The clinical value of cytokines in chronic fatigue syndrome

Journal of Translational Medicine - Tập 17 - Trang 1-12 - 2019
Tiansong Yang1, Yan Yang2, Delong Wang2, Chaoran Li2, Yuanyuan Qu2, Jing Guo2, Tianyu Shi2, Wang Bo2, Zhongren Sun2, Tetsuya Asakawa3,4
1First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
2Heilongjiang University of Chinese Medicine, Harbin, China
3Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
4Research Base of Traditional Chinese Medicine Syndrome, Fujian University of Traditional Chinese Medicine, Fuzhou, China

Tóm tắt

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS. Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices. Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis. Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

Tài liệu tham khảo

Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387–9. Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C. Myalgic encephalomyelitis/chronic fatigue syndrome—evidence for an autoimmune disease. Autoimmun Rev. 2018;17:601–9. Milrad SF, Hall DL, Jutagir DR, Lattie EG, Ironson GH, Wohlgemuth W, Nunez MV, Garcia L, Czaja SJ, Perdomo DM, et al. Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women. J Neuroimmunol. 2017;303:43–50. Tomas C, Newton J, Watson S. A review of hypothalamic–pituitary–adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013;2013:784520. Morris G, Anderson G, Maes M. Hypothalamic–pituitary–adrenal hypofunction in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) as a consequence of activated immune-inflammatory and oxidative and nitrosative pathways. Mol Neurobiol. 2017;54:6806–19. Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014;29:19–36. Tomas C, Brown A, Strassheim V, Elson JL, Newton J, Manning P. Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS ONE. 2017;12:e0186802. Loebel M, Eckey M, Sotzny F, Hahn E, Bauer S, Grabowski P, Zerweck J, Holenya P, Hanitsch LG, Wittke K, et al. Serological profiling of the EBV immune response in chronic fatigue syndrome using a peptide microarray. PLoS ONE. 2017;12:e0179124. Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, et al. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS ONE. 2014;9:e85387. Yalcin S, Kuratsune H, Yamaguchi K, Kitani T, Yamanishi K. Prevalence of human herpesvirus 6 variants A and B in patients with chronic fatigue syndrome. Microbiol Immunol. 1994;38:587–90. Attard L, Bonvicini F, Gelsomino F, Manfredi R, Cascavilla A, Viale P, Varani S, Gallinella G. Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19-associated chronic fatigue syndrome. J Clin Virol. 2015;62:54–7. Kerr JR, Bracewell J, Laing I, Mattey DL, Bernstein RM, Bruce IN, Tyrrell DA. Chronic fatigue syndrome and arthralgia following parvovirus B19 infection. J Rheumatol. 2002;29:595–602. Kenyon JC, Lever AM. XMRV, prostate cancer and chronic fatigue syndrome. Br Med Bull. 2011;98:61–74. Morris G, Berk M, Carvalho AF, Caso JR, Sanz Y, Maes M. The role of microbiota and intestinal permeability in the pathophysiology of autoimmune and neuroimmune processes with an emphasis on inflammatory bowel disease type 1 diabetes and chronic fatigue syndrome. Curr Pharm Des. 2016;22:6058–75. Arnett SV, Clark IA. Inflammatory fatigue and sickness behaviour—lessons for the diagnosis and management of chronic fatigue syndrome. J Affect Disord. 2012;141:130–42. Howard Tripp N, Tarn J, Natasari A, Gillespie C, Mitchell S, Hackett KL, Bowman SJ, Price E, Pease CT, Emery P, et al. Fatigue in primary Sjogren’s syndrome is associated with lower levels of proinflammatory cytokines. RMD Open. 2016;2:e000282. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Naess H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS ONE. 2011;6:e26358. 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. 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;24:1209–17. 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. Blundell S, Ray KK, Buckland M, White PD. Chronic fatigue syndrome and circulating cytokines: a systematic review. Brain Behav Immun. 2015;50:186–95. Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci USA. 2017;114:E7150–8. VanElzakker MB, Brumfield SA, Lara Mejia PS. Neuroinflammation and cytokines in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a critical review of research methods. Front Neurol. 2018;9:1033. Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991;3:292–8. Gupta S, Aggarwal S, See D, Starr A. Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. J Psychiatr Res. 1997;31:149–56. Milrad SF, Hall DL, Jutagir DR, Lattie EG, Czaja SJ, Perdomo DM, Fletcher MA, Klimas N, Antoni MH. Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: a psychoneuroendocrinological structural regression model. Int J Psychophysiol. 2018;131:124–30. Lidbury BA, Kita B, Lewis DP, Hayward S, Ludlow H, Hedger MP, de Kretser DM. Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study. J Transl Med. 2017;15:60. Groven N, Fors EA, Iversen VC, White LR, Reitan SK. Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls. Nord J Psychiatry. 2018;72:556–60. Englebienne P, Verhas M, Herst CV, De Meirleir K. Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue. Med Hypotheses. 2003;60:175–80. Vojdani A, Ghoneum M, Choppa PC, Magtoto L, Lapp CW. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med. 1997;242:465–78. 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;108:171–6. Kerr JR, Tyrrell DA. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Rep. 2003;7:333–41. Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, Peterson DL, Gottschalk CG, Schultz AF, Che X, et al. Distinct plasmaimmune signatures in ME/CFS are present early in the course of illness. Sci Adv. 2015;1:e1400121. Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Serum immune proteins in moderate and severe chronic fatigue syndrome/myalgic encephalomyelitis patients. Int J Med Sci. 2015;12:764–72. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 1998;128:127–37. Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008;70:298–305. Russell L, Broderick G. Illness progression in chronic fatigue syndrome: a shifting immune baseline. BMC Immunol. 2016;17:3. Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH. Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology. 2001;40:743–9. Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Katsuki A, Atake K, Nakamura J. Plasma levels of interleukin-6 and selective serotonin reuptake inhibitor response in patients with major depressive disorder. Hum Psychopharmacol. 2013;28:466–70. Lee KA, Gay CL, Lerdal A, Pullinger CR, Aouizerat BE. Cytokine polymorphisms are associated with fatigue in adults living with HIV/AIDS. Brain Behav Immun. 2014;40:95–103. Lattie EG, Antoni MH, Fletcher MA, Penedo F, Czaja S, Lopez C, Perdomo D, Sala A, Nair S, Fu SH, Klimas N. Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome. Brain Behav Immun. 2012;26:849–58. Yadlapati S, Efthimiou P. Impact of IL-1 inhibition on fatigue associated with autoinflammatory syndromes. Mod Rheumatol. 2016;26:3–8. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009;7:96. Maes M, Twisk FN, Johnson C. Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012;200:754–60. Moneghetti KJ, Skhiri M, Contrepois K, Kobayashi Y, Maecker H, Davis M, Snyder M, Haddad F, Montoya JG. Value of circulating cytokine profiling during submaximal exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. Sci Rep. 2018;8:2779. Del Rio L, Murcia A, Buendia AJ, Alvarez D, Ortega N, Navarro JA, Salinas J, Caro MR. Development of an in vivo model of Chlamydia abortus chronic infection in mice overexpressing IL-10. Vet Microbiol. 2018;213:28–34. Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014;20:94–116. ter Wolbeek M, van Doornen LJ, Kavelaars A, van de Putte EM, Schedlowski M, Heijnen CJ. Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain Behav Immun. 2007;21:1063–74. Borish L, Schmaling K, DiClementi JD, Streib J, Negri J, Jones JF. Chronic fatigue syndrome: identification of distinct subgroups on the basis of allergy and psychologic variables. J Allergy Clin Immunol. 1998;102:222–30. Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2012;10:88. Cifaldi L, Pinto RM, Rana I, Caniglia M, Angioni A, Petrocchi S, Cancrini C, Cursi L, Palumbo G, Zingoni A, et al. NK cell effector functions in a Chediak-Higashi patient undergoing cord blood transplantation: effects of in vitro treatment with IL-2. Immunol Lett. 2016;180:46–53. Zhang Q, Zhou XD, Denny T, Ottenweller JE, Lange G, LaManca JJ, Lavietes MH, Pollet C, Gause WC, Natelson BH. Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999;6:6–13. Kuo YH, Tsai WJ, Loke SH, Wu TS, Chiou WF. Astragalus membranaceus flavonoids (AMF) ameliorate chronic fatigue syndrome induced by food intake restriction plus forced swimming. J Ethnopharmacol. 2009;122:28–34. Clark LV, Buckland M, Murphy G, Taylor N, Vleck V, Mein C, Wozniak E, Smuk M, White PD. Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: case–control study. Clin Exp Immunol. 2017;190:360–71. Metzger K, Fremont M, Roelant C, De Meirleir K. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun. 2008;376:231–3. Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas N, Smith FA, O’Gorman MR, Vernon SD, Taylor R. Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue. J Transl Med. 2012;10:191. Zhang HY, Liu ZD, Hu CJ, Wang DX, Zhang YB, Li YZ. Up-regulation of TGF-beta1 mRNA expression in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. J Formos Med Assoc. 2011;110:701–4. Wyller VB, Nguyen CB, Ludviksen JA, Mollnes TE. Transforming growth factor beta (TGF-beta) in adolescent chronic fatigue syndrome. J Transl Med. 2017;15:245. Roerink ME, van der Schaaf ME, Hawinkels L, Raijmakers RPH, Knoop H, Joosten LAB, van der Meer JWM. Pitfalls in cytokine measurements—plasma TGF-beta1 in chronic fatigue syndrome. Neth J Med. 2018;76:310–3. Roerink ME, Bredie SJH, Heijnen M, Dinarello CA, Knoop H, Van der Meer JWM. Cytokine inhibition in patients with chronic fatigue syndrome: a randomized trial. Ann Intern Med. 2017;166:557–64. Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels L, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a case control study and the effect of anakinra treatment. J Transl Med. 2017;15:267. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010;40:1253–67. Thomas M, Smith A. An investigation into the cognitive deficits associated with chronic fatigue syndrome. Open Neurol J. 2009;3:13–23. Wiborg JF, van Bussel J, van Dijk A, Bleijenberg G, Knoop H. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychother Psychosom. 2015;84:368–76. de Lange FP, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Gray matter volume reduction in the chronic fatigue syndrome. Neuroimage. 2005;26:777–81. de Lange FP, Koers A, Kalkman JS, Bleijenberg G, Hagoort P, van der Meer JW, Toni I. Increase in prefrontal cortical volume following cognitive behavioural therapy in patients with chronic fatigue syndrome. Brain. 2008;131:2172–80. Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Progressive brain changes in patients with chronic fatigue syndrome: a longitudinal MRI study. J Magn Reson Imaging. 2016;44:1301–11. Haider L, Simeonidou C, Steinberger G, Hametner S, Grigoriadis N, Deretzi G, Kovacs GG, Kutzelnigg A, Lassmann H, Frischer JM. Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron. J Neurol Neurosurg Psychiatry. 2014;85:1386–95. Dell’Osso L, Bazzichi L, Baroni S, Falaschi V, Conversano C, Carmassi C, Marazziti D. The inflammatory hypothesis of mood spectrum broadened to fibromyalgia and chronic fatigue syndrome. Clin Exp Rheumatol. 2015;33:S109–16. Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an (1)(1)C-(R)-PK11195 PET study. J Nucl Med. 2014;55:945–50. Chan JS, Li A, Ng SM, Ho RT, Xu A, Yao TJ, Wang XM, So KF, Chan CL. Adiponectin potentially contributes to the antidepressive effects of Baduanjin Qigong exercise in women with chronic fatigue syndrome-like illness. Cell Transplant. 2017;26:493–501. Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Med. 2015;13:28. Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan RM, Bowen JM, Sonis ST. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int J Cancer. 2016;139:2635–45. Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D. Chronic fatigue syndrome: an immunological perspective. Aust N Z J Psychiatry. 1998;32:523–7. VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 2013;81:414–23. Morris G, Maes M. A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis. 2013;28:523–40. Lloyd A, Hickie I, Brockman A, Dwyer J, Wakefield D. Cytokine levels in serum and cerebrospinal fluid in patients with chronic fatigue syndrome and control subjects. J Infect Dis. 1991;164:1023–4. Natelson BH, Weaver SA, Tseng CL, Ottenweller JE. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagn Lab Immunol. 2005;12:52–5. Peterson D, Brenu EW, Gottschalk G, Ramos S. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediators Inflamm. 2015;2015:929720. Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016;21:261–9. Hornig M, Gottschalk CG, Eddy ML, Che X, Ukaigwe JE, Peterson DL, Lipkin WI. Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Transl Psychiatry. 2017;7:e1080. Kerr JR, Christian P, Hodgetts A, Langford PR, Devanur LD, Petty R, Burke B, Sinclair LI, Richards SC, Montgomery J, et al. Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis: disease mechanisms, a diagnostic test and specific treatments. J Clin Pathol. 2007;60:113–6. Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA. Chronic fatigue syndrome—a neuroimmunological model. Med Hypotheses. 2011;77:77–83. Maes M, Twisk FN, Ringel K. 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. Psychother Psychosom. 2012;81:286–95.