Category: Immune System

Inflammation correlates with symptoms in chronic fatigue syndrome

It is not unusual for patients who say they are sick to have normal results on standard laboratory testing. The physician often concludes that there is no “real” illness and that the patients’ symptoms likely stem from a psychological disorder. An alternative conclusion, often honored in the breach, is that the standard laboratory tests are measuring the wrong things.

Chronic fatigue syndrome (CFS)―also called myalgic encephalomyelitis/chronic fatigue syndrome―is such an illness. Often, the condition begins suddenly, following an “infectious-like” illness.

For years, patients do not return to full health. The illness waxes and wanes, and at its worst leads patients to be bedridden or unable to leave their homes. A report from the National Academies estimates that CFS affects up to 2.5 million people in the United States and generates direct and indirect expenses of $17–24 billion annually (1). The most widely used case definition (2) consists only of symptoms. This, along with typically normal results on standard laboratory tests, has raised the question of whether there are any “real” objective, biological abnormalities in CFS. In PNAS, Montoya et al. report the latest evidence that there are such abnormalities.

Indeed, research over the past 30 y has discovered pathology involving the central nervous system (CNS) and autonomic nervous system (ANS), energy metabolism (with associated oxidative and nitrosative stress), and the immune system, as described in a detailed review (4). This Commentary will briefly summarize the evidence, providing citations only to work published since this review. I will then place the report by Montoya et al. (3) in context, and speculate about the pathophysiology of the illness.

Source: Anthony Komaroff. Inflammation correlates with symptoms in chronic fatigue syndrome. PNAS  2017 ; published ahead of print August 15, 2017 doi: 10.1073/pnas.1712475114  http://www.pnas.org/content/early/2017/08/14/1712475114.extract

Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study

Abstract:

Chronic fatigue syndrome (CFS) is characterized by fatigue after exertion. A systematic review suggested that transforming growth factor beta (TGF-β) concentrations are often elevated in cases of CFS when compared to healthy controls. This study attempted to replicate this finding, and investigate whether post-exertional symptoms were associated with altered cytokine protein concentrations and their RNA in CFS patients. Twenty-four patients fulfilling Centers for Disease Control criteria for CFS, but with no comorbid psychiatric disorders, were recruited from two CFS clinics in London, UK. Twenty-one healthy, sedentary controls were matched by gender, age, and other variables. Circulating proteins and RNA were measured for TGF-β, TNF, IL-8, IL-6 and IL-1β.

We measured six further cytokine protein concentrations (IL-2, IL-4, IL-5, IL-10, IL-12p70, and IFN-γ). Measures were taken at rest, and before and after both commuting and aerobic exercise. CFS cases had higher TGF-β protein levels compared to controls at rest (median (quartiles) = 43.9 (19.2, 61.8) versus 18.9 (16.1, 30.0) ng/ml) (p = 0.003), and consistently so over a nine-day period. However, this was a spurious finding due to variation between different assay batches.

There were no differences between groups in changes to TGF-β protein concentrations after either commuting or exercise. All other cytokine protein and RNA levels were similar between cases and controls. Post-exertional symptoms and perceived effort were not associated with any increased cytokines. We were unable to replicate previously found elevations in circulating cytokine concentrations, suggesting that elevated circulating cytokines are not important in the pathophysiology of CFS.

This article is protected by copyright. All rights reserved.

© 2017 British Society for Immunology

Source: Clark LV, Buckland M, Murphy G, Taylor N, Vleck V, Mein C, Wozniak E, Smuk M, White PD. Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study .Clin Exp Immunol. 2017 Aug 5. doi: 10.1111/cei.13023. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28779554

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Abstract:

Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible.

To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding.

On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

Source: Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017 Jul 31. pii: 201710519. doi: 10.1073/pnas.1710519114. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28760971

Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS.

Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls. Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production. One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients.

No single patient displayed any pathological patterns of cellular responses. Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed. In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators.

In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.

Source: Theorell J, Bileviciute-Ljungar I, Tesi B, Schlums H, Johnsgaard MS, Asadi-Azarbaijani B, Bolle Strand E, Bryceson YT. Unperturbed Cytotoxic Lymphocyte Phenotype and Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2017 Jun 26;8:723. doi: 10.3389/fimmu.2017.00723. eCollection 2017. http://journal.frontiersin.org/article/10.3389/fimmu.2017.00723/full (Full article)

Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis

Abstract:

Background: Cytokine studies in chronic fatigue syndrome (CFS) have yielded mixed findings.

Purpose: This investigation evaluated whether network analysis of cytokine production differs between patients with CFS and multiple sclerosis (MS) as compared to a reference group of healthy controls.

Methods: Three subgroups (N = 109) were included: 15 participants who met diagnostic criteria for CFS, 57 participants meeting criteria for MS, and 37 controls. Peripheral blood was obtained and production of a select cytokine profile was determined from stimulated and unstimulated mononuclear cells. Data were generated through the use of a multi-analyte bead suspension array. Pairwise associations were determined for each group, and these associations were used to create a graphical representation of the data. The graph was clustered using an eigenvector community algorithm and results visualized using edges to model the correlations by color and thickness to show direction and strength.

Results: The control and MS groups produced a three-neighborhood relationship regardless of cell condition. While producing a three-neighborhood relationship, the MS group differed significantly from the control group as it displayed stronger relationships among pro-inflammatory cytokines. In contrast, the CFS group displayed a three-neighborhood solution when unstimulated. However, when cells from the CFS group were stimulated, a two-neighborhood model was found that exhibited stronger inter-cytokine correlations. The model found in CFS was significantly different from that found in the control and MS groups.

Conclusion: CFS was characterized by a pattern of global immunologic activation using network analysis, fundamentally different from those found for either MS or control groups.

Source: Matthew Sorenson, Jacob Furst, Herbert Mathews & Leonard A. Jason. Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis. Fatigue: Biomedicine, Health & Behavior, Published online: 07 Jun 2017. http://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1335237?journalCode=rftg20

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

Abstract:

Background: Chronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group.

Methods: CFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings.

Results: A total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated.

Conclusion: Adolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise.

Trial registration Clinical Trials NCT01040429

Source: Chinh Bkrong Nguyen, Lene Alsøe, Jessica M. Lindvall, Dag Sulheim, Even Fagermoen, Anette Winger, Mari Kaarbø, Hilde Nilsen and Vegard Bruun Wyller. Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. Journal of Translational Medicine 2017 15:102. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1201-0 (Full article)

The role of IP-10 in Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a severely debilitating and complex illness of uncertain cause, characterised by prolonged, fatigue triggered by minimal activity. There is evidence that CFS is associated with chronic inflammation. Studies have shown that plasma levels of cytokines are chronically modified in patients with CFS.

This study examined physiological, subjective and cognitive factors associated with plasma cytokine concentrations in a cohort of 92 patients compared with age and sex matched healthy controls. A sub-group of patients and healthy controls (HCs) also underwent more detailed analyses of muscle function, cytokine production and cognitive function. Patients were diagnosed with CFS if they met the Oxford criteria for Chronic Fatigue Syndrome and recommended NICE guidelines. Patients completed a number of validated questionnaires including the Chalder Fatigue Questionnaire (CFQ) which is considered a valid and reliable measure of fatigue in patients with CFS.

Patients with CFS demonstrated a characteristic significant reduction in Maximal Voluntary Contraction Force compared with HCs. Data on plasma concentrations of 27 pro- and anti-inflammatory cytokines were analysed using multiple or logistic regression with age and sex which were significant covariates included in each model. CFS was strongly associated with a limited number of cytokines. Diagnosis of CFS was associated with increased plasma contents of MIP-1a, MIP-1b and RANTES (p<0.05) and marginally with Eotaxin (p=0.07) when modelled individually. MVC and self-reported fatigue both showed particularly strong associations with plasma IP-10 concentrations.

Muscle content of IP-10 mRNA was significantly elevated, suggesting that, at least in part, muscle was a source of this IP-10 but not the other cytokines. Pairwise associations between MVC and cytokines demonstrated that the reduced MVC seen in patients with CFS was strongly associated with plasma levels of IP-10, TNF-α and IL-5. Further analyses revealed strong correlations between plasma RANTES and eotaxin levels and poorer verbal recall and RTs of patients with CFS. The consistent association of IP-10 with the physiological features and of RANTES and eotaxin with the cognitive features of CFS provides compelling evidence for a role of these cytokine/chemokines in the physiological and cognitive pathology of CFS.

This work was funded by the Medical Research Council.

Source: Anne McArdle, Arief Gusnanto, Kate Earl, George Sakellariou, Clare Lawton, Daniel Owens, Graeme Close, Michael Beadsworth and Louise Dye. The role of IP-10 in Chronic Fatigue Syndrome. April 2017, The FASEB Journal, vol. 31 no. 1 Supplement lb789. http://www.fasebj.org/content/31/1_Supplement/lb789.short

 

Chronic fatigue syndrome and the immune system: Where are we now?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by multiple symptoms including fatigue, headaches and cognitive impairment, which have a significantly adverse effect on the normal functioning and well-being of the individual. These symptoms are often triggered or worsened following physical or mental exertion. ME/CFS has long been thought of as having a significant immunological component, but reports describing changes in immune function are often inconsistent between study groups.

Although the wide range of physical, neurocognitive and autonomic symptoms reported have seriously hampered attempts to understand pathophysiological pathways, investment in biomedical research in ME/CFS is finally increasing with a number of novel and promising investigations being published. The onset of ME/CFS may often be linked to (viral) infections which would be consistent with a variety of alterations in natural killer (NK) cell function as described by a number of different groups. Consistency in cytokine data has been lacking so far, although recently more sophisticated approaches have led to more robust data from large patient cohorts.

New hope has also been given to sufferers with the possibility that therapies that deplete B cells can result in clinical improvement. To understand the pathogenic mechanism in this complex condition, it is important to consider repeated analysis in different cohorts. In this review, we will discuss the potential of different components of the immune system to be involved in the pathogenesis of ME/CFS.

Copyright © 2017 Elsevier Masson SAS. All rights reserved

 

Source: Mensah FKF, Bansal AS, Ford B, Cambridge G. Chronic fatigue syndrome and the immune system: Where are we now? Neurophysiol Clin. 2017 Apr 11. pii: S0987-7053(17)30006-0. doi: 10.1016/j.neucli.2017.02.002. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28410877

 

Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and debilitating disorder marked by cognitive and sensory dysfunction and unexplained physical fatigue. Classically, cases present after a prodrome consistent with infection; however, some cases are atypical and have a different presentation and comorbidities that pose challenges for differential diagnosis. We analyzed cerebrospinal fluid (CSF) from 32 cases with classical ME/CFS and 27 cases with atypical ME/CFS using a 51-plex cytokine assay. Atypical subjects differed in cytokine profiles from classical subjects.

In logistic regression models incorporating immune molecules that were identified as potential predictor variables through feature selection, we found strong associations between the atypical ME/CFS phenotype and lower CSF levels of the inflammatory mediators, interleukin 17A and CXCL9. Network analysis revealed an absence of inverse inter-cytokine relationships in CSF from atypical patients, and more sparse positive intercorrelations, than classical subjects. Interleukin 1 receptor antagonist appeared to be a negative regulator in classical ME/CFS, with patterns suggestive of disturbances in interleukin 1 signaling and autoimmunity-type patterns of immune activation.

Immune signatures in the central nervous system of ME/CFS patients with atypical features may be distinct from those with more typical clinical presentations.

 

Source: Hornig M, Gottschalk CG, Eddy ML, Che X, Ukaigwe JE, Peterson DL, Lipkin WI. Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Transl Psychiatry. 2017 Apr 4;7(4):e1080. doi: 10.1038/tp.2017.44. https://www.ncbi.nlm.nih.gov/pubmed/28375204

 

Scientists Discover Biological Evidence of “Atypical” Chronic Fatigue Syndrome

Press Release: NEW YORK, April 4, 2017. Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health are the first to report immune signatures differentiating two subgroups of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): “classical” and “atypical.” This complex, debilitating disease is characterized by symptoms ranging from extreme fatigue after exertion to difficulty concentrating, headaches, and muscle pain.

The study appears in the Nature Publishing Group journal, Translational Psychiatry.

Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses.

Continue reading “Scientists Discover Biological Evidence of “Atypical” Chronic Fatigue Syndrome” →