Journal Mobile Options
Table of Contents
Vol. 81, No. 5, 2012
Issue release date: August 2012
Psychother Psychosom 2012;81:286–295

Inflammatory and Cell-Mediated Immune Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Depression: Inflammatory Markers Are Higher in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome than in Depression

Maes M. · Twisk F.N.M. · Ringel K.
aMaes Clinics, TRIA, Bangkok, Thailand; bME-de-patiënten Foundation, Limmen, The Netherlands; cImmunologische Laboratorien, Aachen, Germany

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS. Methods: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. Results: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS. Conclusions: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared ‘pathway phenotype’, i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Maes M: Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:11–38.
  2. Maes M: Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35: 664–675.
  3. Howren MB, Lamkin DM, Suls J: Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009;71:171–186.
  4. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctôt KL: A metaanalysis of cytokines in major depression. Biol Psychiatry 2010;67:446–457.
  5. Liu Y, Ho RC, Mak A: Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a metaanalysis and meta-regression. J Affect Disord 2011, E-pub ahead of print.
  6. Maes M, Galecki P, Chang YS, Berk M: A review on the oxidative and nitrosative stress (O & NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:676–692.
  7. Leonard B, Maes M: Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathobiology of unipolar depression. Neurosci Biobehav Rev 2012;36:764–785.
  8. Maes M: ‘Functional’ or ‘psychosomatic’ symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression. Neuroendocrinol Lett 2009;30:564–573.

    External Resources

  9. Kellner R: Psychosomatic syndromes, somatization and somatoform disorders. Psychother Psychosom 1994;61:4–24.
  10. 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;121:953–959.
  11. Maes M: Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry 2009;22:75–83.

    External Resources

  12. Maes M, Twisk FN: Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med 2010;8:35.

    External Resources

  13. Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G: Immunological aspects of chronic fatigue syndrome. Autoimmun Rev 2009;8:287–291.
  14. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG: Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 2009;7:96.

    External Resources

  15. Maes M, Mihaylova I, Kubera M, Bosmans E: Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuroendocrinol Lett 2007;28:463–469.
  16. Buchwald D, Wener MH, Pearlman T, Kith P: Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. J Rheumatol 1997;24:372–376.
  17. Matsuda J, Gohchi K, Gotoh N: Serum concentrations of 2’,5′-oligoadenylate synthetase, neopterin, and beta-glucan in patients with chronic fatigue syndrome and in patients with major depression. J Neurol Neurosurg Psychiatry 1994;57:1015–1016.
  18. Chao CC, Gallagher M, Phair J, Peterson PK: Serum neopterin and interleukin-6 levels in chronic fatigue syndrome. J Infect Dis 1990;162:1412–1413.
  19. Maes M, Mihaylova I, Leunis JC: Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuroendocrinol Lett 2006;27:615–621.
  20. Sheng WS, Hu S, Lamkin A, Peterson PK, Chao CC: Susceptibility to immunologically mediated fatigue in C57BL/6 versus Balb/c mice. Clin Immunol Immunopathol 1996;81:161–167.
  21. Sheng WS, Hu S, Ding JM, Chao CC, Peterson PK: Cytokine expression in the mouse brain in response to immune activation by Corynebacterium parvum. Clin Diagn Lab Immunol 2001;8:446–448.
  22. Cavadini G, Petrzilka S, Kohler P, Jud C, Tobler I, Birchler T, Fontana A: TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci USA 2007;104:12843–12848.
  23. Jiang Y, Deacon R, Anthony DC, Campbell SJ: Inhibition of peripheral TNF can block the malaise associated with CNS inflammatory diseases. Neurobiol Dis 2008;32:125–132.
  24. Hermann GE, Rogers RC: TNFalpha: a trigger of autonomic dysfunction. Neuroscientist 2008;14:53–67.
  25. Maes M: An intriguing and hitherto unexplained co-occurrence: depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:784–794.
  26. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4, text revision (DSM-IV-TR). Washington, American Psychiatric Association, 2000.
  27. Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG: A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res 2002;52:501–509.
  28. 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;136:933–939.
  29. Maes M, Mihaylova I, Kubera M, Ringel K: Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry 2012;36:169–175.

    External Resources

  30. March CJ, Mosley B, Larsen A, et al: Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature 1985;315:641–647.
  31. Maes M, Rief W: Diagnostic classifications in depression and somatization should include biomarkers, such as disorders in the tryptophan catabolite (TRYCAT) pathway. Psychiatry Res, in press.
  32. Patarca R: Cytokines and chronic fatigue syndrome. Ann NY Acad Sci 2001;933:185–200.
  33. Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA: Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME 2008;16:19–33.
  34. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG: Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 2009;7:96.

    External Resources

  35. 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;9:81.
  36. 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;24:1209–1217.
  37. 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;17:582–587.
  38. Bellmann-Weiler R, Schroecksnadel K, Holzer C, Larcher C, Fuchs D, Weiss G: IFN-gamma mediated pathways in patients with fatigue and chronic active Epstein-Barr virus infection. J Affect Disord 2008;108:171–176.
  39. Krzyszton CP, Sparkman NL, Grant RW, Buchanan JB, Broussard SR, Woods J, Johnson RW: Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation. Am J Physiol Regul Integr Comp Physiol 2008;295:R1109–R1114.
  40. Carmichael MD, Davis JM, Murphy EA, Carson JA, Van Rooijen N, Mayer E, Ghaffar A: Role of brain macrophages on IL-1beta and fatigue following eccentric exercise-induced muscle damage. Brain Behav Immun 2010;24:564–568.
  41. Nakamura M, Ferreira SH: A peripheral sympathetic component in inflammatory hyperalgesia. Eur J Pharmacol 1987;135:145–153.
  42. Maes M, Van Gastel A, Delmeire L, Kenis G, Bosmans E, Song C: Platelet alpha2 adrenoceptor density in humans: relationships to stress-induced anxiety, psychasthenic constitution, gender and stress-induced changes in the inflammatory response system. Psychol Med 2002;32:919–928.
  43. Hermann GE, Rogers RC: TNFalpha: a trigger of autonomic dysfunction. Neuroscientist 2008;14:53–67.
  44. Murr C, Fuchs D, Gössler W, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G, Esterbauer H, Wachter H: Enhancement of hydrogen peroxide-induced luminol-dependent chemiluminescence by neopterin depends on the presence of iron chelator complexes. FEBS Lett 1994;338:223–226.
  45. Weiss G, Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner-Felmayer G, Semenitz E, Dierich MP, Wachter H: Neopterin modulates toxicity mediated by reactive oxygen and chloride species. FEBS Lett 1993;321:89–92.
  46. Schobersberger W, Hoffmann G, Grote J, Wachter H, Fuchs D: Induction of inducible nitric oxide synthase expression by neopterin in vascular smooth muscle cells. FEBS Lett 1995;377:461–464.
  47. Schobersberger W, Hoffmann G, Hobisch-Hagen P, Bock G, Volkl H, Baier-Bitterlich G, Wirleitner B, Wachter H, Fuchs D: Neopterin and 7,8-dihydroneopterin induce apoptosis in the rat alveolar epithelial cell line L2. FEBS Lett 1996;397:263–268.
  48. Baier-Bitterlich G, Fuchs D, Murr C, Reibnegger G, Werner-Felmayer G, Sgonc R, Böck G, Dierich MP, Wachter H: Effect of neopterin and 7,8-dihydroneopterin on tumor necrosis factor alpha induced programmed cell death. FEBS Lett 1995;364:234–238.
  49. Fava GA, Sonino N: Psychosomatic medicine: a name to keep. Psychother Psychosom 2010;79:1–3.
  50. Heins MJ, Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G: Possible detrimental effects of cognitive behaviour therapy for chronic fatigue syndrome. Psychother Psychosom 2010;79:249–256.
  51. Nater UM, Jones JF, Lin JM, Maloney E, Reeves WC, Heim C: Personality features and personality disorders in chronic fatigue syndrome: a population-based study. Psychother Psychosom 2010;79:312–318.
  52. Honkalampi K, Lehto SM, Koivumaa-Honkanen H, Hintikka J, Niskanen L, Valkonen-Korhonen M, Viinamäki H: Alexithymia and tissue inflammation. Psychother Psychosom 2011;80:359–364.

    External Resources

  53. Cella M, Chalder T, White PD: Does the heterogeneity of chronic fatigue syndrome moderate the response to cognitive behaviour therapy? An exploratory study. Psychother Psychosom 2011;80:353–358.

    External Resources

  54. Lichtenberg P, Belmaker RH: Subtyping major depressive disorder. Psychother Psychosom 2010;79:131–135.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50