Category: Immune System

Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia

Abstract:

The symptoms of chronic fatigue syndrome (CFS) are consistent with cytokine dysregulation. This has led to the hypothesis of immune dysregulation as the cause of this illness. To further test this hypothesis, we did repeated blood sampling for cytokines while patients and matched healthy controls slept in the sleep lab.

Because no one method for assaying cytokines is acknowledged to be better than another, we assayed for protein in serum, message in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs.

We found no evidence of proinflammatory cytokine upregulation. Instead, in line with some of our earlier studies, we did find some evidence to support a role for an increase in interleukin-10, an anti-inflammatory cytokine. Although the changes were small, they may contribute to the common complaint in CFS patients of disrupted sleep.

 

Source: Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, Broderick G, Yamamoto Y, Cherniack NS, Rapoport D, Natelson BH. Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clin Vaccine Immunol. 2010 Apr;17(4):582-7. doi: 10.1128/CVI.00379-09. Epub 2010 Feb 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849324/ (Full article)

 

Immune and hemorheological changes in chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients.

METHODS: Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56(dim)CD16(+) and CD56(bright)CD16(-)) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed.

RESULTS: CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56(bright)CD16(-) NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56(dim)CD16(+) NK cells were similar between the two groups.

CONCLUSION: These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients.

 

Source: Brenu EW, Staines DR, Baskurt OK, Ashton KJ, Ramos SB, Christy RM, Marshall-Gradisnik SM. Immune and hemorheological changes in chronic fatigue syndrome. J Transl Med. 2010 Jan 11;8:1. doi: 10.1186/1479-5876-8-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829521/ (Full article)

 

Serum Cytokine Levels in Postinfective Fatigue Syndrome

TO THE EDITOR—Previous studies have sought evidence for a role of abnormal cytokine activity in patients with chronic fatigue syndrome and have had conflicting results [1–3]. These ambiguous results may reflect heterogeneity in groups of patients considered to have chronic fatigue syndrome and variations in assay systems.

We established postinfective fatigue syndrome as the only well-characterized model of the onset and evolution of chronic fatigue syndrome in a prospective cohort of individuals followed up from the onset of acute infection (Dubbo Infection Outcomes Study [DIOS]) [4]. Longitudinally collected clinical data and blood samples from participants in DIOS provide a unique opportunity for nested case-control studies examining the pathophysiology of chronic fatigue syndrome.

We previously reported the lack of association between cytokine production from cultured peripheral blood mononuclear cells and the postinfective fatigue syndrome- related illness in participants in DIOS [5]. We now report a masked analysis of a longitudinal case-control series from DIOS that extended the number of cytokines tested and focused on serum levels.

Twenty patients with acute infection were selected, including 5 patients with serologically confirmed acute Epstein-Barr virus (EBV) infection followed by postinfective fatigue syndrome lasting ⩾6 months, 5 patients with acute infection (not primary EBV but seropositive for EBV) followed by postinfective fatigue syndrome, and 10 matched control subjects with acute EBV infection followed by prompt recovery. Serum samples and clinical data from baseline and from 3–6 months and 9–12 months after onset of infection were analyzed. Serum samples were coded according to case-control status before transfer to the cytokine analysis laboratory.

Thirty-five analytes were measured in serum samples with use of amultiplex immunoassay, including the chemokines leptin, epithelial cell-derived neutrophil-activating peptide 78, eotaxin, growth-regulated oncogene α, interleukin (IL)-8, interferon (IFN)-inducible protein 10, monocyte chemotactic protein 3, monokine induced by gamma IFN, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, and regulated upon activation normal T cell expressed and secreted; the cytokines IFN-γ, IL-1α, IL-1β, IL-1Ra, IL-4, IL-5, IL-6, IL-7, IL-2, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17F, tumor necrosis factor α, tumor necrosis factor β; and the growth factors nerve growth factor, plate-let-derived growth factor β, transforming growth factor β, vascular endothelial growth factor, fibroblast growth factor β, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

All of the study groups were predominantly female and were matched for both sex distribution (by χ2 test, P = .670) and age (by analysis of variance, P = .597). Cytokine data were analyzed by 2-way analysis of variance examining the effects of time and type of case (EBV postinfective fatigue syndrome, non-EBV postinfective fatigue syndrome, or control) and by Spearman’s correlation between symptom scores and cytokine levels. Because of the number of parameters tested, a conservative threshold for statistical significance (P < .005) was used. Results are shown in Table 1

You can read the rest of this article here: http://cid.oxfordjournals.org/content/50/2/278.full

 

Source: Cameron B, Hirschberg DL, Rosenberg-Hassan Y, Ablashi D, Lloyd AR. Serum cytokine levels in postinfective fatigue syndrome. Clin Infect Dis. 2010 Jan 15;50(2):278-9. doi: 10.1086/649546. http://cid.oxfordjournals.org/content/50/2/278.full (Full article)

 

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?

Abstract:

Cancer and chronic fatigue syndrome (CFS) are both characterised by fatigue and severe disability. Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided.

Special emphasis is given to the relationship between immune dysfunctions and fatigue. Abnormalities in ribonuclease (RNase) L and hyperactivation of nuclear factor kappa beta (NF-kappaB) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and reoccurrence of cancer, and has been documented repeatedly in CFS patients.

The dysregulation of the RNase L pathway, hyperactive NF-kappaB leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases and in the physiopathology of the common symptom fatigue. However, in cancer the relation between the immune dysfunctions and fatigue has been poorly studied. Immunological abnormalities to such as a dysregulated RNase L pathway, hyperactive NF-kappaB, increased oxidative stress and reduced NK cytotoxicity, among others, are present in both diseases.

These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue. Further studies to confirm the hypotheses given here are warranted.

 

Source: Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov;29(11):4717-26. http://ar.iiarjournals.org/content/29/11/4717.long (Full article)

 

Plasma cytokines in women with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) studies from our laboratory and others have described cytokine abnormalities. Other studies reported no difference between CFS and controls. However, methodologies varied widely and few studies measured more than 4 or 5 cytokines. Multiplex technology permits the determination of cytokines for a large panel of cytokines simultaneously with high sensitivity and with only 30 ul of plasma per sample. No widely accepted laboratory test or marker is available for the diagnosis or prognosis of CFS. This study screened plasma factors to identify circulating biomarkers associated with CFS.

METHODS: Cytokines were measured in plasma from female CFS cases and female healthy controls. Multiplex technology provided profiles of 16 plasma factors including the pro -inflammatory cytokines: tumor necrosis factor alpha (TNFalpha), lymphotoxin alpha (LTalpha), interleukin (IL) – IL-Ialpha, IL-1beta, IL-6; TH1 cytokines: interferon gamma (IFNgamma), IL-12p70, IL-2, IL-15; TH2: IL-4, IL-5; TH17 cytokines, IL-17 and IL-23; anti-inflammatory cytokines IL-10, IL-13; the inflammatory mediator and neutrophil attracting chemokine IL-8 (CXCL8). Analysis by receiver operating characteristic (ROC) curve assessed the biomarker potential of each cytokine.

RESULTS: The following cytokines were elevated in CFS compared to controls: LTalpha, IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IL-12. The following cytokines were decreased in CFS: IL-8, IL-13 and IL-15. The following cytokines were not different: TNFalpha, IFNgamma, IL-2, IL-10, IL-23 and IL-17. Applying (ROC) curve analyses, areas under the curves (AUC) for IL-5 (0. 84), LTalpha (0.77), IL-4 (0.77), IL-12 (0.76) indicated good biomarker potential. The AUC of IL-6 (0.73), IL-15 (0.73), IL-8 (0.69), IL-13 (0.68) IL-1alpha (0.62), IL-1beta (0.62) showed fair potential as biomarkers.

CONCLUSION: Cytokine abnormalities are common in CFS. In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to more indicative of immune activation and inflammation, rather than specific for CFS. As such, they are targets for herapeutic strategies. Newer techniques allow evaluation of large panels of cytokines in a cost effective fashion.

 

Source: Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96. doi: 10.1186/1479-5876-7-96. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779802/ (Full article)

 

Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome

Abstract:

Examination of anticardiolipin antibodies (ACAs) in the sera of patients clinically diagnosed with chronic fatigue syndrome (CFS) using an enzyme-linked immunoassay procedure demonstrated the presence of immunoglobulin M isotypes in 95% of CFS serum samples tested. The presence of immunoglobulin G and immunoglobulin A isotypes were also detected in a subset of the samples. Future studies will focus on elucidating whether alterations to mitochondrial inner membranes and/or metabolic functions play a possible role in the expression of ACAs.

 

Source: Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009;23(4):210-2. doi: 10.1002/jcla.20325. https://www.ncbi.nlm.nih.gov/pubmed/19623655

 

Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker

Abstract:

BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes.

METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays.

FINDINGS: There were no significant differences in gene expression for any transcript.

CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.

 

Source: Byrnes A, Jacks A, Dahlman-Wright K, Evengard B, Wright FA, Pedersen NL, Sullivan PF. Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker. PLoS One. 2009 Jun 5;4(6):e5805. doi: 10.1371/journal.pone.0005805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688030/ (Full article)

 

Curcumin, a polyphenolic antioxidant, attenuates chronic fatigue syndrome in murine water immersion stress model

Abstract:

Chronic fatigue syndrome, infection and oxidative stress are interrelated in epidemiological case studies. However, data demonstrating scientific validation of epidemiological claims regarding effectiveness of nutritional supplements for chronic fatigue syndrome are lacking. This study is designed to evaluate the effect of natural polyphenol, curcumin, in a mouse model of immunologically induced fatigue, where purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigens were used as immunogens.

The assessment of chronic fatigue syndrome was based on chronic water-immersion stress test for 10 min daily for 19 days and the immobility time was taken as the marker of fatigue. Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time and hyperalgesia on day 19, as well as marked increase in serum tumor necrosis factor-alpha (TNF-alpha) levels. Concurrent treatment with curcumin resulted in significantly decreased immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as TNF-alpha levels.

These findings strongly suggest that during immunological activation, there is significant increase in oxidative stress and curcumin can be a valuable option in the treatment of chronic fatigue syndrome.

 

Source: Gupta A, Vij G, Sharma S, Tirkey N, Rishi P, Chopra K. Curcumin, a polyphenolic antioxidant, attenuates chronic fatigue syndrome in murine water immersion stress model. Immunobiology. 2009;214(1):33-9. doi: 10.1016/j.imbio.2008.04.003. Epub 2008 Jun 17. https://www.ncbi.nlm.nih.gov/pubmed/19159825

 

Chronic fatigue syndrome and complement activation

Abstract:

This report describes a case of chronic fatigue syndrome (CFS) that followed a well-documented episode of acute Epstein-Barr virus (EBV) mononucleosis. All aetiological tests for chronic fatigue were found to be negative or normal, as were immunological tests. After 2 years of chronic fatigue following the acute illness, measurements of complement split products were performed to test for complement activation. These were positive and remained positive for 14 months, after which the patient then recovered from CFS.

 

Source: Geller RD, Giclas PC. Chronic fatigue syndrome and complement activation. BMJ Case Rep. 2009;2009. pii: bcr08.2008.0819. doi: 10.1136/bcr.08.2008.0819. Epub 2009 Mar 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028106/ (Full article)

 

Association of peripheral inflammatory markers with chronic fatigue in a population-based sample

Abstract:

Alterations in the innate immune response may contribute to the pathogenesis of chronic fatigue syndrome (CFS). However, studies have been limited by small sample sizes, use of patients from tertiary care settings, inappropriate selection of controls, and failure to control for confounding demographic, medical and behavioral factors independently associated with immune activity. It is also not known whether specific symptoms account for observed associations between CFS and the innate immune response.

To address these limitations, the current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with CFS (n=102) and in subjects with unwellness symptoms that did not meet diagnostic criteria for CFS (defined as “insufficient fatigue” [ISF]) (n=240) when compared to subjects who were well (n=115). Log transformed WBC was increased in ISF and was increased at a trend level in CFS. The combined inflammation factor was increased in both CFS and ISF. Subjects with CFS and ISF did not differ on any of the inflammation measures.

In the entire subject population, the physical component summary score (PCS), but not the mental component summary score (MCS), from the Medical Outcomes Study Short Form-36 (SF-36) was negatively associated with each of the inflammation measures. Depressive symptoms were also associated with increased log hs-CRP. After adjustment for age, sex, race, location of residence, BMI, depressive status and immune-modulating medications, subjects classified as ISF continued to demonstrate increased log hs-CRP, WBC and elevations on the inflammation factor when compared to well controls; however, associations between CFS and log hs-CRP and the inflammation factor were no longer statistically significant. After adjustment, PCS score also remained independently associated with each of the inflammation measures.

These findings support a role for innate immune activation in unexplained fatigue and unwellness, but do not suggest that immune activation is specific to CFS.

Comment in: Chronic fatigue syndrome and the immune system: “findings in search of meanings”. [Brain Behav Immun. 2009]

 

Source: Raison CL, Lin JM, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun. 2009 Mar;23(3):327-37. doi: 10.1016/j.bbi.2008.11.005. Epub 2008 Dec 11. https://www.ncbi.nlm.nih.gov/pubmed/19111923