for children and adolescents with CFS/ME.

METHODS: Quantitative methods: We analysed routinely-collected data from a specialist paediatric CFS/ME service in South-West England using: 1) the anchor method, based on Clinical Global Impression (CGI) outcomes at 6 months’ follow-up; 2) the distribution method, based on the standard deviation of baseline SF-36-PFS scores. Qualitative methods: Young people (aged 12-17 years) and parents were asked to complete the SF-36-PFS, marking each question twice: once for where they would currently rate themselves/their child and a second time to show what they felt would be the smallest amount of change for them/their child to feel treatment had made a difference. Semi-structured interviews were designed to explore what factors were deemed important to patients and to what extent an improvement was considered satisfactory. We thematically analysed qualitative interviews from 21 children and their parents.

RESULTS: Quantitative results: Six-month follow-up data were available for 198 children with a mean age of 14 years. Most were female (74%, 146/198) and 95% gave their ethnicity as “White British”. Half the standard deviation of the baseline SF-36-PFS scores was 11.0. “A little better” on the CGI equated to a mean difference on the SF-36-PFS from baseline to 6-month follow-up of 9.0. Qualitative results: Twenty-one children with CFS/ME participated: 16 females (76.2%) with a mean age of 14.4 years. Twenty mothers and two fathers were also interviewed. The median minimal improvement in the SF-36-PFS was 10. Participants indicated that small changes in physical function can lead to important improvements in valued social and family function. Patients and parents were positive about improvement even in the presence of persisting symptoms. Triangulation: The MCID based on the mean score from the three methods was 10.

CONCLUSIONS: Converging evidence indicates future studies in paediatric CFS/ME should use an MCID of 10 on the SF-36-PFS.

Source: Brigden A, Parslow RM, Gaunt D, Collin SM, Jones A, Crawley E. Defining the minimally clinically important difference of the SF-36 physical function subscale for paediatric CFS/ME: triangulation using three different methods. Health Qual Life Outcomes. 2018 Oct 19;16(1):202. doi: 10.1186/s12955-018-1028-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194701/ (Full article)

Pain is associated with reduced quality of life and functional status in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:
Background and aims: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is challenging to live with, often accompanied by pervasive fatigue and pain, accompanied by decreased quality of life (QoL) as well as anxiety and/or depression. Associations between higher pain, lower QoL and higher anxiety and depression have been shown in patients with various chronic pain disorders. Few studies have however examined such associations in a sample of patients with ME/CFS.

The aims of the current study were to examine the impact of pain levels and compare levels of pain, health related QoL, anxiety and depression between patients with ME/CFS and healthy controls. In addition, the study aimed and to examine these relationships within the patient group only.

Methods: This is a cross-sectional questionnaire based study comparing 87 well-diagnosed patients with ME/CFS with 94 healthy controls. The De Paul Symptom Questionnaire (DSQ), the Medical Outcomes Study Short-Form Surveys (SF-36) and the Hospital Anxiety and Depression Scale (HADS) were used to examine and compare pain, physical function, QoL, anxiety and depression in patients and healthy controls. Further the pain variables were divided into pain total, pain intensity and a pain frequency score for analyses of the above mentioned variables within the patient group only.

Results: Significantly higher levels of pain, anxiety and depression, and lower levels of QoL were found in the patient group compared with healthy controls. For the patient group alone, pain was significantly associated with lower QoL in terms of physical functioning, bodily pain, general health functioning, vitality and social functioning capacity. In this patient sample, only frequency of joint pain showed significant difference in psychological variables such as depression and anxiety – depression combined.

Conclusions: ME/CFS patients differ significantly from healthy controls in pain, health related QoL, anxiety and depression. Pain is significantly associated with reduced QoL and overall a lower level of functioning. The relation between pain and anxiety and depression appears less clear. Implications Pain is for many ME/CFS patients associated with reduced physical functioning and reduced QoL. A thorough pain assessment can therefore be essential for clinicians, and subsequent medical pain treatment combined with good pain coping skills may increase functioning level and QoL for these patients. The link between joint pain and psychological factors should also be focused in clinical practice in terms of mapping and counseling. Pain should be further examined to understand the importance it may have for functioning level as reduced function is a main criteria when diagnosing the patients.

Source: Strand EB, Mengshoel AM, Sandvik L, Helland IB, Abraham S, Nes LS. Pain is associated with reduced quality of life and functional status in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scand J Pain. 2018 Oct 16. pii: /j/sjpain.ahead-of-print/sjpain-2018-0095/sjpain-2018-0095.xml. doi: 10.1515/sjpain-2018-0095. [Epub ahead of print]

Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies

Abstract:

Background and aims: The interaction between the immune system and pain has been thoroughly explored in the recent decades. The release of inflammatory mediators from immune cells has the capability of activating neurons and glial cells, in turn sensitizing the nervous system. Both immune system alterations and pain modulation dysfunctions have been shown in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following exercise. However, no studies tried to explore whether these two phenomena are linked and can explain exercise-induced symptoms worsening in people with ME/CFS. We hypothesized that exercise-induced changes in descending pain modulation is associated to changes in immune system functions. We used complement system product C4a and elastase activity as indicators of immune system activity.

Methods: The study design was a secondary analysis of controlled experimental studies. Twenty-two patients with ME/CFS and 22 healthy sedentary controls were enrolled. In experiment 1, subjects performed an aerobic submaximal exercise test; in experiment 2 they underwent a self-paced exercise test. One week of rest period were set between the two exercise tests. Before and after each experiment, subjects underwent clinical assessment, pain thresholds (PPTs) measurement, and blood sampling. Immune system function was assessed measuring complement system C4a products and elastase activity.

Results: Changes in elastase activity were not associated to changes in PPTs. Associations were observed in the ME/CFS group between changes in PPTs and C4a products, following both types of exercise. After submaximal exercise, the change in C4a products was associated with the change in PPT at the thumb in patients (r=0.669, p=0.001). Similarly, after self-paced exercise the change in C4a products was associated witht the change in PPT at the calf in patients (r=0.429, p=0.047). No such correlations were found in healthy controls. Regression analysis showed that C4a changes after the submaximal exercise significantly predicted the change in PPTs (R2=0.236; p=0.02).

Conclusions: Moderate associations between exercise-induced changes in PPTs and immune system activity were found only in ME/CFS. The change in the complement system following submaximal exercise might be able to explain part of the change in patient’s pain thresholds, providing evidence for a potential link between immune system alteration and dysfunctional endogenous pain modulation. These results have to be taken with caution, as only one out of three measures of PPTs was found associated with C4a changes. We cannot reject the hypothesis that C4a might therefore be a confounding factor, and changes during exercise might be mediated by other mechanism. Implications Immune system changes following exercise might contribute to exercise-induced symptoms worsening in patients with ME/CFS. However, the role of the complement system is questionable.

Source: Polli A, Van Oosterwijck J, Meeus M, Lambrecht L, Nijs J, Ickmans K. Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies. Scand J Pain. 2018 Oct 16. pii: /j/sjpain.ahead-of-print/sjpain-2018-0075/sjpain-2018-0075.xml. doi: 10.1515/sjpain-2018-0075. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/30325737

WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue is increasingly common. Conventional medical care is limited in treating chronic fatigue, leading some patients to use traditional Chinese medicine therapies, including herbal medicine.

OBJECTIVES: To assess the effectiveness of traditional Chinese medicine herbal products in treating idiopathic chronic fatigue and chronic fatigue syndrome.

SEARCH METHODS: The following databases were searched for terms related to traditional Chinese medicine, chronic fatigue, and clinical trials: CCDAN Controlled Trials Register (July 2009), MEDLINE (1966-2008), EMBASE (1980-2008), AMED (1985-2008), CINAHL (1982-2008), PSYCHINFO (1985-2008), CENTRAL (Issue 2 2008), the Chalmers Research Group PedCAM Database (2004), VIP Information (1989-2008), CNKI (1976-2008), OCLC Proceedings First (1992-2008), Conference Papers Index (1982-2008), and Dissertation Abstracts (1980-2008). Reference lists of included studies and review articles were examined and experts in the field were contacted for knowledge of additional studies.

SELECTION CRITERIA: Selection criteria included published or unpublished randomized controlled trials (RCTs) of participants diagnosed with idiopathic chronic fatigue or chronic fatigue syndrome comparing traditional Chinese medicinal herbs with placebo, conventional standard of care (SOC), or no treatment/wait lists. The outcome of interest was fatigue.

DATA COLLECTION AND ANALYSIS: 13 databases were searched for RCTs investigating TCM herbal products for the treatment of chronic fatigue. Over 2400 references were located. Studies were screened and assessed for inclusion criteria by two authors.

MAIN RESULTS: No studies that met all inclusion criteria were identified.

AUTHORS’ CONCLUSIONS: Although studies examining the use of TCM herbal products for chronic fatigue were located, methodologic limitations resulted in the exclusion of all studies. Of note, many of the studies labelled as RCTs and conducted in China did not utilize rigorous randomization procedures. Improvements in methodology in future studies is required for meaningful synthesis of data.

Source: Adams D, Wu T, Yang X, Tai S, Vohra S. WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2018 Oct 15;10:CD006348. doi: 10.1002/14651858.CD006348.pub3. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30321452

Reciprocal associations between daily need-based experiences, energy, and sleep in chronic fatigue syndrome

Abstract:

OBJECTIVE: Previous findings indicate that patients with chronic fatigue syndrome (CFS) report significant day-to-day fluctuations in subjective energy and sleep. Herein, we examined whether daily variation in the satisfaction and frustration of the basic psychological needs for autonomy, competence, and relatedness would contribute to daily variation in subjective energy and quality and quantity of sleep. In addition, we examined whether daily variation in sleep would contribute to daily need-based experiences through (i.e., mediated by) daily fluctuations in subjective energy.

METHOD: CFS patients (N = 120; 92% female; Mage = 42.10 years, SD = 10.46) completed a diary for 14 days which assessed their need-based experiences and subjective energy every evening and sleep every morning.

RESULTS: Results indicated that subjective energy, sleep, and need experiences fluctuated significantly from day to day. Daily need satisfaction related to less daily fatigue and more daily vitality, while the opposite pattern was observed for daily need frustration. Daily need frustration was also uniquely related to poorer daily sleep quality. Lastly, better daily sleep quality was also uniquely related to more daily need satisfaction and less daily need frustration via (i.e., mediated by) daily variation in subjective energy. These reciprocal within-day associations remained significant after controlling for the previous day’s level of each outcome, with the exception of the relation between need frustration and sleep quality.

CONCLUSION: The present findings underscore the reciprocal day-to-day association between need-based experiences and subjective energy in CFS. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Source: Campbell R, Vansteenkiste M, Delesie L, Tobback E, Mariman A, Vogelaers D, Mouratidis A. Reciprocal associations between daily need-based experiences, energy, and sleep in chronic fatigue syndrome. Health Psychol. 2018 Oct 15. doi: 10.1037/hea0000621. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30321019