Chronic Fatigue Syndrome/myalgic Encephalomyelitis Research Articles

Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.

Background: Mast cells (MCs) mediate inflammation through neuropeptides and cytokines, along with histamine and reactive oxygen species (ROS). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an illness characterized by an unexplained disabling fatigue with multiple physiological impairments as well as dysregulated cytokine profiles. Objective: To determine mast cell phenotypes in isolated human PBMCs, in healthy controls and in CFS/ME patients. Second, determine receptor expression of RAGE and its ligand high mobility group box 1 protein (HMGB1). Method: Moderately severe CFS/ME patients (n=12, mean age 39.25±SD3.52 years), severe CFS/ME patients (n=6, mean age 43.00±SD4.02 years) and healthy controls (n=13, mean age 42.69±SD3.87 years) were included in this study. CFS/ME patients were classified according to the 2011 International Consensus Criteria. LSRFortessa X-20 Flow cytometry was used for the identification of phenotypic peripheral mast cell population in PBMCs using an exclusion marker Lin2 cocktail (anti-CD3, anti-CD14, anti-CD19, anti-CD20 and anti-CD56) and inclusion markers (CD117, CD34, FCeRI, chymase, HLA-DR and CD154) following comparative investigation. HMGB1 and soluble RAGE expression in plasma was measured by sandwich ELISA assay. Results: There was a significant increase in CD117+CD34+FCeRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls. There was a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cell populations in the severe CFS/ME compared with healthy controls and moderate CFS/ME. There were no significant differences between groups for HMGB1 and sRAGE. Conclusions: This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naive MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients. Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required. Key words: Chronic Fatigue Syndrome; Mast Cells; Receptor for advanced glycation end products; RAGE; Ligand High Mobility Group Box 1 protein (HMGB1); Myalgic Encephalomyelitis

Implementing resources to support the diagnosis and management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in primary care: A qualitative study.

BackgroundPrevious research has highlighted that many GPs lack the confidence and knowledge to diagnose and manage people with CFS/ME. Following the development of an online training module for GPs, and an information pack and DVD for patients, this study explored the extent to which these resources can be implemented in routine primary care.MethodsSemi structured qualitative interviews were completed with patients and GPs across North West England. All interviews were transcribed and analysed using open exploratory thematic coding. Following this thematic analysis, the authors conducted a further theory-driven analysis of the data guided by Normalisation Process Theory.ResultsWhen used in line with advice from the research team, the information resource and training were perceived as beneficial to both patients and GPs in the diagnosis and management of CFS/ME. However, 47 % of patients in this study did not receive the information pack from their GP. When the information pack was used, it was often incomplete, sent in the post, and GPs did not work with patients to discuss the materials. Only13 out of 21 practices completed the training module due to time pressures and the low priority placed on low prevalence, contentious, hard to manage conditions. When the module was completed, many GPs stated that it was not feasible to retain the key messages as they saw so few patients with the condition. Due to the complexity of the condition, GPs also believed that the diagnosis and management of CFS/ME should take place in a specialist care setting.ConclusionWhile barriers to the implementation of training and resources for CFS/ME remain, there is a need to support CFS/ME patients to access reliable, evidence based information outside primary care. Our findings suggest that future research should develop an online resource for patients to support self-management.Electronic supplementary materialThe online version of this article (doi:10.1186/s12875-016-0453-8) contains supplementary material, which is available to authorized users.

Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients.

BackgroundTransient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis. TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation. The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19+ B cells, CD56bright and CD56dim cell populations from CFS/ME patients.ResultsTRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56bright TRPM3 35.72 % ± 7.37; CD56dim 5.74 % ± 2.00; B lymphocytes 2.05 % ± 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19+ B cells (1.56 ± 0.191) and CD56bright NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti-IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19+ B lymphocytes. CD56bright NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients.ConclusionsThe results from this preliminary investigation identify, for the first time, TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME.Electronic supplementary materialThe online version of this article (doi:10.1186/s40659-016-0087-2) contains supplementary material, which is available to authorized users.

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

ABSTRACTChronic 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.- 2ʹ-5ʹ 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.

Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients.

BackgroundNo epidemiological investigations have previously been conducted in Australia according to the current clinical definitions of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to describe sociodemographic and illness characteristics of Australian patients with CFS/ME.MethodsA cross-sectional survey on the medical history of patients enrolled in an Australian CFS/ME research database between April 2013 and April 2015. Participants were classified according to Fukuda criteria and International Consensus Criteria.ResultsA total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. The mean age of all patients was 46.4 years (standard deviation 12.0); the majority were female (78.61%), Caucasian, and highly educated. Of these, 30.28% met Fukuda criteria. A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress. Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified.ConclusionThis is the first study to summarize sociodemographic and illness characteristics of a cohort of Australian CFS/ME patients. This is vital for identifying potential risk factors and predictors associated with CFS/ME and for guiding decisions regarding health care provision, diagnosis, and management.

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.

BackgroundNatural 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.MethodsFlow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56brightCD16dim/− and CD56dimCD16+ 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 CD56brightCD16dim/− and CD56dimCD16+ NK cell function using flow cytometric protocols.ResultsCFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56dimCD16+ NK cells compared to the non-fatigued controls (n = 11) after incubation with K562 cells. CD56brightCD16dim/− NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.ConclusionsThis is the first study to report significant differences in MAPK intracellular signalling molecules in CD56dimCD16+ and CD56brightCD16dim/− NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56dimCD16+ and CD56brightCD16dim/− NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0859-z) contains supplementary material, which is available to authorized users.

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

ObjectiveTo 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...

Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.

Mast cells (MCs) mediate inflammation through neuropeptides and cytokines, along with histamine and reactive oxygen species (ROS). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an illness characterized by an unexplained disabling fatigue with multiple physiological impairments as well as dysregulated cytokine profiles. To determine mast cell phenotypes in isolated human PBMCs, in healthy controls and in CFS/ME patients. Second, determine receptor expression of RAGE and its ligand high mobility group box 1 protein (HMGB1). Moderately severe CFS/ME patients (n=12, mean age 39.25 ± SD3.52 years), severe CFS/ME patients (n=6, mean age 43.00 ± SD4.02 years) and healthy controls (n=13, mean age 42.69 ± SD3.87 years) were included in this study. CFS/ME patients were classified according to the 2011 International Consensus Criteria. LSRFortessa X-20 Flow cytometry was used for the identification of phenotypic peripheral mast cell population in PBMCs using an exclusion marker Lin2 cocktail (anti-CD3, anti-CD14, anti-CD19, anti-CD20 and anti-CD56) and inclusion markers (CD117, CD34, FCεRI, chymase, HLA-DR and CD154) following comparative investigation. HMGB1 and soluble RAGE expression in plasma was measured by sandwich ELISA assay. There was a significant increase in CD117⁺CD34⁺FCεRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls. There was a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cell populations in the severe CFS/ME compared with healthy controls and moderate CFS/ME. There were no significant differences between groups for HMGB1 and sRAGE. This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naïve MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients. Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.

BACKGROUNDThe etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME.METHODMessenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).RESULTSThe expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.CONCLUSIONSIn severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

Understanding Muscle Dysfunction in Chronic Fatigue Syndrome.

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.

Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients.

Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated. The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs). Comparison of KIR and allelic polymorphism frequencies revealed no significant differences between 20 CFS/ME patients and 20 NFCs. A lower frequency of the telomeric A/B motif (P < 0.05) was observed in CFS/ME patients compared with NFCs. This pilot study is the first to report the differences in the frequency of KIR on the telomeric A/B motif in CFS/ME patients. Further studies with a larger CFS/ME cohort are required to validate these results.

A New Era for Immunotherapeutic Approaches in Multiple Sclerosis Treatment

Recent studies have shown that many pathological conditions, including neurodegenerative disorders, are always the result of innate immune dysregulations. In multiple sclerosis (MS), innate immunity has shown induce proinflammatory responses, mainly mediated by specific innate immune receptors, as well as Toll-like receptors (TLRs). Interestingly, whereas activation of TLR-MyD88 dependent signaling pathway induces inflammation and MS progression, TLR3 activation MyD88 independent seems to play a beneficial effect, probably due to its ability to enhance endogenous IFN-β production, that in turn down regulates proinflammatory responses. Consequently, new therapeutic approaches based on TLR up and/or down regulation could offer promising results. In addition to several classes of TLR antagonists represented by different types of antibodies, nanobodies, mimetic molecules and RNAselective interference compounds, TLR3 agonists appear particularly interesting due to their capability of inducing IFN-β production. Among these, Ampligen® shows early promise, since it has shown positive results in several phase III trials for the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS.

Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis.

Patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and multiple sclerosis (MS) suffer from debilitating fatigue which is not alleviated by rest. In addition to the fatigue-related symptoms suffered by patients with CFS/ME and MS, dysfunction of the immune system and, in particular, reduced natural killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS. The purpose of this pilot study was to compare NK cellular mechanisms in patients with CFS/ME and MS to investigate potential dysfunctions in the NK cell activity pathway. Flow cytometry protocols assessed CD56(dim) CD16(+) and CD56(bright) CD16(+/-) NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins. All participants in this study were female and included 14 patients with CFS/ME, nine patients with MS and 19 non-fatigued controls. The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune-enhancing medications. In the MS cohort, KIR2DL5 was significantly increased on CD56(bright) CD16(+/-) NK cells and expression of CD94 was significantly increased on CD56(dim) CD16(+) NK cells in comparison with the controls. Co-expression of CD57 and perforin was significantly increased on CD56(dim) CD16(+) NK cells from patients with CFS/ME compared to the MS and non-fatigued control participants. The results from this pilot study suggest that NK cells from patients with CFS/ME and MS may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine

BackgroundChronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination. MethodsUsing the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression. ResultsThe incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91–1.04), while it was 2.04 (95% CI: 1.78–2.33) after being diagnosed with influenza infection during the peak pandemic period. ConclusionsPandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME.

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts

ObjectiveTo investigate differences between young children, adolescents and adults with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).Study designComparison of clinical cohorts from 8 paediatric and 27 adult CFS/ME services in the UK...

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients.

BackgroundResearch has identified immunological abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), a heterogeneous illness with an unknown cause and absence of diagnostic test. There have been no CFS/ME studies examining innate and adaptive immune cells longitudinally in patients with varying severities. This is the first study to investigate immune cells over 6 months while also examining CFS/ME patients of varying symptom severity.MethodsParticipants were grouped into 18 healthy controls, 12 moderate and 12 severe CFS/ME patients and flow cytometry was used to examine cell parameters at 0 and 6 months.ResultsOver time, iNKT CD62L expression significantly increased in moderate CFS/ME patients and CD56bright NK receptors differed in severe CFS/ME. Naïve CD8+T cells, CD8−CD4− and CD56−CD16− iNKT phenotypes, γδ2T cells and effector memory subsets were significantly increased in severe CFS/ME patients at 6 months. Severe CFS/ME patients were significantly reduced in CD56brightCD16dim NKG2D, CD56dimCD16− KIR2DL2/DL3, CD94−CD11a− γδ1T cells and CD62L+CD11a− γδ1T cells at 6 months.ConclusionsSevere CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8+T cell markers, NK cell receptors and γδT cells at 6 months. This highlights the importance of further assessing these potential immune biomarkers longitudinally in both moderate and severe CFS/ME patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0653-3) contains supplementary material, which is available to authorized users.

The Role of Toll-Like Receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A New Promising Therapeutic Approach?

Perturbations in immune processes play an important role in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), a multifactorial disorder mainly characterized by severe and prolonged fatigue and tipically affecting a variety of bodily systems including the immune system. Recent reports have shown that CFS/ME is an inflammatory disorder may be associated with autoimmune responses, mainly characterized by reduced functional activity of most immune cells, including neutrophils, natural killer cells, monocytes/macrophage and dendritic cells, together with dysregulations in cytokine levels, responsible for changes in the adaptive immune system. Interactions between gut microorganisms and host immune function have been shown to contribute to aberrant inflammation in CFS/ME patients. Commensal and/or pathogen-associated molecular patterns detected by Toll-like receptors (TLRs) expressed on intestinal epithelial cells appear to trigger inflammatory signaling cascade leading to neuroinflammation and neurodegeneration. This paper examines the role of TLR-mediated innate immunity in CFS/ME with evaluation of the current literature, also discussing about innovative therapeutic approaches represented by immunomodulators TLR-targeting.

Is Chronic Fatigue Syndrome/Myalgic Encephalomyelitis a Relevant Diagnosis in Patients with Suspected Side Effects to Human Papilloma Virus Vaccine?

The quad rivalent human papilloma virus vaccine (Q-HPV-vaccine) was included into the Danish childhood vaccination program in 2009. During the past years possible side effects have been described in several countries encompassing a collection of symptoms consistent with pronounced autonomic dysfunction coupled with severe non-migraine-like headache, excessive fatigue, cognitive dysfunction, gastrointestinal discomfort and widespread pain of a neuropathic character. The assessment of the prevalence and the possible pattern in symptoms suspected to be side effects has been hampered by a lack of consistency in the diagnostic criteria applied on seemingly similar symptom complexes. As fatigue and fatigability is a prominent symptom in many of the patients with suspected side effects to the vaccine, chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)c ould be suspected to be a suitable diagnosis. We have performed a retrospective analysis on the applicability of the CFS/ME diagnosis in 39 patients referred to our Syncope Unit from May 2011 to April 2015 for clinical evaluation including a head-up tilt test. The patients were referred due to orthostatic intolerance and symptoms compatible with autonomic dysfunction occurring in a close temporal association to vaccination with the Q-HPV vaccine. We found that 34 (87%) and 35(90%) of the patients fulfilled the diagnostic criteria for CFS/ME regarding to the Canadian and the IOM (Institute of Medicine) criteria respectively and suggest that CFS/ME may be a suitable diagnosis for patients with severe and persistent suspected side effects to the Q-HPV vaccine. For the time being we can neither confirm nor dismiss a causal link between the vaccine and the disabling symptoms, but a consensus on the classification of the patients is needed in order to attain a more systematic clinical and scientific approach to this challenge. Common diagnostic criteria could hopefully result in a specific treatment protocol and thereby strengthen the worldwide program to combat cancers caused by human papilloma virus.

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

BackgroundAbnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors.ResultsCFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4+T and CD8+T cells. Moderate CFS/ME patients had increased CD8+ CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5+ on CD4+T cells and BTLA4+ on CD4+T central memory cells. Moderate CFS/ME patients also had reduced CD8+T central memory LFA-1, total CD8+T KLRG1, naïve CD4+T KLRG1 and CD56dimCD16− NK cell CD2+ and CD18+CD2+. Severe CFS/ME patients had increased CD18+CD11c− in the CD56dimCD16− NK cell phenotype and reduced NKp46 in CD56brightCD16dim NK cells.ConclusionsThis research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0101-4) contains supplementary material, which is available to authorized users.

Perceived fatigue interference and depressed mood: comparison of chronic fatigue syndrome/myalgic encephalomyelitis patients with fatigued breast cancer survivors

Objective: Persistent fatigue and depressive symptoms are both highly prevalent among patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) as well as breast cancer survivors. This study aimed to assess and directly compare perceptions of fatigue as highly interfering in one's daily functioning in both patient populations to better understand their relationships with depressed mood. Methods: Participants were 95 female CFS/ME patients and 67 females who were approximately five years post-treatment for stage 0–III breast cancer presenting with clinically elevated fatigue severity. Self-report measures were obtained on participants' fatigue-related interference in daily functioning and fatigue severity as well as depressed mood. Hierarchical regression was used to test effects controlling for relevant demographic, psychosocial, and medical covariates. Results: CFS/ME patients endorsed greater depressed mood and fatigue interference than did fatigued breast cancer survivors, p < .001. These factors were significantly positively correlated among CFS/ME patients (β = .36, p < .001), but not among the fatigued breast cancer survivors (β = .18, p = .19). Conclusions: CFS/ME patients reported elevated fatigue symptoms and depression relative to fatigued breast cancer survivors. In the former group, greater depressed mood was highly and significantly associated with greater fatigue-related inference in daily activities. Potential targets for cognitive behavioral interventions are discussed.