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Published in: Journal of Translational Medicine 1/2009

Open Access 01-12-2009 | Research

Plasma cytokines in women with chronic fatigue syndrome

Authors: Mary Ann Fletcher, Xiao Rong Zeng, Zachary Barnes, Silvina Levis, Nancy G Klimas

Published in: Journal of Translational Medicine | Issue 1/2009

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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 α (TNFα), lymphotoxin α (LTα), interleukin (IL) - IL-Iα, IL-1β, IL-6; TH1 cytokines: interferon γ (IFNγ), 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: LTα, IL-1α, IL-1β, 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: TNFα, IFNγ, IL-2, IL-10, IL-23 and IL-17. Applying (ROC) curve analyses, areas under the curves (AUC) for IL-5 (0. 84), LTα (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-1α (0.62), IL-1β (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.
Appendix
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Literature
1.
go back to reference Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003, 163: 1530-1536. 10.1001/archinte.163.13.1530.CrossRefPubMed Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC: Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003, 163: 1530-1536. 10.1001/archinte.163.13.1530.CrossRefPubMed
2.
go back to reference Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S: A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999, 159: 2129-2137. 10.1001/archinte.159.18.2129.CrossRefPubMed Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S: A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999, 159: 2129-2137. 10.1001/archinte.159.18.2129.CrossRefPubMed
3.
go back to reference Bombardier C, Buchwald D: Outcome and prognosis of patients with chronic fatigue vs. chronic fatigue syndrome. Arch Intern Med. 1995, 155: 2105-2110. 10.1001/archinte.155.19.2105.CrossRefPubMed Bombardier C, Buchwald D: Outcome and prognosis of patients with chronic fatigue vs. chronic fatigue syndrome. Arch Intern Med. 1995, 155: 2105-2110. 10.1001/archinte.155.19.2105.CrossRefPubMed
4.
go back to reference Bombardier C, Buchwald D: Chronic Fatigue, Chronic Fatigue Syndrome, and Fibromyalgia. Disability and Health-Care Use. Med Care. 1996, 34: 924-930. 10.1097/00005650-199609000-00005.CrossRefPubMed Bombardier C, Buchwald D: Chronic Fatigue, Chronic Fatigue Syndrome, and Fibromyalgia. Disability and Health-Care Use. Med Care. 1996, 34: 924-930. 10.1097/00005650-199609000-00005.CrossRefPubMed
5.
go back to reference Klimas NG, Morgan R, Salvado F, Fletcher MA: Immunologic abnormalities of chronic fatigue syndrome. J Clin Microbiol. 1990, 28: 1403-1410.PubMedCentralPubMed Klimas NG, Morgan R, Salvado F, Fletcher MA: Immunologic abnormalities of chronic fatigue syndrome. J Clin Microbiol. 1990, 28: 1403-1410.PubMedCentralPubMed
6.
go back to reference Evengård B, Klimas N: Chronic fatigue syndrome: Probable pathogenesis and possible treatments. Drugs. 2002, 62: 2433-2446. 10.2165/00003495-200262170-00003.CrossRefPubMed Evengård B, Klimas N: Chronic fatigue syndrome: Probable pathogenesis and possible treatments. Drugs. 2002, 62: 2433-2446. 10.2165/00003495-200262170-00003.CrossRefPubMed
7.
go back to reference Evengård B, Jonzon E, Sandberg A, Theorell T, Lindh G: Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden. Psychiatry Clin Neurosci. 2003, 57: 361-368. 10.1046/j.1440-1819.2003.01132.x.CrossRefPubMed Evengård B, Jonzon E, Sandberg A, Theorell T, Lindh G: Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden. Psychiatry Clin Neurosci. 2003, 57: 361-368. 10.1046/j.1440-1819.2003.01132.x.CrossRefPubMed
8.
go back to reference Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein , Brus I: Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985, 102: 7-16.CrossRefPubMed Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein , Brus I: Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985, 102: 7-16.CrossRefPubMed
9.
go back to reference Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T, Herberman R, Kiecolt-Glaser J, Williams MV: Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun. 2005, 19: 91-103. 10.1016/j.bbi.2004.09.001.CrossRefPubMed Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T, Herberman R, Kiecolt-Glaser J, Williams MV: Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain Behav Immun. 2005, 19: 91-103. 10.1016/j.bbi.2004.09.001.CrossRefPubMed
10.
go back to reference Ledina D, Bradarić N, Milas I, Ivić I, Brncić N, Kuzmicić N: Chronic fatigue syndrome after Q fever. Med Sci Monit. 2007, 13: CS88-92.PubMed Ledina D, Bradarić N, Milas I, Ivić I, Brncić N, Kuzmicić N: Chronic fatigue syndrome after Q fever. Med Sci Monit. 2007, 13: CS88-92.PubMed
11.
go back to reference DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H: Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA. 1991, 88: 2922-6. 10.1073/pnas.88.7.2922.PubMedCentralCrossRefPubMed DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H: Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA. 1991, 88: 2922-6. 10.1073/pnas.88.7.2922.PubMedCentralCrossRefPubMed
12.
go back to reference Holmes MJ, Diack DS, Easingwood RA, Cross JP, Carlisle B: Electron microscopic immunocytological profiles in chronic fatigue syndrome. J Psychiatr Res. 1997, 31: 115-22. 10.1016/S0022-3956(96)00048-9.CrossRefPubMed Holmes MJ, Diack DS, Easingwood RA, Cross JP, Carlisle B: Electron microscopic immunocytological profiles in chronic fatigue syndrome. J Psychiatr Res. 1997, 31: 115-22. 10.1016/S0022-3956(96)00048-9.CrossRefPubMed
13.
go back to reference Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA: Detection of infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science . 2009, 326: 585-589. 10.1126/science.1179052.CrossRefPubMed Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA: Detection of infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science . 2009, 326: 585-589. 10.1126/science.1179052.CrossRefPubMed
14.
go back to reference Maher K, Klimas NG, Fletcher MA: Immunology. Handbook of Chronic Fatigue. Edited by: Jason LA, Fennell PA, Taylor RR. 2003, Hoboken, NJ: John Wiley & Sons, 124-151. Maher K, Klimas NG, Fletcher MA: Immunology. Handbook of Chronic Fatigue. Edited by: Jason LA, Fennell PA, Taylor RR. 2003, Hoboken, NJ: John Wiley & Sons, 124-151.
15.
go back to reference Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG: Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsych. 2001, 8: 51-6. 10.1207/S15324826AN0801_7.CrossRef Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG: Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsych. 2001, 8: 51-6. 10.1207/S15324826AN0801_7.CrossRef
16.
go back to reference Gupta S, Aggarwal S, See D, Starr A: Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. J Psych Res. 1997, 31: 149-56. 10.1016/S0022-3956(96)00063-5.CrossRef Gupta S, Aggarwal S, See D, Starr A: Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. J Psych Res. 1997, 31: 149-56. 10.1016/S0022-3956(96)00063-5.CrossRef
17.
18.
go back to reference Skowera A, Cleare A, Blair D, Bevis L, Wessely S, Peakman M: High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004, 135: 294-302. 10.1111/j.1365-2249.2004.02354.x.PubMedCentralCrossRefPubMed Skowera A, Cleare A, Blair D, Bevis L, Wessely S, Peakman M: High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004, 135: 294-302. 10.1111/j.1365-2249.2004.02354.x.PubMedCentralCrossRefPubMed
19.
go back to reference Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994, 121: 953-9.CrossRefPubMed Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A: The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994, 121: 953-9.CrossRefPubMed
20.
go back to reference Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Res. 2003, 3: 25-10.1186/1472-6963-3-25.CrossRef Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER, International Chronic Fatigue Syndrome Study Group: Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Res. 2003, 3: 25-10.1186/1472-6963-3-25.CrossRef
22.
go back to reference Zweig MH, Campbell G: Receiver-Operating Characteristic (ROC) plots: A fundamental evaluation tool in Clinical Medicine. Clin Chem. 1993, 39: 561-577.PubMed Zweig MH, Campbell G: Receiver-Operating Characteristic (ROC) plots: A fundamental evaluation tool in Clinical Medicine. Clin Chem. 1993, 39: 561-577.PubMed
23.
go back to reference Waldmann TA: The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev Immun. 2006, 6: 595-601. 10.1038/nri1901.CrossRefPubMed Waldmann TA: The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev Immun. 2006, 6: 595-601. 10.1038/nri1901.CrossRefPubMed
24.
go back to reference Boniface K, Blom B, Liu YJ, de Waal Malefyt R: From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev. 2008, 226: 132-46. 10.1111/j.1600-065X.2008.00714.x.PubMedCentralCrossRefPubMed Boniface K, Blom B, Liu YJ, de Waal Malefyt R: From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev. 2008, 226: 132-46. 10.1111/j.1600-065X.2008.00714.x.PubMedCentralCrossRefPubMed
25.
go back to reference Iwakura Y, Ishigame H: The IL-23/IL-17 axis in inflammation J. Clin Invest. 2006, 116: 1218-1222. 10.1172/JCI28508.CrossRef Iwakura Y, Ishigame H: The IL-23/IL-17 axis in inflammation J. Clin Invest. 2006, 116: 1218-1222. 10.1172/JCI28508.CrossRef
26.
go back to reference Straus SE, Dale JK, Wright R, Metcalfe DD: Allergy and the chronic fatigue syndrome. J Allergy Clin Immunol. 1988, 81 (5 Pt 1): 791-5. 10.1016/0091-6749(88)90933-5.CrossRefPubMed Straus SE, Dale JK, Wright R, Metcalfe DD: Allergy and the chronic fatigue syndrome. J Allergy Clin Immunol. 1988, 81 (5 Pt 1): 791-5. 10.1016/0091-6749(88)90933-5.CrossRefPubMed
27.
go back to reference Goldberg RB: Cytokine and Cytokine-like Inflammation Markers, Endothelial Dysfunction and Imbalanced Coagulation in Development of Diabetes and Its Complications. J Clin Endocrinol Metab. 2009, 94: 3171-82. 10.1210/jc.2008-2534.CrossRefPubMed Goldberg RB: Cytokine and Cytokine-like Inflammation Markers, Endothelial Dysfunction and Imbalanced Coagulation in Development of Diabetes and Its Complications. J Clin Endocrinol Metab. 2009, 94: 3171-82. 10.1210/jc.2008-2534.CrossRefPubMed
28.
go back to reference Lin F, Nguyen CM, Wang SJ, Saadi W, Gross SP, Jeon NL: Effective neutrophil chemotaxis is strongly influenced by mean IL-8 concentration. Biochem Biophys Res Commun. 2004, 319: 576-81. 10.1016/j.bbrc.2004.05.029.CrossRefPubMed Lin F, Nguyen CM, Wang SJ, Saadi W, Gross SP, Jeon NL: Effective neutrophil chemotaxis is strongly influenced by mean IL-8 concentration. Biochem Biophys Res Commun. 2004, 319: 576-81. 10.1016/j.bbrc.2004.05.029.CrossRefPubMed
29.
go back to reference Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL: Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006, 2: e25-10.1371/journal.ppat.0020025.PubMedCentralCrossRefPubMed Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, Silverman RH, DeRisi JL: Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog. 2006, 2: e25-10.1371/journal.ppat.0020025.PubMedCentralCrossRefPubMed
30.
go back to reference Waldman WJ, Williams MV, Lemeshow S, Binkley P, Guttridge D, Kiecolt-Glaser JK, Knight DA, Ladner KJ, Glaser R: Epstein-Barr virus-encoded dUTPase enhances proinflammatory cytokine production by macrophages in contact with endothelial cells: evidence for depression-induced atherosclerotic risk. Brain Behav Immun. 2008, 2: 215-23. 10.1016/j.bbi.2007.07.007.CrossRef Waldman WJ, Williams MV, Lemeshow S, Binkley P, Guttridge D, Kiecolt-Glaser JK, Knight DA, Ladner KJ, Glaser R: Epstein-Barr virus-encoded dUTPase enhances proinflammatory cytokine production by macrophages in contact with endothelial cells: evidence for depression-induced atherosclerotic risk. Brain Behav Immun. 2008, 2: 215-23. 10.1016/j.bbi.2007.07.007.CrossRef
31.
go back to reference Ariza ME, Glaser R, Kaumaya PT, Jones C, Williams MV: The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol. 2009, 182: 851-9.CrossRefPubMed Ariza ME, Glaser R, Kaumaya PT, Jones C, Williams MV: The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. J Immunol. 2009, 182: 851-9.CrossRefPubMed
32.
go back to reference Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara T, Seya T, Imai S, Fujieda M, Kawa K, Takada K: Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. J Exp Med. 2009, 206: 2091-9. 10.1084/jem.20081761.PubMedCentralCrossRefPubMed Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara T, Seya T, Imai S, Fujieda M, Kawa K, Takada K: Epstein-Barr virus (EBV)-encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. J Exp Med. 2009, 206: 2091-9. 10.1084/jem.20081761.PubMedCentralCrossRefPubMed
33.
go back to reference Whistler T, Fletcher MA, Lonergan W, Zeng XR, Lin JM, Laperriere A, Vernon SD, Klimas NG: Impaired immune function in Gulf War Illness. BMC Med Genomic. 2009, 5: 12-10.1186/1755-8794-2-12.CrossRef Whistler T, Fletcher MA, Lonergan W, Zeng XR, Lin JM, Laperriere A, Vernon SD, Klimas NG: Impaired immune function in Gulf War Illness. BMC Med Genomic. 2009, 5: 12-10.1186/1755-8794-2-12.CrossRef
34.
go back to reference Fuite J, Vernon SD, Broderick G: Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis. Genomics. 2008, 92: 393-9. 10.1016/j.ygeno.2008.08.008.CrossRefPubMed Fuite J, Vernon SD, Broderick G: Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis. Genomics. 2008, 92: 393-9. 10.1016/j.ygeno.2008.08.008.CrossRefPubMed
Metadata
Title
Plasma cytokines in women with chronic fatigue syndrome
Authors
Mary Ann Fletcher
Xiao Rong Zeng
Zachary Barnes
Silvina Levis
Nancy G Klimas
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2009
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-7-96

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