Tag: immune activation

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

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

Abstract:

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels.

This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity.

Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS.

Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms.

HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

 

Source: Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2016 Oct 20. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27766535

 

Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression

Abstract:

BACKGROUND: Depression is characterized by activation of cell-mediated immunity (CMI), including increased neopterin levels, and increased pro-inflammatory cytokines (PICs), such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα). These PICs may induce depressive, melancholic and chronic fatigue (CF) symptoms.

METHODS: We examined serum neopterin and plasma PIC levels in depressive subgroups in relation to the depressive subtypes and the melancholic and CF symptoms of depression. Participants were 85 patients with depression and in 26 normal controls. Severity of depression was assessed with the Hamilton Depression Rating Scale (HDRS) and severity of CF with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Serum neopterin was significantly higher in depressed patients and in particular in those with melancholia. There were positive correlations between serum neopterin, the plasma PICs and the number of previous depressive episodes. Neopterin and TNFα were associated with melancholia, while both PICs were associated with CF. Melancholia-group membership was predicted by the HDRS and neopterin, and CF group membership by age, the FF score and serum TNFα.

DISCUSSION: Depression and melancholia are accompanied by CMI activation, suggesting that neopterin plays a role in their pathophysiology, e.g. through activation of oxidative and nitrosative stress and apoptosis pathways. The intertwined CMI and inflammatory responses are potentially associated with the onset of depression and with the melancholic and CF symptoms of depression. Exposure to previous depressive episodes may magnify the size of CMI and PIC responses, possibly increasing the likelihood of new depressive episodes. CMI activation and inflammation may contribute to the staging or recurrence of depression.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: Maes M, Mihaylova I, Kubera M, Ringel K. Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 10;36(1):169-75. doi: 10.1016/j.pnpbp.2011.09.006. Epub 2011 Sep 16. https://www.ncbi.nlm.nih.gov/pubmed/21945535

 

Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood

Abstract:

BACKGROUND: Genomic profiling of peripheral blood reveals altered immunity in chronic fatigue syndrome (CFS) however interpretation remains challenging without immune demographic context. The object of this work is to identify modulation of specific immune functional components and restructuring of co-expression networks characteristic of CFS using the quantitative genomics of peripheral blood.

METHODS: Gene sets were constructed a priori for CD4+ T cells, CD8+ T cells, CD19+ B cells, CD14+ monocytes and CD16+ neutrophils from published data. A group of 111 women were classified using empiric case definition (U.S. Centers for Disease Control and Prevention) and unsupervised latent cluster analysis (LCA). Microarray profiles of peripheral blood were analyzed for expression of leukocyte-specific gene sets and characteristic changes in co-expression identified from topological evaluation of linear correlation networks.

RESULTS: Median expression for a set of 6 genes preferentially up-regulated in CD19+ B cells was significantly lower in CFS (p = 0.01) due mainly to PTPRK and TSPAN3 expression. Although no other gene set was differentially expressed at p < 0.05, patterns of co-expression in each group differed markedly. Significant co-expression of CD14+ monocyte with CD16+ neutrophil (p = 0.01) and CD19+ B cell sets (p = 0.00) characterized CFS and fatigue phenotype groups. Also in CFS was a significant negative correlation between CD8+ and both CD19+ up-regulated (p = 0.02) and NK gene sets (p = 0.08). These patterns were absent in controls.

CONCLUSION: Dissection of blood microarray profiles points to B cell dysfunction with coordinated immune activation supporting persistent inflammation and antibody-mediated NK cell modulation of T cell activity. This has clinical implications as the CD19+ genes identified could provide robust and biologically meaningful basis for the early detection and unambiguous phenotyping of CFS.

 

Source: Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of inflammatory immune signaling in chronic fatigue syndrome: A pilot study of gene expression in peripheral blood. Behav Brain Funct. 2008 Sep 26;4:44. doi: 10.1186/1744-9081-4-44. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569951/ (Full article)

 

Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis

Abstract:

The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance had any correlation with these disease states.

The isoprenoid metabolites–digoxin, dolichol, and ubiquinone–RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free-radical metabolism, glycoconjugate metabolism, and RBC membrane composition was also assessed. Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG CoA reductase activity and serum digoxin levels were increased in myalgic encephalomyelitis (ME). There were increased levels of tryptophan catabolites–nicotine, strychnine, quinolinic acid, and serotonin–and decreased levels of tyrosine catabolites–dopamine, noradrenaline, and morphine in ME. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual GAG fractions, and lysosomal enzymes in ME. Reduced levels of ubiquinone, reduced glutathione, and free-radical scavenging enzymes, as well as increased lipid peroxidation products and nitric oxide, were noticed in ME.

The biochemical patterns in ME correlated with those obtained in right hemispheric chemical dominance. The role of hypothalamic digoxin and neurotransmitter induced immune activation, altered glycoconjugate metabolism, and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive dysfunction, and mitochondrial dysfunction related myalgia in the pathogenesis of ME is stressed. ME occurs in individuals with right hemispheric chemical dominance.

 

Source: Kurup RK, Kurup PA. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. Int J Neurosci. 2003 May;113(5):683-701. https://ammes.orgwp-admin/post-new.php

 

RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a disorder characterized by debilitating fatigue associated with immunological abnormalities. The etiology remains unclear. A low-molecular-mass (37 kDa) isoform of RNase L has been described in peripheral blood mononuclear cell (PBMC) extracts, and the ratio of two isoforms of RNase L (37 kDa/83 kDa) has been proposed as a potential biochemical marker of CFS. In a prospective case-control study, we tested whether the RNase L 37-kDa/83-kDa ratio could discriminate a SFC population.

We compared the ratio of RNase L isoforms in PBMCs from 11 patients with CFS (6 women and 5 men; mean age +/- standard deviation, 43.2 +/- 13.8 years) and PBMCs from 14 healthy well-matched volunteers (10 women and 4 men; age, 39.1 +/- 11.6 years). A ratio of RNase L of 0.4 used as a threshold allowed diagnosis of CFS with high sensitivity (91%; 95% confidence interval [CI], 57 to 99%) and specificity (71%; 95% CI, 41 to 90%). The positive and negative prognostic values were 71% (95% CI, 41 to 90%) and 91% (95% CI, 57 to 99%), respectively.

In the absence of acute infection or chronic inflammation, a high RNase L ratio could distinguish CFS patients from healthy volunteers. Additional large studies and follow-up studies are required to confirm the stability of this high ratio of RNase L isoforms in a CFS group.

Comment in: 37-Kilodalton/83-kilodalton RNase L isoform ratio in peripheral blood mononuclear cells: analytical performance and relevance for chronic fatigue syndrome. [Clin Diagn Lab Immunol. 2005]

 

Source: Tiev KP, Demettre E, Ercolano P, Bastide L, Lebleu B, Cabane J. RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome. Clin Diagn Lab Immunol. 2003 Mar;10(2):315-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC150526/ (Full article)

 

Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report

Abstract:

OBJECTIVE: The aim of this study was to examine the possible role of the immune system in the pathophysiology of chronic fatigue syndrome and fibromyalgia syndrome and in the differential diagnosis of depression by investigating changes in peripheral blood mononuclear cell levels of beta-endorphin, an endogenous opioid known to be involved in regulation of the immune system function.

DESIGN: Beta-endorphin concentrations were measured by radioimmunoassay in peripheral blood mononuclear cells from healthy controls (n = 8) and patients with chronic fatigue syndrome (n = 17), fibromyalgia syndrome (n = 5), or depression (n = 10).

RESULTS: Beta-endorphin concentrations were significantly lower in patients with chronic fatigue syndrome or fibromyalgia syndrome than in normal subjects and depressed patients (p <0.001 and p <0.01, respectively). They were significantly higher in depressed patients than in controls (p <0.01).

CONCLUSIONS: Evaluation of peripheral blood mononuclear cell beta-endorphin concentrations could represent a diagnostic tool for chronic fatigue syndrome and fibromyalgia and help with differential diagnosis of these syndromes versus depression. The results obtained are also consistent with the hypothesis that the immune system is activated in both chronic fatigue syndrome and fibromyalgia syndrome.

 

Source: Panerai AE, Vecchiet J, Panzeri P, Meroni P, Scarone S, Pizzigallo E, Giamberardino MA, Sacerdote P. Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report. Clin J Pain. 2002 Jul-Aug;18(4):270-3. http://www.ncbi.nlm.nih.gov/pubmed/12131069

 

Cytokines and chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) patients show evidence of immune activation, as demonstrated by increased numbers of activated T lymphocytes, including cytotoxic T cells, as well as elevated levels of circulating cytokines. Nevertheless, immune cell function of CFS patients is poor, with low natural killer cell cytotoxicity (NKCC), poor lymphocyte response to mitogens in culture, and frequent immunoglobulin deficiencies, most often IgG1 and IgG3.

Immune dysfunction in CFS, with predominance of so-called T-helper type 2 and proinflammatory cytokines, can be episodic and associated with either cause or effect of the physiological and psychological function derangement and/or activation of latent viruses or other pathogens. The interplay of these factors can account for the perpetuation of disease with remission/exacerbation cycles. A T-helper type 2 predominance has been seen among Gulf War syndrome patients and this feature may also be present in other related disorders, such as multiple chemical sensitivity. Therapeutic intervention aimed at induction of a more favorable cytokine expression pattern and immune status appears promising.

 

Source: Patarca R. Cytokines and chronic fatigue syndrome.  Ann N Y Acad Sci. 2001 Mar;933:185-200. http://www.ncbi.nlm.nih.gov/pubmed/12000020

 

A twin study of the etiology of prolonged fatigue and immune activation

Abstract:

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors.

Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwin-crosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation.

By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49-0.69 versus 0.42-0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = -0.07 to -0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation.

PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

 

Source: Hickie IB, Bansal AS, Kirk KM, Lloyd AR, Martin NG. A twin study of the etiology of prolonged fatigue and immune activation. Twin Res. 2001 Apr;4(2):94-102. http://www.ncbi.nlm.nih.gov/pubmed/11665341

 

Is depression associated with immune activation?

Abstract:

BACKGROUND: Some research immunologists have suggested that major depression amd chronic fatigue syndrome (CFS) are characterized by immune activation. To test this hypothesis, we compared immunological function in patients with major depression and in patients with CFS who developed major depression after the onset of CFS to that of sedentary healthy controls.

METHODS: Subjects completed the Centers for Epidemiological Study-Depression (CES-D) questionnaire and allowed venisection. We performed flow cytometric analysis on 13 groups of white blood cells and used a reverse transcriptase PCR method to assay m-RNA of eight cytokines.

RESULTS: CES-D scores were high in both patient groups and did not differ significantly. We found no evidence for immune activation in either patient group. Instead the data suggested immunological downregulation in depression.

LIMITATIONS: Not all the subjects in the two patient groups were off antidepressants.

CONCLUSIONS: The data indicate that immune activation is not necessary in depression–either alone or with CFS.

 

Source: Natelson BH, Denny T, Zhou XD, LaManca JJ, Ottenweller JE, Tiersky L, DeLuca J, Gause WC. Is depression associated with immune activation? J Affect Disord. 1999 May;53(2):179-84. http://www.ncbi.nlm.nih.gov/pubmed/10360413