2016 – Page 11 – American ME and CFS Society

ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56 dim CD16+ and CD56 bright CD16 dim/- natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Natural Killer (NK) cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases (MAPK) pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1/2, ERK1/2, p38 and JNK. Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS/ME patients.

METHODS: Flow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56(bright)CD16(dim/-) and CD56(dim)CD16(+) NK cells following stimulation with K562 tumour cells or phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56(bright)CD16(dim/-) and CD56(dim)CD16(+) NK cell function using flow cytometric protocols.

RESULTS: CFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56(dim)CD16(+) NK cells compared to the non-fatigued controls (n = 11) after incubation with K562 cells. CD56(bright)CD16(dim/-) NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.

CONCLUSIONS: This is the first study to report significant differences in MAPK intracellular signalling molecules in CD56(dim)CD16(+) and CD56(bright)CD16(dim/-) NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56(dim)CD16(+) and CD56(bright)CD16(dim/-) NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.

Source: Huth TK, Staines D, Marshall-Gradisnik S. ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56 dim CD16+ and CD56 bright CD16 dim/- natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2016 Apr 21;14:97. doi: 10.1186/s12967-016-0859-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839077/ (Full article)

Case definitions integrating empiric and consensus perspectives

Abstract:

BACKGROUND: There has been considerable controversy regarding how to name and define the illnesses known as myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). The IOM report has proposed a new clinical criteria and name for this illness, but aspects of these recommendations have been scrutinized by patients and scientists.

PURPOSE: It is possible that both empiric and consensus approaches could be used to help settle some of these diagnostic challenges. Using patient samples collected in the United States, Great Britain, and Norway (N=556), the current study attempted to categorize patients using more general as well as more restricted case definitions.

RESULTS: Overall, the outcomes suggest that there might be four groupings of patients, with the broadest category involving those with chronic fatigue (N=62), defined by 6 or more months of fatigue which can be cannot be explained by medical or psychiatric conditions. A second category involves those patients that have chronic fatigue that can be explained by a medical or psychiatric condition (N=47). A third category involves more specific criteria that have been posited both by the IOM report, a Canadian Clinical Case criteria, a ME-ICC criteria and a more empiric approach. These efforts have specified domains of substantial reductions of activity, post-exertional malaise, neurocognitive impairment, and sleep dysfunction (N=346). Patients with these characteristics were more functionally impaired than those meeting just chronic fatigue criteria, p < .05. Finally, those meeting even more restrictive ME criteria proposed by Ramsay, identified a smaller and even more impaired group, p < .05.

DISCUSSION: The advantages of using such empirical and consensus approaches to develop reliable classification and diagnostic efforts are discussed.

Source: Jason LA, McManimen S, Sunnquist M, Brown A, Furst J, Newton JL, Strand EB. Case definitions integrating empiric and consensus perspectives. Fatigue. 2016;4(1):1-23. Epub 2016 Jan 19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831204/ (Full article)

Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome

Abstract:

BACKGROUND: The NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3) is an intracellular protein complex that plays an important role in innate immune sensing. Its activation leads to the maturation of caspase-1 and regulates the cleavage of interleukin (IL)-1β and IL-18. Various studies have shown that activation of the immune system plays a pivotal role in the development of fatigue. However, the mechanisms underlying the association between immune activation and fatigue remained elusive, and few reports have described the involvement of NLRP3 inflammasome activation in fatigue.

METHODS: We established a mouse fatigue model with lipopolysaccharide (LPS, 3 mg/kg) challenge combined with swim stress. Both behavioural and biochemical parameters were measured to illustrate the characteristics of this model. We also assessed NLRP3 inflammasome activation in the mouse diencephalon, which is the brain region that has been suggested to be responsible for fatigue sensation. To further identify the role of NLRP3 inflammasome activation in the pathogenesis of chronic fatigue syndrome (CFS), NLRP3 KO mice were also subjected to LPS treatment and swim stress, and the same parameters were evaluated.

RESULTS: Mice challenged with LPS and subjected to the swim stress test showed decreased locomotor activity, decreased fall-off time in a rota-rod test and increased serum levels of IL-1β and IL-6 compared with untreated mice. Serum levels of lactic acid and malondialdehyde (MDA) were not significantly altered in the treated mice. We demonstrated increased NLRP3 expression, IL-1β production and caspase-1 activation in the diencephalons of the treated mice. In NLRP3 KO mice, we found remarkably increased locomotor activity with longer fall-off times and decreased serum IL-1β levels compared with those of wild-type (WT) mice after LPS challenge and the swim stress test. IL-1β levels in the diencephalon were also significantly decreased in the NLRP3 KO mice. By contrast, IL-6 levels were not significantly altered.

CONCLUSIONS: These findings suggest that LPS-induced fatigue is an IL-1β-dependent process and that the NLRP3/caspase-1 pathway is involved in the mechanisms of LPS-induced fatigue behaviours. NLRP3/caspase-1 inhibition may be a promising therapy for fatigue treatment.

Source: Zhang ZT, Du XM, Ma XJ, Zong Y, Chen JK, Yu CL, Liu YG, Chen YC, Zhao LJ, Lu GC. Activation of the NLRP3 inflammasome in lipopolysaccharide-induced mouse fatigue and its relevance to chronic fatigue syndrome. J Neuroinflammation. 2016 Apr 5;13(1):71. doi: 10.1186/s12974-016-0539-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822300/ (Full article)

Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Abstract:

Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA).

Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2′-5′ adenylate synthetase, protein kinase R).

Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.

Source: Mitchell WM. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Expert Rev Clin Pharmacol. 2016 Jun;9(6):755-70. Doi: 10.1586/17512433.2016.1172960. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917909/ (Full article)

How do women with chronic fatigue syndrome/myalgic encephalomyelitis rate quality and coordination of healthcare services? A cross-sectional study

Abstract:

OBJECTIVE: To test the association between self-rated health and self-rated degree of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and CFS/ME patients’ assessment of quality of primary care, specialist care and coordination of care.

DESIGN: Cross-sectional study.

SETTING: Self-reported questionnaire data from women members of The Norwegian ME Association obtained in 2013.

PARTICIPANTS: 431 women with CFS/ME aged 16-73 years.

MAIN OUTCOME MEASURE: The participants’ assessment of quality in primary care, specialist care and in coordination of care (good/very good or poor/very poor). Main explanatory variables: self-rated health and self-rated degree of CFS/ME.

RESULTS: Quality of care was rated poor by 60.6% in primary care, by 47.7% in specialist care, and by 71.2% regarding coordination of care. Poorer self-rated health increased the probability of rating quality in primary care poor, particularly among women 40 years and over (OR 2.38, 95% CI 1.63 to 3.49), women with university education (OR 2.57, CI 1.68 to 3.94), and owing to less frequent general practitioner (GP) visits (OR 2.46, CI 1.60 to 3.78). Poorer self-rated health increased the probability of rating quality poor in specialist care (OR 1.38, CI 1.05 to 1.82), but not in coordination of care. A more severe CFS/ME was associated with a higher probability of rating quality in primary care poor (OR 0.61, CI 0.38 to 0.93). Frequent visitors and those with a long GP relationship were less likely to report primary care quality as poor.

CONCLUSIONS: A large proportion of women with CFS/ME rated quality of care poor/very poor in primary care, specialist care and in coordination of care. The dissatisfaction was higher for primary care than for specialist care. Overall, poorer self-rated health and a more severe CFS/ME were associated with lower quality scores in primary and specialist care, but not in coordination of care. Healthcare services, as assessed by women with CFS/ME, do have a large potential for improvement.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Source: Hansen AH, Lian OS. How do women with chronic fatigue syndrome/myalgic encephalomyelitis rate quality and coordination of healthcare services? A cross-sectional study. BMJ Open. 2016 Apr 4;6(4):e010277. doi: 10.1136/bmjopen-2015-010277. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823449/ (Full article)

Cognitive Dysfunction in Chronic Fatigue Syndrome: a Review of Recent Evidence

Abstract:

Cognitive difficulties represent a common and debilitating feature of the enigmatic chronic fatigue syndrome (CFS). These difficulties manifest as self-reported problems with attention, memory, and concentration and present objectively as slowed information processing speed particularly on complex tasks requiring sustained attention. The mechanisms underlying cognitive dysfunction remain to be established; however, alterations in autonomic nervous system activity and cerebral blood flow have been proposed as possibilities.

Heterogeneity in the experience of cognitive impairment, as well as differences in the methods utilised to quantify dysfunction, may contribute to the difficulties in establishing plausible biological underpinnings. The development of a brief neurocognitive battery specifically tailored to CFS and adoption by the international research community would be beneficial in establishing a profile of cognitive dysfunction. This could also provide better insights into the underlying biological mechanisms of cognitive dysfunction in CFS and enhance the development of targeted treatments.

Source: Cvejic E, Birch RC, Vollmer-Conna U. Cognitive Dysfunction in Chronic Fatigue Syndrome: a Review of Recent Evidence. Curr Rheumatol Rep. 2016 May;18(5):24. doi: 10.1007/s11926-016-0577-9. https://www.ncbi.nlm.nih.gov/pubmed/27032787

Treatment expectations influence the outcome of multidisciplinary rehabilitation treatment in patients with CFS

Abstract:

OBJECTIVE: To improve the effectiveness of treatment in patients with chronic fatigue syndrome it is worthwhile studying factors influencing outcomes. The aims of this study were (1) to assess the association of expectancy and credibility on treatment outcomes, and (2) to identify baseline variables associated with treatment expectancy and credibility.

METHODS: 122 patients were included in a randomized controlled trial of whom 60 received cognitive behavioural therapy (CBT) and 62 multidisciplinary rehabilitation treatment (MRT). Expectancy and credibility were measured with the credibility and expectancy questionnaire. Outcomes of treatment, fatigue, and quality of life (QoL), were measured at baseline and post-treatment. Multiple linear regressions were performed to analyse associations.

RESULTS: In explaining fatigue and the physical component of the QoL, the effect of expectancy was significant for MRT, whereas in CBT no such associations were found. The main effect of expectancy on the mental component of QoL was not significant. For credibility, the overall effect on fatigue and the physical component of QoL was not significant. In explaining the mental component of QoL, the interaction between treatment and credibility was significant. However, the effects within each group were not significant. In the regression model with expectancy as dependent variable, only treatment centre appeared significantly associated. In explaining credibility, treatment centre, treatment allocation and depression contributed significantly.

CONCLUSIONS: For clinical practice it seems important to check the expectations of the patient, since expectations influence the outcome after MRT.

Source: Vos-Vromans DC, Huijnen IP, Rijnders LJ, Winkens B, Knottnerus JA, Smeets RJ. Treatment expectations influence the outcome of multidisciplinary rehabilitation treatment in patients with CFS. J Psychosom Res. 2016 Apr;83:40-5. doi: 10.1016/j.jpsychores.2016.02.004. Epub 2016 Feb 17. https://www.ncbi.nlm.nih.gov/pubmed/27020075

Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), and Multiple Sclerosis (MS) may share some similarities in relation to reduced NK cell activity. It is likely that other cells such as regulatory T (Tregs), invariant Natural Killer T (iNKT) and gamma delta T (γδ T) cells may also be dysregulated in CFS/ME and MS.

OBJECTIVE: To evaluate and compare specific immune regulatory cells of patients with CFS/ME, patients with MS and healthy controls.

METHOD: Sixty three volunteers were included in this study: 24 were CFS/ME patients, 11 were MS patients and 27 were healthy controls. Blood samples were obtained from all participants for flow cytometry analysis of iNKT cells, Tregs and γδ T cell phenotypes.

RESULTS: We observed a significant increase in Tregs in the CFS/ME group (p≤0.05) compared to the healthy control group. Total γδ and γδ2 T cells were significantly reduced in MS patients in comparison with the healthy control group. Conversely, CD4+iNKT percentage of iNKT, was significantly increased in the CFS/ME group compared with healthy controls and the double-negative iNKT percentage of iNKT significantly decreased compared with the healthy control group.

CONCLUSIONS: This study has not identified any immunological disturbances that are common in both MS and CFS/ME patients. However, the differential expression of cell types between the conditions investigated suggests different pathways of disease. These differences need to be explored in further studies.

Source: Ramos S, Brenu E, Broadley S, Kwiatek R, Ng J, Nguyen T, Freeman S, Staines D, Marshall-Gradisnik S. Regulatory T, natural killer T and γδ T cells in multiple sclerosis and chronic fatigue syndrome/myalgic encephalomyelitis: a comparison. Asian Pac J Allergy Immunol. 2016 Dec;34(4):300-305. doi: 10.12932/AP0733. http://apjai-journal.org/wp-content/uploads/2016/12/8RegulatoryTnaturalkillerAPJAIVol34No4December2016P300.pdf (Full text as PDF)

Understanding Muscle Dysfunction in Chronic Fatigue Syndrome

Abstract:

Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level.

Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis.

Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction.

Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.

Source: Rutherford G, Manning P, Newton JL. Understanding Muscle Dysfunction in Chronic Fatigue Syndrome. J Aging Res. 2016;2016:2497348. doi: 10.1155/2016/2497348. Epub 2016 Feb 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779819/ (Full article)

Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions

Abstract:

BACKGROUND: Neurocognitive difficulties are commonly reported by patients suffering from chronic fatigue syndrome (CFS). Moderate improvements from ‘best practice’ therapy are promising, but to date reported efficacy is based entirely on subjective measures. This is problematic, given the well-documented divergence between subjective perceptions and actual neurocognitive performance, including in this patient group.

MATERIAL AND METHODS: Subjective and objective measures of neurocognitive performance were obtained from 25 patients with well-characterized CFS before and after the completion of a 12-week graded-activity program incorporating a cognitive training component. Additionally, self-reported symptoms, cardiac autonomic activity (a relevant biomarker of stress responsivity), and their relation to neurocognitive improvements were examined.

RESULTS: Substantive post-intervention improvements in subjective (p=0.006) and objective (including faster responses speeds and greater accuracy, p’s<0.001) neurocognitive performance were documented. Participants also demonstrated reduced autonomic reactivity to the cognitive challenge at follow-up (p’s≤0.01). These improvements were accompanied by improvements in symptom ratings (p’s≤0.01). However, subjective ratings of neurocognitive difficulties, and CFS-related symptoms were not linked to objective performance improvements.

CONCLUSIONS: These initial data provide the first evidence of objective neurocognitive performance improvements accompanied by a significant reduction in responsiveness in stress-related neural pathways consequent to cognitive-behavioral/graded exercise therapy programs. These findings provide support for the effectiveness of such programs in remediating clinical status. These promising findings warrant further investigation, including replication in a larger sample utilizing more controlled study designs.

Source: Cvejic E, Lloyd AR, Vollmer-Conna U. Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions. Compr Psychiatry. 2016 Apr;66:166-75. doi: 10.1016/j.comppsych.2016.02.002. Epub 2016 Feb 9. https://www.ncbi.nlm.nih.gov/pubmed/26995250