Tag: cytokines

Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome

Abstract:

OBJECTIVES: Stressors and emotional distress responses impact chronic fatigue syndrome (CFS) symptoms, including fatigue. Having better stress management skills might mitigate fatigue by decreasing emotional distress. Because CFS patients comprise a heterogeneous population, we hypothesized that the role of stress management skills in decreasing fatigue may be most pronounced in the subgroup manifesting the greatest neuroimmune dysfunction.

METHODS: In total, 117 individuals with CFS provided blood and saliva samples, and self-report measures of emotional distress, perceived stress management skills (PSMS), and fatigue. Plasma interleukin-1-beta (IL-1β, IL-2, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α), and diurnal salivary cortisol were analyzed. We examined relations among PSMS, emotional distress, and fatigue in CFS patients who did and did not evidence neuroimmune abnormalities.

RESULTS: Having greater PSMS related to less fatigue (p=.019) and emotional distress (p<.001), greater diurnal cortisol slope (p=.023) and lower IL-2 levels (p=.043). PSMS and emotional distress related to fatigue levels most strongly in CFS patients in the top tercile of IL-6, and emotional distress mediated the relationship between PSMS and fatigue most strongly in patients with the greatest circulating levels of IL-6 and a greater inflammatory (IL-6):anti-inflammatory (IL-10) cytokine ratio.

DISCUSSION: CFS patients having greater PSMS show less emotional distress and fatigue, and the influence of stress management skills on distress and fatigue appear greatest among patients who have elevated IL-6 levels. These findings support the need for research examining the impact of stress management interventions in subgroups of CFS patients showing neuroimmune dysfunction.

Copyright © 2012 Elsevier Inc. All rights reserved.

 

Source: Lattie EG, Antoni MH, Fletcher MA, Penedo F, Czaja S, Lopez C, Perdomo D, Sala A, Nair S, Fu SH, Klimas N. Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Brain Behav Immun. 2012 Aug;26(6):849-58. doi: 10.1016/j.bbi.2012.02.008. Epub 2012 Mar 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572196/ (Full article)

 

Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome

Abstract:

BACKGROUND/PURPOSE: It has been shown that the abnormality in immune cells in chronic fatigue syndrome (CFS) patients is closely associated with the participation of TGF-β. In order to study the relationship between TGF-β1 and CFS, we investigated the mRNA levels of TGF-β1 in peripheral blood mononuclear cells (PBMCs) in patients with CFS.

METHODS: Fluorescent quantitative real time reverse-transcription polymerase chain reaction (FQ-RT-PCR) was performed to test TGF-β1 mRNA expression in PBMCs in 63 cases of CFS, 50 cases of disease controls, and 50 cases of healthy controls.

RESULTS: The mean value of TGF-β1 mRNA expression in CFS patients was ΔΔCt=1.17±0.58, which was significantly higher than the disease controls (ΔΔCt=0.07±1.08, df=111, p < 0.01) and the healthy controls (ΔΔCt=0.00±1.63, df=111, p < 0.01). No significant difference was detected between disease and healthy controls (p > 0.05).

CONCLUSION: The expression of TGF-β1 in PBMCs is significantly elevated in patients with CFS. It might be correlated to the pathogenesis of the disease.

Copyright © 2011. Published by Elsevier B.V.

 

Source: Zhang HY, Liu ZD, Hu CJ, Wang DX, Zhang YB, Li YZ. Up-regulation of TGF-β1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. J Formos Med Assoc. 2011 Nov;110(11):701-4. doi: 10.1016/j.jfma.2011.09.006. Epub 2011 Oct 22. http://www.jfma-online.com/article/S0929-6646(11)00070-2/fulltext (Full article)

 

Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin

Abstract:

BACKGROUND: There is evidence that inflammatory pathways and cell-mediated immunity (CMI) play an important role in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Activation of inflammatory and CMI pathways, including increased levels of cytokines, is known to induce fatigue and somatic symptoms. Given the broad spectrum inflammatory state in ME/CFS, the aim of this study was to examine whether inflammatory and CMI biomarkers are increased in individuals with ME/CFS.

METHODS: In this study we therefore measured plasma interleukin-(IL)1, tumor necrosis factor (TNF)α, and PMN-elastase, and serum neopterin and lysozyme in 107 patients with ME/CFS, 37 patients with chronic fatigue (CF), and 20 normal controls. The severity of ME/CFS was measured with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale.

RESULTS: Serum IL-1, TNFα, neopterin and lysozyme are significantly higher in patients with ME/CFS than in controls and CF patients. Plasma PMN-elastase is significantly higher in patients with ME/CFS than in controls and CF patients and higher in the latter than in controls. Increased IL-1 and TNFα are significantly correlated with fatigue, sadness, autonomic symptoms, and a flu-like malaise; neopterin is correlated with fatigue, autonomic symptoms, and a flu-like malaise; and increased PMN-elastase is correlated with concentration difficulties, failing memory and a subjective experience of infection.

CONCLUSIONS: The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNFα.

Copyright © 2011 Elsevier B.V. All rights reserved.

 

Source: Maes M, Twisk FN, Kubera M, Ringel K. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012 Feb;136(3):933-9. doi: 10.1016/j.jad.2011.09.004. Epub 2011 Oct 4. https://www.ncbi.nlm.nih.gov/pubmed/21975140

 

Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

BACKGROUND: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is characterised by severe prolonged fatigue, and decreases in cognition and other physiological functions, resulting in severe loss of quality of life, difficult clinical management and high costs to the health care system. To date there is no proven pathomechanism to satisfactorily explain this disorder. Studies have identified abnormalities in immune function but these data are inconsistent. We investigated the profile of markers of immune function (including novel markers) in CFS/ME patients.

METHODS: We included 95 CFS/ME patients and 50 healthy controls. All participants were assessed on natural killer (NK) and CD8(+) T cell cytotoxic activities, Th1 and Th2 cytokine profile of CD4(+) T cells, expression of vasoactive intestinal peptide receptor 2 (VPACR2), levels of NK phenotypes (CD56(bright) and CD56(dim)) and regulatory T cells expressing FoxP3 transcription factor.

RESULTS: Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10, IFN-γ, TNF-α, CD4(+)CD25(+) T cells, FoxP3 and VPACR2 expression. Cytotoxic activity of NK and CD8(+) T cells and NK phenotypes, in particular the CD56(bright) NK cells were significantly decreased in CFS/ME patients. Additionally granzyme A and granzyme K expression were reduced while expression levels of perforin were significantly increased in the CFS/ME population relative to the control population. These data suggest significant dysregulation of the immune system in CFS/ME patients.

CONCLUSIONS: Our study found immunological abnormalities which may serve as biomarkers in CFS/ME patients with potential for an application as a diagnostic tool.

 

Source: Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM. Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. J Transl Med. 2011 May 28;9:81. doi: 10.1186/1479-5876-9-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120691/ (Full article)

 

Immunologic and psychosocial status in chronic fatigue syndrome

Abstract:

OBJECTIVE: The aim of the study was to investigate the immunologic functions and psychosocial status in patients with chronic fatigue syndrome (CFS).

METHODS: Twenty-five patients with CFS diagnosed by the international CFS definition criteria and 20 age- and gender-matched healthy controls were recruited. Depression was assessed by Beck Depression Inventory (BDI) and health status was assessed by Nottingham Health Profile (NHP). Monoclonal antibodies (MAbs) were measured to identify the following NK cell subsets: CD3, CD4, CD8 and CD56 and cytokine measurements were performed for IL2r, IL6 and IL8 in both patients and control subjects.

RESULTS: The BDI and NHP scores of CFS group were found to be significantly higher than in the control group. The absolute numbers of CD56 cell were also significantly decreased in the patients with CFS compared with the healthy controls. There were no other significant differences of NK cell activity (CD3, CD4 and CD8) and there were significant differences in IL6 and IL2r levels between patients and controls. There were significant correlations between serum IL-6 level and sleep, social isolation and physical ability NHP subscores, and between CD56 NK cell activity and emotional reaction NHP sub score in CFS patients.

CONCLUSION: Significantly higher ratios of psychological and physical disturbances were found in patients with CFS. Decreased CD56 NK cell activity and increased IL2r levels seem to be important immunopathologic changes in CFS. IL-6 and CD 56 NK cell activity may play an important role in sleep, physical, social, and physicological manifestations of CFS (Tab. 3, Fig. 1, Ref. 36).

Full Text in free PDF http://bmj.fmed.uniba.sk/2011/11204-12.pdf

 

Source: Nas K, Cevik R, Batum S, Sarac AJ, Acar S, Kalkanli S. Immunologic and psychosocial status in chronic fatigue syndrome. Bratisl Lek Listy. 2011;112(4):208-12. https://www.ncbi.nlm.nih.gov/pubmed/21585130

 

Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature

Abstract:

BACKGROUND: The recent identification of xenotropic murine leukemia virus-related virus (XMRV) in the blood of patients with chronic fatigue syndrome (CFS) establishes that a retrovirus may play a role in the pathology in this disease. Knowledge of the immune response might lead to a better understanding of the role XMRV plays in this syndrome. Our objective was to investigate the cytokine and chemokine response in XMRV-associated CFS.

MATERIALS AND METHODS: Using Luminex multi-analyte profiling technology, we measured cytokine and chemokine values in the plasma of XMRV-infected CFS patients and compared these data to those of healthy controls. Analysis was performed using the Gene Expression Pattern Analysis Suite and the Random Forest tree classification algorithm.

RESULTS: This study identifies a signature of 10 cytokines and chemokines which correctly identifies XMRV/CFS patients with 93% specificity and 96% sensitivity.

CONCLUSION: These data show, for the first time, an immunological pattern associated with XMRV/CFS.

 

Source: Lombardi VC, Hagen KS, Hunter KW, Diamond JW, Smith-Gagen J, Yang W, Mikovits JA. Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature. In Vivo. 2011 May-Jun;25(3):307-14. https://www.ncbi.nlm.nih.gov/pubmed/21576403

 

Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study

Abstract:

Fatigue is a common complaint among adolescents. We investigated the course of fatigue in females during the transition from adolescence to young adulthood and examined psychological, immunological, and life style risk factors for development of fatigue and chronic fatigue syndrome (CFS)-related symptoms.

Six hundred and thirty-three healthy females (age 14.63±1.37 years) filled out questionnaires measuring fatigue severity, depressive symptoms, anxiety, chronic fatigue syndrome (CFS)-related symptoms, sleep features, and life style characteristics at baseline and 4½ years thereafter.

Of 64 participants LPS- and CD2CD28-induced cytokine data at baseline were available. The best predictor of fatigue in young adulthood was previous fatigue severity. In participants who were non-fatigued during adolescence and who experienced a notable increase in fatigue, fatigue development was preceded by emotional problems and CFS-related complaints during adolescence. Increases as well as decreases in fatigue severity were accompanied by respectively increase and decrease in depressive symptoms and anxiety, suggesting that these symptoms cluster and co-vary over time.

Higher interferon (IFN)-γ, higher IFN-γ/interleukin (IL)-4 ratio, lower tumor necrosis factor-α and lower IL-10 at baseline were related to fatigue severity at follow up. The rise in total number of CFS-related symptoms at follow up was predicted by anxiety and decreased physical activity during adolescence. Sleep and substance use were associated with fatigue severity and anxiety and depression.

In conclusion, vulnerability to develop fatigue and associated symptoms in young adulthood can to a certain extent be identified already years before the manifestation of complaints.

Copyright © 2011 Elsevier Inc. All rights reserved.

 

Source: ter Wolbeek M, van Doornen LJ, Kavelaars A, Tersteeg-Kamperman MD, Heijnen CJ. Fatigue, depressive symptoms, and anxiety from adolescence up to young adulthood: a longitudinal study. Brain Behav Immun. 2011 Aug;25(6):1249-55. doi: 10.1016/j.bbi.2011.04.015. Epub 2011 Apr 28. https://www.ncbi.nlm.nih.gov/pubmed/21549830

 

A Chinese herbal decoction, Danggui Buxue Tang, improves chronic fatigue syndrome induced by food restriction and forced swimming in rats

Abstract:

Danggui Buxue Tang (DBT), a Chinese medicinal decoction that contains Radix Angelicae sinensis (Danggui) and Radix Astragali (Huangqi) at a ratio of 1:5, is used commonly for treating women’s ailments. The present study explored the effects of this preparation on chronic fatigue syndrome (CFS).

Rats were subjected to a combination of food restriction and forced swimming to induce CFS, and rats were gavaged once daily with either 12 or 24 g/kg DBT for 28 days. Body weights, T-cell subset counts, (3) H-TdR incorporation measurements and mRNA levels of IL-1β, TNF-α, NF-кB, p38MAPK and JNK were determined on days 14 and 28. The swimming endurance capacity was measured on day 28.

Rats that received DBT exhibited increased body weight and endurance capacity, corrected T cell subsets counts, increased (3) H-TdR incorporation and decreased mRNA levels of IL-1β, TNF-α, NF-кB, p38MAPK and JNK compared with rats that did not receive DBT. The results indicate that DBT can ameliorate CFS through immune modulation and may act to normalize cytokines and their related signaling pathways.

Copyright © 2011 John Wiley & Sons, Ltd.

 

Source: Liu Y, Zhang HG, Li XH. A Chinese herbal decoction, Danggui Buxue Tang, improves chronic fatigue syndrome induced by food restriction and forced swimming in rats. Phytother Res. 2011 Dec;25(12):1825-32. doi: 10.1002/ptr.3499. Epub 2011 Apr 15. https://www.ncbi.nlm.nih.gov/pubmed/21495102

 

A panel of biomarkers accurately identifies CFS/ME patients and contributes to the understanding of the pathophysiology of the disorder

Abstract: 

Background: CFS/ME is a debilitating illness for which no specific biomarkers have been identified, although several immune abnormalities including neuroinflammation have been described. The goal of this study was to assemble a panel of immune and inflammatory markers, with the ability to accurately identify CFS/ME cases.

Objectives: From observations made in clinical practice, four markers were selected (immune and inflammatory). These markers were initially investigated to establish differences between CFS/ME cases and controls. We then evaluated their potential usefulness as a diagnostic biomarker by establishing their specificity and sensitivity.

Methods: Venous blood was collected from 70 male and 70 female CFS/ME patients (mean age 43 and 44 years, respectively – Fukuda case definition was used) as well as 70 male and 70 female healthy controls (mean age 43.5 and 44.5 years, respectively).

Serum Interleukin 8 (IL-8), soluble CD14 (sCD14, a surrogate marker for bacterial LPS), and prostaglandin E2 (PGE2) were measured for all subjects as were absolute CD3- / CD57+ lymphocytes counts (CD57+ lymph), according to accepted clinical laboratory techniques.

We then established median values for all analysed parameters; independent sample t-test, Mann-Whitney test and ROC curve analysis were used to investigate difference linked to gender and age.

Results: ROC Statistics (area under the ROC curve) revealed a significant difference between CFS/ME cases and controls (p <0.001) for the four parameters separately, both in the male and female cohorts. Sensitivity was 74.3 – 80 % (females) and 52.1 – 85.9 % (males). Specificity was 57.1 – 98.1 (females) and 65.7 – 88.6 (males).

Logistic regression analysis for the combination of parameters in our panel (IL-8, sCD14, PGE2 and CD57+ lymph) correctly predicted in 89.36 % of male CFS/ME cases and in 97.14 % of female CFS/ME cases.

Conclusions: This panel differentiates CFS/ME cases from controls with high sensitivity and specificity and therefore represents a potential tool in selecting CFS/ME subjects for clinical studies. Each of these four biological markers relate strongly to the disorder.

PGE2 activates dendritic cells and suppresses their ability to attract T cells. It also suppresses the function of macrophages and neutrophils as well as Th1, CTL-, NK-cell mediated type 1 immunity (e.g. CD3- / CD57+ lymphocytes). PGE2 additionally promotes Th2, Th17 and Tregs and also modulates chemokine production (e.g. IL-8).

When taken together, these data suggest that lipopolysaccharide (LPS), likely from gut bacteria, plays an important role in the pathophysiology of CFS/ME.

This screening panel represents an initial step toward identifying biomarkers to broadly diagnose subjects with CFS/ME.

Subsequent markers will be required to subcategorize CFS/ME subjects in order to tailor therapeutic solutions.

 

Source: Kenny L. De Meirleir1,2, Tatjana Mijatovic3, Eugene Bosmans3, Nossa Van den Vonder2, Vincent Lombardi1. A panel of biomarkers accurately identifies CFS/ME patients and contributes to the understanding of the pathophysiology of the disorder. Abstract from IACFS/ME Conference 2016 Program.

1. Nevada Center for Biomedical Research at University
of Nevada, Reno, USA
2. Himmunitas vzw, Brussels, Belgium
3. RED Laboratories NV, Zellik, Belgium

 

A formal analysis of cytokine networks in chronic fatigue syndrome

Abstract:

Chronic Fatigue Syndrome (CFS) is a complex illness affecting 4 million Americans for which no characteristic lesion has been identified. Instead of searching for a deficiency in any single marker, we propose that CFS is associated with a profound imbalance in the regulation of immune function forcing a departure from standard pre-programmed responses.

To identify these imbalances we apply network analysis to the co-expression of 16 cytokines in CFS subjects and healthy controls. Concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12, 13, 15, 17 and 23, IFN-γ, lymphotoxin-α (LT-α) and TNF-α were measured in the plasma of 40 female CFS and 59 case-matched controls. Cytokine co-expression networks were constructed from the pair-wise mutual information (MI) patterns found within each subject group.

These networks differed in topology significantly more than expected by chance with the CFS network being more hub-like in design. Analysis of local modularity isolated statistically distinct cytokine communities recognizable as pre-programmed immune functional components.

These showed highly attenuated Th1 and Th17 immune responses in CFS. High Th2 marker expression but weak interaction patterns pointed to an established Th2 inflammatory milieu. Similarly, altered associations in CFS provided indirect evidence of diminished NK cell responsiveness to IL-12 and LT-α stimulus.

These observations are consistent with several processes active in latent viral infection and would not have been uncovered by assessing marker expression alone. Furthermore this analysis identifies key sub-networks such as IL-2:IFN-γ:TNF-α that might be targeted in restoring normal immune function.

Copyright © 2010 Elsevier Inc. All rights reserved.

Comment in: Letter to the editor re: “A formal analysis of cytokine networks in chronic fatigue syndrome” by Broderick et al. [Brain Behav Immun. 2010]

 

Source: Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct;24(7):1209-17. doi: 10.1016/j.bbi.2010.04.012. Epub 2010 May 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/ (Full article)