cytokines – Page 6 – American ME and CFS Society

Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease of unknown etiology lasting for a minimum of 6 months but usually for many years, with features including fatigue, cognitive impairment, myalgias, post-exertional malaise, and immune system dysfunction. Dysregulation of cytokine signaling could give rise to many of these symptoms. Cytokines are present in both plasma and extracellular vesicles, but little investigation of EVs in ME/CFS has been reported. Therefore, we aimed to characterize the content of extracellular vesicles (EVs) isolated from plasma (including circulating cytokine/chemokine profiling) from individuals with ME/CFS and healthy controls.

Methods: We included 35 ME/CFS patients and 35 controls matched for age, sex and BMI. EVs were enriched from plasma by using a polymer-based precipitation method and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM) and immunoblotting. A 45-plex immunoassay was used to determine cytokine levels in both plasma and isolated EVs from a subset of 19 patients and controls. Linear regression, principal component analysis and inter-cytokine correlations were analyzed.

Results: ME/CFS individuals had significantly higher levels of EVs that ranged from 30 to 130 nm in size as compared to controls, but the mean size for total extracellular vesicles did not differ between groups. The enrichment of typical EV markers CD63, CD81, TSG101 and HSP70 was confirmed by Western blot analysis and the morphology assessed by TEM showed a homogeneous population of vesicles in both groups. Comparison of cytokine concentrations in plasma and isolated EVs of cases and controls yielded no significant differences. Cytokine-cytokine correlations in plasma revealed a significant higher number of interactions in ME/CFS cases along with 13 inverse correlations that were mainly driven by the Interferon gamma-induced protein 10 (IP-10), whereas in the plasma of controls, no inverse relationships were found across any of the cytokines. Network analysis in EVs from controls showed 2.5 times more significant inter-cytokine interactions than in the ME/CFS group, and both groups presented a unique negative association.

Conclusions: Elevated levels of 30-130 nm EVs were found in plasma from ME/CFS patients and inter-cytokine correlations revealed unusual regulatory relationships among cytokines in the ME/CFS group that were different from the control group in both plasma and EVs. These disturbances in cytokine networks are further evidence of immune dysregulation in ME/CFS.

Source: Giloteaux L, O’Neal A, Castro-Marrero J, Levine SM, Hanson MR. Cytokine profiling of extracellular vesicles isolated from plasma in myalgic encephalomyelitis/chronic fatigue syndrome: a pilot study. J Transl Med. 2020 Oct 12;18(1):387. doi: 10.1186/s12967-020-02560-0. PMID: 33046133. https://pubmed.ncbi.nlm.nih.gov/33046133/

Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is mainly symptom-based, and the etiology is still unclear. Here, we evaluated the pathological changes in the brain of a mouse model of CFS and studied the effects of Kampo medicine.

A mouse model of CFS was established through six repeated injections of Brucella abortus (BA) every two weeks for a period of 12 weeks. Neuroinflammation was measured by estimating interleukin (IL)-1β, IL-6, and interferon-gamma (IFN-γ), and oxidative stress by nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE) 6 weeks after the last injection. Hippocampal neurogenesis was evaluated through Ki-67, doublecortin (DCX), and 5-bromodeoxyuridine (BrdU) assays. The effects of Kampo medicines (Hochuekkito (TJ-41) and Hachimijiogan (TJ-7)) on neuroinflammation during CFS were studied.

The wheel-running activity of mice was decreased by about 50% compared to baseline at 6 weeks after the last BA injection. The levels of IL-1β, IL-6, 3-NT, and 4-HNE were increased in both the cortex and the hippocampus of CFS mice at 6 weeks after the last BA injection. Hippocampal neurogenesis was unchanged in CFS mice. Treatment with TJ-41 and TJ-7 reduced the expressions of IL-1β, IL-6, and IFN-γ in the hippocampus but not in the cortex.

The results of the present study indicate that neuroinflammation and oxidative stress play important roles in the pathogenesis of CFS. The data further suggest that treatment with TJ-41 and TJ-7 could help reduce the inflammation associated with CFS in the hippocampus, but failed to improve the symptoms in CFS mice.

Source: He Q, Sawada M, Yamasaki N, Akazawa S, Furuta H, Uenishi H, Meng X, Nakahashi T, Ishigaki Y, Moriya J. Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine. Biol Pharm Bull. 2020;43(1):110-115. doi: 10.1248/bpb.b19-00616. https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_article (Full article)

Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study

Abstract:

The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To this purpose, patients diagnosed according to Fukuda’s criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations.

Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction. Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction.

Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients. This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients. The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients.

No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient, whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.

Source: Venturini L, Bacchi S, Capelli E, Lorusso L, Ricevuti G, Cusa C. Modification of Immunological Parameters, Oxidative Stress Markers, Mood Symptoms, and Well-Being Status in CFS Patients after Probiotic Intake: Observations from a Pilot Study. Oxid Med Cell Longev. 2019 Nov 23;2019:1684198. doi: 10.1155/2019/1684198. eCollection 2019. https://www.hindawi.com/journals/omcl/2019/1684198/ (Full study)

Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation

Abstract:

Background: Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.

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

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

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

Source: Martin A.Jonsjö, JennyÅström, Michael P.Jones, Bianka Karshikoff, Karin Lodin, Linda Holmström, Lars Agréus, Rikard K.Wicksell, John Axelsson, Mats Lekander, Gunnar L.Olsson, Mike Kemani, Anna Andreasson. Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation. Brain, Behavior, & Immunity – Health. Available online 17 December 2019, 100028. https://www.sciencedirect.com/science/article/pii/S2666354619300298 (Full study)

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines.

We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects.

Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

Source: Mandarano AH, Maya J, Giloteaux L, Peterson DL, Maynard M, Gottschalk CG, Hanson MR. Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations. J Clin Invest. 2019 Dec 12. pii: 132185. doi: 10.1172/JCI132185. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31830003

A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)

Abstract:

BACKGROUND: Cytokines in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) patients compared with healthy controls have been extensively studied. However, the evidence regarding whether a baseline difference between CFS/ME/SEID patients and the normal population remains unclear. The aim of this study was to conduct a systematic review of the literature regarding cytokines in CFS/ME/SEID and whether there is a significant difference in cytokine levels between this patient group and the normal population.

METHODS: Pubmed, Scopus, Medline (EBSCOHost), and EMBASE databases were searched to source relevant studies for CFS/ME/SEID. The review included any studies examining cytokines in CFS/ME/SEID patients compared with healthy controls. Results of the literature search were summarised according to aspects of their study design and outcome measures, namely, cytokines. Quality assessment was also completed to summarise the level of evidence available.

RESULTS: A total of 16,702 publications were returned using our search terms. After screening of papers according to our inclusion and exclusion criteria, 15 studies were included in the review. All the included studies were observational case control studies. Ten of the studies identified measured serum cytokines in CFS/ME/SEID patients, and four measured cytokines in other physiological fluids of CFS/ME/SEID patients. The overall quality assessment revealed most papers included in this systematic review to be consistent.

CONCLUSIONS: Despite the availability of moderate quality studies, the findings of this review are inconclusive as to whether cytokines play any definitive role in CFS/ME/SEID, and consequently, they would not serve as reliable biomarkers. Therefore, in light of these results, it is recommended that further efforts toward a diagnostic test and treatment for CFS/ME/SEID continue to be developed in a range of research fields.

Source: Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019 Aug 24;19(1):207. doi: 10.1186/s12883-019-1433-0. https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1433-0 (Full article)

The clinical value of cytokines in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS.

Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices.

Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis. Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

Source: Yang T, Yang Y, Wang D, Li C, Qu Y, Guo J, Shi T, Bo W, Sun Z, Asakawa T. The clinical value of cytokines in chronic fatigue syndrome. J Transl Med. 2019 Jun 28;17(1):213. doi: 10.1186/s12967-019-1948-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1948-6 (Full article)

Cytokine profiles in patients with Q fever fatigue syndrome

Abstract:

Background: Q fever fatigue syndrome (QFS) is a state of prolonged fatigue following around 20% of acute Q fever cases. It is thought that chronic inflammation plays a role in its aetiology. To test this hypothesis we measured circulating cytokines and the exvivo cytokine production in patients with QFS and compared to various control groups.

Materials/methods: Peripheral blood mononuclear cells (PBMCs), whole blood, and serum were collected from 20 QFS patients, 19 chronic fatigue syndrome (CFS) patients, 19 Q fever seropositive controls, and 25 age- and sex-matched healthy controls. Coxiella-specific ex-vivo production of tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-6, and interferon (IFN) was measured, together with a total of 92 circulating inflammatory proteins.

Results: PBMCs of QFS patients produced more IL-6 (P = 0.0001), TNFα (P = 0.0002), and IL-1β (P = 0.0005) than the various control groups when stimulated with Coxiella antigen. QFS patients had distinct differences in circulating inflammatory markers compared to the other groups, including higher concentrations of circulating IL-6 and IFNγ.

Conclusion: QFS patients showed signs of chronic inflammation compared to asymptomatic Q fever seropositive controls, CFS patients, and healthy controls, of which the monocyte-derived cytokines TNFα, IL-1β, and especially IL-6, are likely crucial components.

Source: Raijmakers, Ruud P.H. et al. Cytokine profiles in patients with Q fever fatigue syndrome. Journal of Infection , Volume 0 , Issue 0 , DOI: https://doi.org/10.1016/j.jinf.2019.01.006

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying.

The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement.

The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable.

We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies.

We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

Source: Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front. Neurol., 10 January 2019 | https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full?fbclid=IwAR3KxhofUaLakZRPNiyBliNHSlJvUOdsVqVf5cED_i6o5gF9MCbWxpeS298#h7 (Full article)

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [− 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10−7, 1 × 10−5, and 3 × 10−3, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

Source: Kenny L. De Meirleir, Tatjana Mijatovic, Krishnamurthy Subramanian, Karen A. Schlauch and Vincent C. Lombardi. Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. Journal of Translational Medicine201816:322
https://doi.org/10.1186/s12967-018-1696-z Received: 1 September 2018, Accepted: 14 November 2018, Published: 21 November 2018 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1696-z (Full article)