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Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study

Authors: Brett A. Lidbury, Badia Kita, Donald P. Lewis, Susan Hayward, Helen Ludlow, Mark P. Hedger, David M. de Kretser

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

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Abstract

Background

Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available.

Methods

A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals.

Results

Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma.

Conclusion

Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.
Literature
1.
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
2.
go back to reference Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014;4:2.CrossRef Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014;4:2.CrossRef
3.
go back to reference Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11:7–115.CrossRef Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11:7–115.CrossRef
4.
go back to reference Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270:327–38.CrossRefPubMedPubMedCentral Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270:327–38.CrossRefPubMedPubMedCentral
5.
go back to reference Clayton EW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA. 2015;313:1101–2.CrossRefPubMed Clayton EW. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA. 2015;313:1101–2.CrossRefPubMed
6.
go back to reference Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS ONE. 2010;5:e10817.CrossRefPubMedPubMedCentral Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, et al. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS ONE. 2010;5:e10817.CrossRefPubMedPubMedCentral
7.
go back to reference Hedger MP, de Kretser DM. The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev. 2013;24:285–95.CrossRefPubMed Hedger MP, de Kretser DM. The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev. 2013;24:285–95.CrossRefPubMed
8.
go back to reference de Kretser DM, Bensley JG, Pettila V, Linko R, Hedger MP, Hayward S, et al. Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study. Crit Care. 2013;17:R263.CrossRefPubMedPubMedCentral de Kretser DM, Bensley JG, Pettila V, Linko R, Hedger MP, Hayward S, et al. Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study. Crit Care. 2013;17:R263.CrossRefPubMedPubMedCentral
9.
go back to reference Chen JL, Walton KL, Al-Musawi SL, Kelly EK, Qian H, La M, et al. Development of novel activin-targeted therapeutics. Mol Ther. 2015;23:434–44.CrossRefPubMed Chen JL, Walton KL, Al-Musawi SL, Kelly EK, Qian H, La M, et al. Development of novel activin-targeted therapeutics. Mol Ther. 2015;23:434–44.CrossRefPubMed
10.
go back to reference Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, et al. Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood. 2012;120:431–9.CrossRefPubMed Besson-Fournier C, Latour C, Kautz L, Bertrand J, Ganz T, Roth MP, et al. Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling. Blood. 2012;120:431–9.CrossRefPubMed
11.
go back to reference Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J Intern Med. 2014;275:409–17.CrossRefPubMed Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J Intern Med. 2014;275:409–17.CrossRefPubMed
12.
go back to reference Jason LA, Unger ER, Dimitrakoff JD, Fagin AP, Houghton M, Cook DB, et al. Minimum data elements for research reports on CFS. Brain Behav Immun. 2012;26:401–6.CrossRefPubMedPubMedCentral Jason LA, Unger ER, Dimitrakoff JD, Fagin AP, Houghton M, Cook DB, et al. Minimum data elements for research reports on CFS. Brain Behav Immun. 2012;26:401–6.CrossRefPubMedPubMedCentral
13.
go back to reference Knight PG, Muttukrishna S, Groome NP. Development and application of a two-site enzyme immunoassay for the determination of ‘total’ activin-A concentrations in serum and follicular fluid. J Endocrinol. 1996;148:267–79.CrossRefPubMed Knight PG, Muttukrishna S, Groome NP. Development and application of a two-site enzyme immunoassay for the determination of ‘total’ activin-A concentrations in serum and follicular fluid. J Endocrinol. 1996;148:267–79.CrossRefPubMed
14.
go back to reference Ludlow H, Phillips DJ, Myers M, McLachlan RI, de Kretser DM, Allan CA, et al. A new ‘total’ activin B enzyme-linked immunosorbent assay (ELISA): development and validation for human samples. Clin Endocrinol. 2009;71:867–73.CrossRef Ludlow H, Phillips DJ, Myers M, McLachlan RI, de Kretser DM, Allan CA, et al. A new ‘total’ activin B enzyme-linked immunosorbent assay (ELISA): development and validation for human samples. Clin Endocrinol. 2009;71:867–73.CrossRef
15.
go back to reference O’Connor AE, McFarlane JR, Hayward S, Yohkaichiya T, Groome NP, de Kretser DM. Serum activin A and follistatin concentrations during human pregnancy: a cross-sectional and longitudinal study. Hum Reprod. 1999;14:827–32.CrossRefPubMed O’Connor AE, McFarlane JR, Hayward S, Yohkaichiya T, Groome NP, de Kretser DM. Serum activin A and follistatin concentrations during human pregnancy: a cross-sectional and longitudinal study. Hum Reprod. 1999;14:827–32.CrossRefPubMed
16.
go back to reference Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129–37.CrossRefPubMed Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med. 1999;159:2129–37.CrossRefPubMed
17.
go back to reference Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013;11:93.CrossRefPubMedPubMedCentral Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013;11:93.CrossRefPubMedPubMedCentral
18.
go back to reference Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004;135:294–302.CrossRefPubMedPubMedCentral Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004;135:294–302.CrossRefPubMedPubMedCentral
19.
go back to reference Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J Psychosom Res. 2003;55:79–90.CrossRefPubMed Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J Psychosom Res. 2003;55:79–90.CrossRefPubMed
20.
go back to reference Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, et al. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013;20:1736–42.CrossRefPubMedPubMedCentral Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, et al. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013;20:1736–42.CrossRefPubMedPubMedCentral
21.
go back to reference Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, Staines D, et al. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediat Inflamm. 2015. doi:10.1155/2015/929720. Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, Staines D, et al. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediat Inflamm. 2015. doi:10.​1155/​2015/​929720.
22.
go back to reference Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, et al. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. J Clin Immunol. 1997;17:160–6.CrossRefPubMed Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, et al. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. J Clin Immunol. 1997;17:160–6.CrossRefPubMed
23.
go back to reference Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, et al. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991;3:292–8.CrossRefPubMed Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, et al. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991;3:292–8.CrossRefPubMed
24.
go back to reference Sarhan D, Palma M, Mao Y, Adamson L, Kiessling R, Mellstedt H, et al. Dendritic cell regulation of NK-cell responses involves lymphotoxin-alpha, IL-12, and TGF-beta. Eur J Immunol. 2015;45:1783–93.CrossRefPubMed Sarhan D, Palma M, Mao Y, Adamson L, Kiessling R, Mellstedt H, et al. Dendritic cell regulation of NK-cell responses involves lymphotoxin-alpha, IL-12, and TGF-beta. Eur J Immunol. 2015;45:1783–93.CrossRefPubMed
25.
go back to reference Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990;28:1403–10.PubMedPubMedCentral Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990;28:1403–10.PubMedPubMedCentral
26.
go back to reference Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1. J Immunol. 1995;155:1066–73.PubMed Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1. J Immunol. 1995;155:1066–73.PubMed
27.
go back to reference Viel S, Marcais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9:19.CrossRef Viel S, Marcais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, et al. TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9:19.CrossRef
28.
go back to reference Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K, et al. Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases. Cancer. 1994;73:2275–9.CrossRefPubMed Shirai Y, Kawata S, Tamura S, Ito N, Tsushima H, Takaishi K, et al. Plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma. Comparison with chronic liver diseases. Cancer. 1994;73:2275–9.CrossRefPubMed
29.
go back to reference Pfeiffer A, Middelberg-Bisping K, Drewes C, Schatz H. Elevated plasma levels of transforming growth factor-beta 1 in NIDDM. Diabetes Care. 1996;19:1113–7.CrossRefPubMed Pfeiffer A, Middelberg-Bisping K, Drewes C, Schatz H. Elevated plasma levels of transforming growth factor-beta 1 in NIDDM. Diabetes Care. 1996;19:1113–7.CrossRefPubMed
30.
go back to reference Grainger DJ, Mosedale DE, Metcalfe JC. TGF-beta in blood: a complex problem. Cytokine Growth Factor Rev. 2000;11(1–2):133–45.CrossRefPubMed Grainger DJ, Mosedale DE, Metcalfe JC. TGF-beta in blood: a complex problem. Cytokine Growth Factor Rev. 2000;11(1–2):133–45.CrossRefPubMed
31.
go back to reference Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, et al. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci USA. 2007;104:16239–44.CrossRefPubMedPubMedCentral Jones KL, Mansell A, Patella S, Scott BJ, Hedger MP, de Kretser DM, et al. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc Natl Acad Sci USA. 2007;104:16239–44.CrossRefPubMedPubMedCentral
32.
go back to reference Chen JL, Walton KL, Winbanks CE, Murphy KT, Thomson RE, Makanji Y, et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 2014;28:1711–23.CrossRefPubMed Chen JL, Walton KL, Winbanks CE, Murphy KT, Thomson RE, Makanji Y, et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 2014;28:1711–23.CrossRefPubMed
33.
go back to reference Fang DYP, Lu B, Hayward S, de Kretser DM, Cowan PJ, Dwyer KM. The role of activin A and B and the benefit of follistatin treatment in renal ischemia-reperfusion injury in mice. Transplant Direct. 2016;2:e87.CrossRefPubMedPubMedCentral Fang DYP, Lu B, Hayward S, de Kretser DM, Cowan PJ, Dwyer KM. The role of activin A and B and the benefit of follistatin treatment in renal ischemia-reperfusion injury in mice. Transplant Direct. 2016;2:e87.CrossRefPubMedPubMedCentral
34.
go back to reference Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009;39:283–96.CrossRefPubMedPubMedCentral Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009;39:283–96.CrossRefPubMedPubMedCentral
Metadata
Title
Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study
Authors
Brett A. Lidbury
Badia Kita
Donald P. Lewis
Susan Hayward
Helen Ludlow
Mark P. Hedger
David M. de Kretser
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/s12967-017-1161-4

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