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Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment

Authors: Megan E. Roerink, Hans Knoop, Ewald M. Bronkhorst, Henk A. Mouthaan, Luuk J. A. C. Hawinkels, Leo A. B. Joosten, Jos W. M. van der Meer

Published in: Journal of Translational Medicine | Issue 1/2017

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Abstract

Background

Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades.

Methods

Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA.

Results

In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls.

Conclusions

In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.
Trial Registration: ClinicalTrials.gov Identifier: NCT02108210, Registered April 2014
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Literature
1.
go back to reference Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–9.CrossRefPubMed Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–9.CrossRefPubMed
2.
go back to reference Reeves WC, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3(1):25.CrossRefPubMedPubMedCentral Reeves WC, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3(1):25.CrossRefPubMedPubMedCentral
3.
go back to reference Solomon L, Reeves WC. Factors influencing the diagnosis of chronic fatigue syndrome. Arch Intern Med. 2004;164(20):2241–5.CrossRefPubMed Solomon L, Reeves WC. Factors influencing the diagnosis of chronic fatigue syndrome. Arch Intern Med. 2004;164(20):2241–5.CrossRefPubMed
4.
go back to reference National Collaborating Centre for Primary Care UK. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy). Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London: National Collaborating Centre for Primary Care; 2007. National Collaborating Centre for Primary Care UK. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy). Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London: National Collaborating Centre for Primary Care; 2007.
5.
go back to reference Collin SM, et al. Chronic fatigue syndrome (CFS) symptom-based phenotypes in two clinical cohorts of adult patients in the UK and The Netherlands. J Psychosom Res. 2016;81:14–23.CrossRefPubMed Collin SM, et al. Chronic fatigue syndrome (CFS) symptom-based phenotypes in two clinical cohorts of adult patients in the UK and The Netherlands. J Psychosom Res. 2016;81:14–23.CrossRefPubMed
8.
go back to reference Lunde S, et al. Serum BAFF and APRIL Levels, T-lymphocyte subsets, and immunoglobulins after B-cell depletion using the monoclonal anti-CD20 antibody rituximab in myalgic encephalopathy/chronic fatigue syndrome. PLoS ONE. 2016;11(8):e0161226.CrossRefPubMedPubMedCentral Lunde S, et al. Serum BAFF and APRIL Levels, T-lymphocyte subsets, and immunoglobulins after B-cell depletion using the monoclonal anti-CD20 antibody rituximab in myalgic encephalopathy/chronic fatigue syndrome. PLoS ONE. 2016;11(8):e0161226.CrossRefPubMedPubMedCentral
11.
go back to reference Brenu EW, et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012;10:88.CrossRefPubMedPubMedCentral Brenu EW, et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012;10:88.CrossRefPubMedPubMedCentral
12.
go back to reference Rajeevan MS, et al. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol. 2015;76(8):553–60.CrossRefPubMed Rajeevan MS, et al. Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Hum Immunol. 2015;76(8):553–60.CrossRefPubMed
13.
go back to reference Schlauch KA, et al. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Transl Psychiatry. 2016;6:e730.CrossRefPubMedPubMedCentral Schlauch KA, et al. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome. Transl Psychiatry. 2016;6:e730.CrossRefPubMedPubMedCentral
14.
go back to reference Blundell S, et al. Chronic fatigue syndrome and circulating cytokines: a systematic review. Brain Behav Immun. 2015;50:186–95.CrossRefPubMed Blundell S, et al. Chronic fatigue syndrome and circulating cytokines: a systematic review. Brain Behav Immun. 2015;50:186–95.CrossRefPubMed
15.
go back to reference Montoya JG, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017;114(34):E7150–8.CrossRefPubMedPubMedCentral Montoya JG, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017;114(34):E7150–8.CrossRefPubMedPubMedCentral
19.
go back to reference Aguilar-Mahecha A, et al. The effect of pre-analytical variability on the measurement of MRM-MS-based mid- to high-abundance plasma protein biomarkers and a panel of cytokines. PLoS ONE. 2012;7(6):e38290.CrossRefPubMedPubMedCentral Aguilar-Mahecha A, et al. The effect of pre-analytical variability on the measurement of MRM-MS-based mid- to high-abundance plasma protein biomarkers and a panel of cytokines. PLoS ONE. 2012;7(6):e38290.CrossRefPubMedPubMedCentral
20.
go back to reference Solier C, Langen H. Antibody-based proteomics and biomarker research—current status and limitations. Proteomics. 2014;14(6):774–83.CrossRefPubMed Solier C, Langen H. Antibody-based proteomics and biomarker research—current status and limitations. Proteomics. 2014;14(6):774–83.CrossRefPubMed
21.
go back to reference Assarsson E, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE. 2014;9(4):e95192.CrossRefPubMedPubMedCentral Assarsson E, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE. 2014;9(4):e95192.CrossRefPubMedPubMedCentral
22.
23.
go back to reference Roerink ME, et al. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflamm. 2017;14(1):16.CrossRef Roerink ME, et al. Interleukin-1 as a mediator of fatigue in disease: a narrative review. J Neuroinflamm. 2017;14(1):16.CrossRef
24.
go back to reference Roerink ME, et al. Cytokine inhibition in patients with chronic fatigue syndrome: a randomized trial. Cytokine inhibition in patients with chronic fatigue syndrome. Ann Intern Med. 2017;166(8):557–64.CrossRefPubMed Roerink ME, et al. Cytokine inhibition in patients with chronic fatigue syndrome: a randomized trial. Cytokine inhibition in patients with chronic fatigue syndrome. Ann Intern Med. 2017;166(8):557–64.CrossRefPubMed
26.
go back to reference Vercoulen JH, Alberst M, Bleijenberg G. De Checklist Individual Strength (CIS). Gedragstherapie. 1999;32:131–6. Vercoulen JH, Alberst M, Bleijenberg G. De Checklist Individual Strength (CIS). Gedragstherapie. 1999;32:131–6.
27.
go back to reference Vercoulen JH, et al. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res. 1994;38(5):383–92.CrossRefPubMed Vercoulen JH, et al. Dimensional assessment of chronic fatigue syndrome. J Psychosom Res. 1994;38(5):383–92.CrossRefPubMed
28.
go back to reference Wiborg JF, et al. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychother Psychosom. 2015;84(6):368–76.CrossRefPubMed Wiborg JF, et al. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychother Psychosom. 2015;84(6):368–76.CrossRefPubMed
29.
go back to reference Derogatis LR, Savitz KL. Handbook of psychological assessment in primary care settings. Vol. 236. New Jersey: Lawrence Erlbaum Associates; 2000. p. 297–334. Derogatis LR, Savitz KL. Handbook of psychological assessment in primary care settings. Vol. 236. New Jersey: Lawrence Erlbaum Associates; 2000. p. 297–334.
30.
go back to reference Jo C, et al. Random-graft polymer-directed synthesis of inorganic mesostructures with ultrathin frameworks. Angew Chem Int Ed Engl. 2014;53(20):5117–21.PubMed Jo C, et al. Random-graft polymer-directed synthesis of inorganic mesostructures with ultrathin frameworks. Angew Chem Int Ed Engl. 2014;53(20):5117–21.PubMed
31.
go back to reference Landi A, et al. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Cytokine. 2016;78:27–36.CrossRefPubMed Landi A, et al. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Cytokine. 2016;78:27–36.CrossRefPubMed
32.
go back to reference Hawinkels LJ, et al. Tissue level, activation and cellular localisation of TGF-beta1 and association with survival in gastric cancer patients. Br J Cancer. 2007;97(3):398–404.CrossRefPubMedPubMedCentral Hawinkels LJ, et al. Tissue level, activation and cellular localisation of TGF-beta1 and association with survival in gastric cancer patients. Br J Cancer. 2007;97(3):398–404.CrossRefPubMedPubMedCentral
34.
go back to reference Tibshirani R. Regression shrinkage and selection via the Lasso. J Roy Stat Soc. 1996;58(1):267–88. Tibshirani R. Regression shrinkage and selection via the Lasso. J Roy Stat Soc. 1996;58(1):267–88.
35.
go back to reference Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36.CrossRefPubMed Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143(1):29–36.CrossRefPubMed
36.
go back to reference Steyerberg EW. Clinical prediction models: a practical approach to development, validation, and updating. New York: Springer; 2009.CrossRef Steyerberg EW. Clinical prediction models: a practical approach to development, validation, and updating. New York: Springer; 2009.CrossRef
37.
go back to reference Croxford AL, Kulig P, Becher B. IL-12-and IL-23 in health and disease. Cytokine Growth Factor Rev. 2014;25(4):415–21.CrossRefPubMed Croxford AL, Kulig P, Becher B. IL-12-and IL-23 in health and disease. Cytokine Growth Factor Rev. 2014;25(4):415–21.CrossRefPubMed
38.
go back to reference Zundler S, Neurath MF. Interleukin-12: functional activities and implications for disease. Cytokine Growth Factor Rev. 2015;26(5):559–68.CrossRefPubMed Zundler S, Neurath MF. Interleukin-12: functional activities and implications for disease. Cytokine Growth Factor Rev. 2015;26(5):559–68.CrossRefPubMed
39.
go back to reference Cua DJ, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.CrossRefPubMed Cua DJ, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.CrossRefPubMed
40.
go back to reference White AT, et al. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010;47(4):615–24.PubMedPubMedCentral White AT, et al. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010;47(4):615–24.PubMedPubMedCentral
41.
go back to reference Khaiboullina SF, et al. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine. 2015;72(1):1–8.CrossRefPubMed Khaiboullina SF, et al. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine. 2015;72(1):1–8.CrossRefPubMed
42.
43.
go back to reference Hurteau JA, et al. Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2001;82(1):7–10.CrossRefPubMed Hurteau JA, et al. Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2001;82(1):7–10.CrossRefPubMed
44.
go back to reference van Herpen CM, et al. Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. Clin Cancer Res. 2004;10(8):2626–35.CrossRefPubMed van Herpen CM, et al. Intratumoral administration of recombinant human interleukin 12 in head and neck squamous cell carcinoma patients elicits a T-helper 1 profile in the locoregional lymph nodes. Clin Cancer Res. 2004;10(8):2626–35.CrossRefPubMed
45.
go back to reference Ries CH, et al. CSF-1/CSF-1R targeting agents in clinical development for cancer therapy. Curr Opin Pharmacol. 2015;23:45–51.CrossRefPubMed Ries CH, et al. CSF-1/CSF-1R targeting agents in clinical development for cancer therapy. Curr Opin Pharmacol. 2015;23:45–51.CrossRefPubMed
46.
go back to reference Muller AF, et al. Neutralization of colony-stimulating factor 1 receptor prevents sickness behavior syndrome by reprogramming inflammatory monocytes to produce IL-10. Brain Behav Immun. 2015;48:78–85.CrossRefPubMed Muller AF, et al. Neutralization of colony-stimulating factor 1 receptor prevents sickness behavior syndrome by reprogramming inflammatory monocytes to produce IL-10. Brain Behav Immun. 2015;48:78–85.CrossRefPubMed
47.
go back to reference Hawinkels LJ, Ten Dijke P. Exploring anti-TGF-beta therapies in cancer and fibrosis. Growth Factors. 2011;29(4):140–52.CrossRefPubMed Hawinkels LJ, Ten Dijke P. Exploring anti-TGF-beta therapies in cancer and fibrosis. Growth Factors. 2011;29(4):140–52.CrossRefPubMed
48.
49.
go back to reference Rondina MT, et al. Whole blood flow cytometry measurements of in vivo platelet activation in critically-Ill patients are influenced by variability in blood sampling techniques. Thromb Res. 2012;129(6):729–35.CrossRefPubMed Rondina MT, et al. Whole blood flow cytometry measurements of in vivo platelet activation in critically-Ill patients are influenced by variability in blood sampling techniques. Thromb Res. 2012;129(6):729–35.CrossRefPubMed
50.
go back to reference Clark LV, et al. Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study. Clin Exp Immunol. 2017;190:360–71.CrossRefPubMed Clark LV, et al. Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control study. Clin Exp Immunol. 2017;190:360–71.CrossRefPubMed
51.
go back to reference Norris LA, Bonnar J. Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives. Thromb Haemost. 1994;72(6):926–30.PubMed Norris LA, Bonnar J. Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives. Thromb Haemost. 1994;72(6):926–30.PubMed
52.
go back to reference Fernandez-Martinez E, et al. Immunomodulatory effects by oral contraceptives in normal and cholestatic female rats: role of cytokines. Int Immunopharmacol. 2014;21(1):10–9.CrossRefPubMed Fernandez-Martinez E, et al. Immunomodulatory effects by oral contraceptives in normal and cholestatic female rats: role of cytokines. Int Immunopharmacol. 2014;21(1):10–9.CrossRefPubMed
53.
go back to reference van Kuppeveld FJ, van der Meer JW. XMRV and CFS–the sad end of a story. Lancet. 2012;379(9814):e27–8.CrossRefPubMed van Kuppeveld FJ, van der Meer JW. XMRV and CFS–the sad end of a story. Lancet. 2012;379(9814):e27–8.CrossRefPubMed
54.
go back to reference Page TH, et al. Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood. J Immunol. 2010;185(6):3694–701.CrossRefPubMed Page TH, et al. Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood. J Immunol. 2010;185(6):3694–701.CrossRefPubMed
55.
go back to reference Endres S, et al. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol. 1989;19(12):2327–33.CrossRefPubMed Endres S, et al. In vitro production of IL 1 beta, IL 1 alpha, TNF and IL2 in healthy subjects: distribution, effect of cyclooxygenase inhibition and evidence of independent gene regulation. Eur J Immunol. 1989;19(12):2327–33.CrossRefPubMed
56.
go back to reference Tosato G, Jones KD. Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. Blood. 1990;75(6):1305–10.PubMed Tosato G, Jones KD. Interleukin-1 induces interleukin-6 production in peripheral blood monocytes. Blood. 1990;75(6):1305–10.PubMed
57.
go back to reference Emsley HC, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76(10):1366–72.CrossRefPubMedPubMedCentral Emsley HC, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76(10):1366–72.CrossRefPubMedPubMedCentral
58.
go back to reference Van Tassell BW, et al. Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PLoS ONE. 2012;7(3):e33438.CrossRefPubMedPubMedCentral Van Tassell BW, et al. Enhanced interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure. PLoS ONE. 2012;7(3):e33438.CrossRefPubMedPubMedCentral
59.
go back to reference Pusch G, et al. Early Dynamics of P-selectin and interleukin 6 predicts outcomes in ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24(8):1938–47.CrossRefPubMed Pusch G, et al. Early Dynamics of P-selectin and interleukin 6 predicts outcomes in ischemic stroke. J Stroke Cerebrovasc Dis. 2015;24(8):1938–47.CrossRefPubMed
60.
go back to reference Lewith G, et al. Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome. J Psychosom Res. 2016;87:37–42.CrossRefPubMed Lewith G, et al. Complementary and alternative healthcare use by participants in the PACE trial of treatments for chronic fatigue syndrome. J Psychosom Res. 2016;87:37–42.CrossRefPubMed
61.
go back to reference Boneva RS, et al. Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia. Health Qual Life Outcomes. 2009;7:67.CrossRefPubMedPubMedCentral Boneva RS, et al. Use of medications by people with chronic fatigue syndrome and healthy persons: a population-based study of fatiguing illness in Georgia. Health Qual Life Outcomes. 2009;7:67.CrossRefPubMedPubMedCentral
62.
go back to reference Mueller-Using S, et al. Factors associated with performing tuberculosis screening of HIV-positive patients in Ghana: LASSO-based predictor selection in a large public health data set. BMC Public Health. 2016;16:563.CrossRefPubMedPubMedCentral Mueller-Using S, et al. Factors associated with performing tuberculosis screening of HIV-positive patients in Ghana: LASSO-based predictor selection in a large public health data set. BMC Public Health. 2016;16:563.CrossRefPubMedPubMedCentral
Metadata
Title
Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment
Authors
Megan E. Roerink
Hans Knoop
Ewald M. Bronkhorst
Henk A. Mouthaan
Luuk J. A. C. Hawinkels
Leo A. B. Joosten
Jos W. M. van der Meer
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1371-9

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