Skip to main content

Advertisement

SpringerLink
Log in

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome

  • Review Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ME:

Myalgic Encephalomyelitis

WHO:

World Health Organization

CFS:

Chronic fatigue syndrome

PICs:

Pro-inflammatory cytokines

TNFα:

Tumor necrosis factor

IL-6:

Interleukin-6

NK:

Natural killer

O&NS:

Oxidative and nitrosative stress

NF-κB:

Nuclear factor κB

2-5A:

2′-5′-oligoadenylate

RNaseL:

2-5A-dependent ribonuclease L

PKR:

Protein kinase R

COX-2:

Cyclo-oxygenase 2

IFNγ:

Interferon γ

Th:

T helper

TGF-β1:

Transforming growth factor

Treg:

T regulatory

ATP:

Adenosine triphosphate

LPS:

Lipopolysaccharide

TLR:

Toll-like receptor

BBB:

Blood brain barrier

SPECT:

Single-photon emission computed tomography

PET:

Positron emission tomography

T MRI:

Tesla magnetic-resonance imaging

HPA:

Hypothalamic-pituitary-adrenal

MS:

Multiple sclerosis

IDO:

2,3-dioxygenase

TRYCAT:

Tryptophan catabolite

NMDA:

N-methyl-D-aspartate

NADP:

Nicotinamide adenine dinucleotide phosphate

STAT3:

Signal Transducer and Activator of Transcription 3

Foxp3:

Forkhead box P3

PBMCs:

Peripheral blood mononuclear cells

SNPs:

Single nucleotide polymorphisms

References

  • Afzali B, Lombardi G, Lechler RI, Lord GM (2007) The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 148(1):32–46

    PubMed  CAS  Google Scholar 

  • Ak P, Levine AJ (2010) p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism. FASEB J 24(10):3643–3652

    PubMed  CAS  Google Scholar 

  • Anderson G, Maes M, Berk M (2012) Biological underpinnings of the commonalities in depression, somatization, and Chronic Fatigue Syndrome. Med Hypotheses 78(6):752–756

    Google Scholar 

  • Aulak KS, Miyagi M, Yan L et al (2001) Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci USA 98:12056–12061

    PubMed  CAS  Google Scholar 

  • Bankhead T, Chaconas G (2007) The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens. Mol Microbiol 65:1547–1558

    PubMed  CAS  Google Scholar 

  • Barnden LR, Crouch B, Kwiatek R et al (2011) A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. NMR Biomed 24:1302–1312

    PubMed  Google Scholar 

  • Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y, Shoenfeld Y (2008) Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. Isr Med Assoc J 10:79–82

    PubMed  Google Scholar 

  • Bayley-Bucktrout SL, Caulkins SC, Goings G, Fischer JAA, Dzionek A, Miller SD (2008) Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of dendritic cells in multiple sclerosis. J Immunol 180:6457–6461

    Google Scholar 

  • Behnsen J, Hartmann A, Schmaler J, Gehrke A, Brakhage AA, Zipfel PF (2008) The opportunistic human pathogenic fungus Aspergillus fumigatus evades the host complement system. Infect Immun 76:820–827

    PubMed  CAS  Google Scholar 

  • Benarroch EE (2011) Clinical implications of neuroscience research. Neurology 77:1198–1204

    PubMed  Google Scholar 

  • Bennett AL, Chao CC, Hu S et al (1997) Elevation of bioactive transforming growth factor-beta in serum of patients with chronic fatigue syndrome. J Clin Immunol 17:160–166

    PubMed  CAS  Google Scholar 

  • Berg S, Sappington PL, Guzik LJ, Delude RL, Fink MP (2003) Proinflammatory cytokines increase the rate of glycolysis and adenosine-5′-triphosphate turnover in cultured rat enterocytes. Crit Care Med 31:1203–1212

    PubMed  CAS  Google Scholar 

  • Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35(3):804–817

    PubMed  CAS  Google Scholar 

  • Biswal B, Kunwar P, Natelson BH (2011) Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci 301:9–11

    PubMed  Google Scholar 

  • Blatteis CM, Sehic E (1997) Circulating pyrogen signaling of the brain. Ann NY Acad Sci 813:445–447

    PubMed  CAS  Google Scholar 

  • Bodet D, Glaize G, Dabadie MP, Geffard M (2004) Immunological follow-up for multiple slerosis. Immuno-Analyse & Biol Specialise 19:138–147

    Google Scholar 

  • Bot A, Smith KA, von Herrath M (2004) Molecular and cellular control of T1/T2 immunity at the interface between antimicrobial defense and immune pathology. DNA Cell Biol 23(6):341–350

    PubMed  CAS  Google Scholar 

  • Boullerne A, Petry KG, Geffard M (1996) Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol 65:75–81

    PubMed  CAS  Google Scholar 

  • Brasier AR (2006) The NF-kappaB regulatory network. Cardiovasc Toxicol 6(2):111–130

    PubMed  CAS  Google Scholar 

  • Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA (2010) A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun 24:1209–1217

    PubMed  CAS  Google Scholar 

  • Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355

    PubMed  CAS  Google Scholar 

  • Buchwald D, Wener MH, Pearlman T, Kith P (1997) Markers of inflammation and immune activation in chronic fatigue and chronic fatigue syndrome. J Rheumatol 24(2):372–376

    PubMed  CAS  Google Scholar 

  • Calabrese V, Scapagnini G, Ravagna A et al (2003) Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Neurochem Res 28:1321–1328

    PubMed  CAS  Google Scholar 

  • Cannon JG, Angel JB, Abad LW et al (1997) Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome. J Clin Immunol 17:253–261

    PubMed  CAS  Google Scholar 

  • Carruthers BM, van de Sande MI, De Meirleir KL et al (2011) Myalgic encephalomyelitis: international consensus criteria. J Intern Med 270:327–338

    PubMed  CAS  Google Scholar 

  • Castagna A, Le Grazie C, Accordini A, Giulidori P, Cavalli G, Bottiglieri T, Lazzarin A (1995) Cerebrospinal fluid S-adenosylmethionine (SAMe) and glutathione concentrations in HIV infection: effect of parenteral treatment with SAMe. Neurology 45(9):1678–1683

    PubMed  CAS  Google Scholar 

  • Cavadini G, Petrzilka S, Kohler P et al (2007) TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci U S A 104:12843–12848

    PubMed  CAS  Google Scholar 

  • Chai LY, Netea MG, Vonk AG, Kullberg BJ (2009) Fungal strategies for overcoming host innate immune response. Med Mycol 47:227–236

    PubMed  CAS  Google Scholar 

  • Chao CC, Janoff EN, Hu SX et al (1991) Altered cytokine release in PBMC cultures from patients with the chronic fatigue syndrome. Cytokine 3:292–298

    PubMed  CAS  Google Scholar 

  • Chaudhuri A, Behan PO (2004) In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids 71:181–183

    PubMed  CAS  Google Scholar 

  • Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM (2003) Proton magnetic resonance spectroscopy of basal Ganglia in chronic fatigue syndrome. Brian Imaging Neuro Report 14:225–228

    CAS  Google Scholar 

  • Chaumeil MM, Valette J, Guillermier M (2009) Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating 31P MRS for measuring brain ATP synthesis. Proc Natl Acad Sci U S A 106:3988–3993

    PubMed  CAS  Google Scholar 

  • Chernyak BV (1997) Redox regulation of the mitochondrial permeability transition pore. Biosci Rep 17(3):293–302

    PubMed  CAS  Google Scholar 

  • Csillag A, Boldogh I, Pazmandi K et al (2010) Pollen-induced oxidative stress influences both innate and adaptive immune responses via altering dendritic cell functions. J Immunol 184:2377–2385

    PubMed  CAS  Google Scholar 

  • Culley DJ, Raghavan SV, Waly M et al (2007) Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg 105:83–88

    PubMed  CAS  Google Scholar 

  • Danishpajooh IO, Gudi T, Chen Y, Kharitonov VG, Sharma VS, Boss GR (2001) Nitric oxide inhibits methionine synthase activity in vivo and disrupts carbon flow through the folate pathway. J Biol Chem 276:27296–27303

    PubMed  CAS  Google Scholar 

  • De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K (2000) Exercise capacity in chronic fatigue syndrome. Arch Intern Med 160:3270–3277

    PubMed  Google Scholar 

  • de Jager W, Bourcier K, Rijkers GT, Prakken BJ, Seyfert-Margolis V (2009) Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. BMC Immunol 10:52

    PubMed  Google Scholar 

  • Del Rey A, Roggero E, Randolf A et al (2006) IL-1 resets glucose homeostasis at central levels. PNAS 103:16039–16044

    PubMed  Google Scholar 

  • Demitrack MA, Crofford LJ (1998) Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci 840:684–697

    PubMed  CAS  Google Scholar 

  • Demitrack MA, Dale JK, Straus SE et al (1991) Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 73:1224–1234

    PubMed  CAS  Google Scholar 

  • Duke RC (1989) Self recognition by T cells. I. Bystander killing of target cells bearing syngeneic MHC antigens. J Exp Med 170:59–71

    PubMed  CAS  Google Scholar 

  • Dykens JA, Will Y, Wiseman RW, Jeneson JAL (2008) Noninvasive assessment of mitochondrial function using nuclear magnetic resonance spectroscopy. In: Dykens JA, Will Y (eds) Drug-induced mitochondrial dysfunction. Wiley, Hoboken, Chapter 4. p 55

    Google Scholar 

  • Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1b: role of endogenous prostaglandins. J Neurosci 18:9471–9479

    PubMed  CAS  Google Scholar 

  • Engler H, Doenlen R, Engler A et al (2011) Acute amygdaloid response to systemic inflammation. Brain Behav Immun 25:1384–1392

    PubMed  CAS  Google Scholar 

  • Ericsson A, Arias C, Sawchenko PE (1997) Evidence for an in- tramedullary prostaglandin-dependent mechanism in the activation of stress-related neuroendocrine circuitry by intravenous interleukin-1. J Neurosci 17:7166–7179

    PubMed  CAS  Google Scholar 

  • Ferrari CC, Tarelli R (2011) Parkinson's disease and systemic inflammation. Parkinsons Dis 2011:436813

    PubMed  Google Scholar 

  • Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P (2004) Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler J 10:165–169

    CAS  Google Scholar 

  • Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG (2009) Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 7:96

    PubMed  Google Scholar 

  • Fletcher MA, Zeng XR, Maher K et al (2010) Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One 5(5):e10817

    PubMed  Google Scholar 

  • Fransson ME, Liljenfeldt LSE, Fagius J, Tötterman TH, Loskog ASI (2009) The T-cell pool is anergized in patients with multiple sclerosis in remission. Immunology 126:92–101

    PubMed  CAS  Google Scholar 

  • Fujinami RS, von Herrath MG, Christen U, Whitton JL (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19:80–94

    PubMed  CAS  Google Scholar 

  • Fukuda K, Straus SE, Hickie I, Sharpe M, Dobbins JG, Komaroff AL (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 121:953–959

    PubMed  CAS  Google Scholar 

  • Fulton RJ, McDade RL, Smith PL, Kienker LJ, Kettman JR Jr (1997) Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 43:1749–1756

    PubMed  CAS  Google Scholar 

  • Fulya I, Mehmet O, Handan A, Vedat B (2006) Cytokine measurements in lymphocyte culture supernatant of inactive lepromatous leprosy patients. Ind J Med Microbiol 24:121–123

    CAS  Google Scholar 

  • Gallaher ZR, Ryu V, Herzog T, Ritter RC, Czaja K (2012) Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy. Neurosci Lett 513:31–36

    PubMed  CAS  Google Scholar 

  • Gardner A, Boles RG (2008) Symptoms of solarization as a rapid screening tool for mitochondrial dysfunction in depression. Biopsychosoc Med 22(2):7

    Google Scholar 

  • Garrabou G, Sanjurjo E, Miró O et al (2006) Noninvasive diagnosis of mitochondrial dysfunction in HAART-related hyperlactatemia. Clin Infect Dis 42:584–585

    PubMed  Google Scholar 

  • Geffard M, Bodet D, Martinet Y, Dabadie M-P (2002) Detection of the specific IgM and IgA circulating in sera of multiple sclerosis patients: interest and perspectives. Immuno-Analyse & Biol Spec 17:302–310

    Google Scholar 

  • Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21:404–412

    PubMed  CAS  Google Scholar 

  • Gewurz BE, Vyas JM, Ploegh HL (2007) Herpesvirus evasion of T-cell immunity. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, Cambridge, Chapter 2

    Google Scholar 

  • Goehler LE, Relton JK, Dripps D et al (1997) Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune- to-brain communication. Brain Res Bull 43:357–364

    PubMed  CAS  Google Scholar 

  • Goehler LE, Gaykema RP, Opitz N, Reddaway R, Badr N, Lyte M (2005) Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun 19:334–344

    PubMed  Google Scholar 

  • Goya R, Sun MGF, Morin RD et al (2010) SNVMix: predicting single nucleotide variants from next-generation sequencing of tumors. Bioinformatics 26:730–736

    PubMed  CAS  Google Scholar 

  • Greco A, Tannock C, Brostoff J, Costa DC (1997) Brain MR in Chronic fatigue syndrome. Am J Neuroradiol 18:1265–1269

    PubMed  CAS  Google Scholar 

  • Griffiths HR, Moller L, Bartosz G et al (2002) Biomarkers. Mol Aspects Med 23:101–208

    PubMed  CAS  Google Scholar 

  • Groussard C, Morel I, Chevanne M, Monnier M, Cillard J, Delamarche A (2000) Free radical scavenging and antioxidant effects of lactate ion: an in vitro study. J Appl Physiol 89(1):169–175

    PubMed  CAS  Google Scholar 

  • Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158

    PubMed  CAS  Google Scholar 

  • Hahn S, Gehri R, Erb P (1995) Mechanism and biological significance of CD4-mediated cytotoxicity. Immunol Rev 146:57–79

    PubMed  CAS  Google Scholar 

  • Haldorsen K, Bjelland I, Bolstad AI, Jonsson R, Brun JG (2011) A five-year prospective study of fatigue in primary Sjögren's syndrome. Arthritis Res Ther 13(5):R167

    PubMed  CAS  Google Scholar 

  • Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford University Press, New York

    Google Scholar 

  • Hautecoeur P, Forzy G, Gallois P, Demirbilek V, Feugas O (1997) Variations of IL2, IL6, TNF alpha plasmatic levels in relapsing remitting multiple sclerosis. Acta Neurol Belg 97:240–243

    PubMed  CAS  Google Scholar 

  • Heesen C, Nawrath L, Reich C, Bauer N, Schulz K-H, Gold SM (2006) Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 77:34–39

    PubMed  CAS  Google Scholar 

  • Herkenham M, Lee HY, Baker RA (1998) Temporal and spatial patterns of c-fos mRNA induced by intravenous interleukin-1: a cascade of non-neuronal cellular activation at the blood brain barrier. J Comp Neurol 400:175–196

    PubMed  CAS  Google Scholar 

  • Herrod HG (1993) Management of the patient with IgG subclass deficiency and/or selective antibody deficiency. Ann Allergy 70:3–8

    PubMed  CAS  Google Scholar 

  • Hilgers A, Frank J (1994) Chronic fatigue syndrome. Immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr 144:399–406

    PubMed  CAS  Google Scholar 

  • Holley AK, St Clair DK (2009) Watching the watcher: regulation of p53 by mitochondria. Future Oncol 5(1):117–130

    PubMed  CAS  Google Scholar 

  • Ingersoll MA, Platt AM, Potteaux S, Randolph GJ (2011) Monocyte trafficking in acute and chronic inflammation. Trends Immunol 32:470–477

    PubMed  CAS  Google Scholar 

  • Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74:1–13

    PubMed  CAS  Google Scholar 

  • Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S (2005) Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med 257:299–310

    PubMed  CAS  Google Scholar 

  • Jung DJ, Jin DH, Hong SW, Kim JE, Shin JS, Kim D, Cho BJ, Hwang YI, Kang JS, Lee WJ (2010) Foxp3 expression in p53-dependent DNA damage responses. J Biol Chem 285(11):7995–8002

    PubMed  CAS  Google Scholar 

  • Kantengwa S, Jornot L, Devenoges C, Nicod LP (2003) Superoxide anions induce the maturation of human dendritic cells. Am J Respir Crit Care Med 167:431–437

    PubMed  Google Scholar 

  • Karchin R (2009) Next generation tools for the annotation of human SNPs. Brief Bioinform 10:35–52

    PubMed  CAS  Google Scholar 

  • Kennedy G, Spence V, McLaren M, Hill S, Belch J (2003) Increased plasma isoprostanes and other markers of oxidative stress in chronic fatigue syndrome. J Thromb Haemost 1 (Suppl): P0182

  • Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ (2005) Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med 39:584–589

    PubMed  CAS  Google Scholar 

  • Kerkeni M, Addad F, Chauffert M et al (2006) Hyperhomocysteinemia, endothelial nitric oxide synthase polymorphism, and risk of coronary artery disease. Clin Chem 52:53–58

    PubMed  CAS  Google Scholar 

  • Khalaf H, Jass J, Olsson PE (2010) Differential cytokine regulation by NF-kappaB and AP-1 in Jurkat T-cells. BMC Immunol 11:26

    PubMed  Google Scholar 

  • Kiely A, McClenaghan NH, Flatt PR, Newsholme P (2007) Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic ß-cell line. J Endocrinol 195:113–123

    PubMed  CAS  Google Scholar 

  • Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313

    PubMed  CAS  Google Scholar 

  • Klein R, Berg PA (1995) High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res 1:21–26

    PubMed  CAS  Google Scholar 

  • Klimas NG, Salvato FR, Morgan R, Fletcher MA (1990) Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 28:1403–1410

    PubMed  CAS  Google Scholar 

  • Komaroff AL, Cho TA (2011) Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol 31:325–337

    PubMed  Google Scholar 

  • Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517

    Google Scholar 

  • Kortekaas TR, Leenders KL, van Oostrom JCH et al (2005) Blood-brain barrier dysfunction in Parkinsonian midbrain in vivo. Ann Neurology 57:176–179

    CAS  Google Scholar 

  • Krueger JM, Majade JA (1987) Sleep and the immune response. Ann NY Acad Sci 496:510–516

    PubMed  CAS  Google Scholar 

  • Kunert A, Losse J, Gruszin C et al (2007) Immune evasion of the human pathogen Pseudomonas aeruginosa: elongation factor Tuf is a factor H and plasminogen binding protein. J Immunol 179:2979–2988

    PubMed  CAS  Google Scholar 

  • Lal G, Yin N, Xu J et al (2011) Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function. Am J Transplant 11:203–214

    PubMed  CAS  Google Scholar 

  • Landay AL, Jessop C, Lennette ET, Levy JA (1991) Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 338:707–712

    PubMed  CAS  Google Scholar 

  • Lane RJM, Barrett MC, Woodrow D et al (1998) Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry 64:362–367

    PubMed  CAS  Google Scholar 

  • Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, Natelson BH (1999) Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 171:3–7

    PubMed  CAS  Google Scholar 

  • Larsson HB, Tofts PS (1992) Measurement of blood-brain barrier permeability using dynamic Gd-DTPA scanning–a comparison of methods. Magn Reson Med 24:174–176

    PubMed  CAS  Google Scholar 

  • Layser RB (1978) Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 312:1227–1230

    Google Scholar 

  • Le Grand D, Solsona M, Rosengarten R, Poumarat F (1996) Adaptive surface antigen variation in Mycoplasma bovis to the host immune response. FEMS Microbiol Lett 144:267–275

    PubMed  Google Scholar 

  • Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785

    PubMed  CAS  Google Scholar 

  • Liang H, Xu L, Zhou C, Zhang Y, Xu M, Zhang C (2011) Vagal activities are involved in antigen-specific immune inflammation in the intestine. J Gastroenterol Hepatol 26:1065–1071

    PubMed  CAS  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    PubMed  CAS  Google Scholar 

  • Linthorst AC, Flachskamm C, Müller-Preuss P, Holsboer F, Reul JM (1995) Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci 15:2920–2934

    PubMed  CAS  Google Scholar 

  • Longhini AL, von Glehn F, Brandão CO et al (2011) Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse. J Neuroinflammation 8:2

    PubMed  CAS  Google Scholar 

  • Maes M (2009) Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, solarization and psychosomatic symptoms. Curr Opin Psychiatry 22:75–83

    PubMed  Google Scholar 

  • Maes M (2011a) 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 35:784–794

    PubMed  CAS  Google Scholar 

  • Maes M (2011b) Nooit meer moe: CVS ontmaskerd. Uitgever: Zorro Uitgeverij. Brugge. ISBN: 9461680015/9789461680013

  • Maes M, Twisk FN (2009) Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett 30:677–693

    PubMed  Google Scholar 

  • Maes M, Twisk FN (2010) 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 8:35

    PubMed  Google Scholar 

  • Maes M, Mihaylova I, De Ruyter M (2005a) Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS. Neuro Endocrinol Lett 26(5):487–492

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Leunis JC (2005b) In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett 26:745–751

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, De Ruyter M (2006a) Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord 90:141–147

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Leunis JC (2006b) Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett 27:615–621

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Bosmans E (2007a) Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett 28:456–462

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Bosmans E (2007b) Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuro Endocrinol Lett 28:463–469

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009a) Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett 30:462–469

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009b) Increased 8- hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett 30:715–722

    PubMed  CAS  Google Scholar 

  • Maes M, Ruckoanich P, Chang YS, Mahanonda N, Berk M (2011) Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 35:769–783

    PubMed  CAS  Google Scholar 

  • Maes M, Twisk FNM, Johnson C (2012a) 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. Psychiatr Res Apr 20. doi:10.1016/j.psychres.2012.03.031

  • Maes M, Twisk FN, Kubera M, Ringel K (2012b) Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased interleukin-1, tumor necrosis factor-4a, PMN-elastase, lysozyme and neopterin. J Affect Disord 136:933–939

    PubMed  CAS  Google Scholar 

  • Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M (2012c) Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord 136:909–917

    PubMed  CAS  Google Scholar 

  • Maher CO, Anderson RE, Martin HS, McClelland RL, Meyer FB (2003) Interleukin-1beta and adverse effects on cerebral blood flow during long-term global hypoperfusion. J Neurosurg 99:907–912

    PubMed  CAS  Google Scholar 

  • Manuel-y-Keenoy B, Moorkens G, Vertommen J, Noe M, Neve J, De Leeuw I (2000) Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. J Amer Coll Nutrition 19:374–382

    CAS  Google Scholar 

  • Manuel-y-Keenoy B, Moorkens G, Vertommen J, De Leeuw I (2001) Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci 68:2037–2049

    PubMed  CAS  Google Scholar 

  • Martín P, Sánchez-Madrid F (2011) CD69: an unexpected regulator of TH17 cell-driven inflammatory responses. Sci Signal 4(165):pe14

    PubMed  Google Scholar 

  • Mathew SJ, Mao X, Keegan KA et al (2009) Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed 22:251–258

    PubMed  CAS  Google Scholar 

  • Matoba S, Kang JG, Patino WD et al (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653

    PubMed  CAS  Google Scholar 

  • Meeus M, Mistiaen W, Lambrecht L, Nijs J (2009) Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res 29:4717–4726

    PubMed  Google Scholar 

  • Meulemans A, Gerlo E, Seneca S et al (2007) The aerobic forearm exercise test, a non-invasive tool to screen for mitochondrial disorders. Acta Neurol Belg 107:78–83

    PubMed  Google Scholar 

  • Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M (2007) Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett 28(4):477–483

    PubMed  Google Scholar 

  • Mohankumar PS, Thyagarajan S, Quadri SK (1991) Interleukin-1 stimulates the release of dopamine and dihydroxyphenylacetic acid from the hypothalamus in vivo. Life Sci 48:925–930

    PubMed  CAS  Google Scholar 

  • Morgan D, Oliveira-Emilio HR, Keane D et al (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–369

    PubMed  CAS  Google Scholar 

  • Moss RB, Mercandetti A, Vojdani A (1999) TNF-alpha and chronic fatigue syndrome. J Clin Immunol 9:314–316

    Google Scholar 

  • Mukherjee A, Morosky SA, Delorme-Axford E et al (2011) The Coxsackievirus B 3Cpro protease cleaves MAVS and TRIF to attenuate host Type I interferon and apoptotic Signaling. PLoS Pathog 7(3):e1001311

    PubMed  CAS  Google Scholar 

  • Murrough JW, Mao X, Collins KA et al (2010) Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder. NMR Biomed 23:643–650

    PubMed  CAS  Google Scholar 

  • Mus AM, Cornelissen F, Asmawidjaja PS et al (2010) Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis. Arthritis Rheum 62:1043–1050

    PubMed  CAS  Google Scholar 

  • Myhill S, Booth NE, McLaren-Howard J (2009) Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2:1–16

    PubMed  CAS  Google Scholar 

  • Naess H, Sundal E, Myhr KM, Nyland HI (2010) Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo 24:185–188

    PubMed  Google Scholar 

  • Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, Broderick G, Yamamoto Y, Cherniack NS, Rapoport D, Natelson BH (2010) Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clin Vaccine Immunol 17(4):582–587

    PubMed  CAS  Google Scholar 

  • Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE (2007) Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 100:519–526

    PubMed  CAS  Google Scholar 

  • Nijs J, Meeus M, McGregor NR et al (2005) Chronic fatigue syndrome: exercise performance related to immune dysfunction. Med Sci Sports Exerc 37:1647–1654

    PubMed  CAS  Google Scholar 

  • Nishikai M, Tomomatsu S, Hankins RW et al (2001) Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology 40:806–810

    PubMed  CAS  Google Scholar 

  • Niu G, Wright KL, Ma Y et al (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440

    PubMed  CAS  Google Scholar 

  • Obal F Jr, Krueger JM (2003) Biochemical regulation of non-rapid-eye-movement sleep. Front Biosci 8:d520–550

    PubMed  CAS  Google Scholar 

  • Ogawa M, Nishiura T, Yoshimura M et al (1998) Decreased nitric oxide-mediated natural killer cell activation in chronic fatigue syndrome. Eur J Clin Invest 28:937–943

    PubMed  CAS  Google Scholar 

  • Ortega-Hernandez OD, Shoenfeld Y (2009) Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann NY Acad Sci 1173:600–609

    PubMed  CAS  Google Scholar 

  • Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E (1998) Peroxidative damage to cardiac mitochondria: cytochrome oxidase and cardiolipin alterations. FEBS Lett 424:155–158

    PubMed  CAS  Google Scholar 

  • Patrick NJ, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR (2008) Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imaging 28:364–372

    Google Scholar 

  • Perrin R, Embleton K, Pentreath VW, Jackson A (2010) Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. Br J Radiol 83:419–423

    PubMed  CAS  Google Scholar 

  • Perry VH, Newman TA, Cunningham C (2003) The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 4:103–112

    PubMed  CAS  Google Scholar 

  • Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews Immunol 7:161–167

    CAS  Google Scholar 

  • Perry VH, Nicoll JAR, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201

    PubMed  Google Scholar 

  • Phelps DT, Ferro TJ, Higgins PJ, Shankar R, Parker DM, Johnson A (1995) TNF-alpha induces peroxynitrite-mediated depletion of lung endothelial glutathione via protein kinase C. Am J Physiol 269(4 Pt 1):L551–559

    PubMed  CAS  Google Scholar 

  • Pincus S (2005) Potential role of infections in chronic inflammatory diseases. ASM News 71:529–535

    Google Scholar 

  • Pokryszko-Dragan A, Frydecka I, Kosmaczewska A, Ciszak L, Bilińnska M, Gruszka E, Podemski R, Frydecka D (2012) Stimulated peripheral production of interferon-gamma is related to fatigue and depression in multiple sclerosis. Clin Neurol Neurosurg. doi:10.1016/j.clineuro.2012.02.048

  • Puri BK, Jakeman PM, Agour M et al (2011) Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study. Br J Radiol [Pub. ahead of print] doi:10.1259/bjr/93889091

  • Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462

    PubMed  Google Scholar 

  • Radolf JD (1994) Role of outer membrane architecture in immune evasion by Treponema pallidum and Borrelia burgdorferi. Trends Microbiol 2:307–311

    PubMed  CAS  Google Scholar 

  • Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Ann Rev Immunol 27:119–145

    CAS  Google Scholar 

  • Riazi K, Galic MA, Kuzmiski JB, Ho W, Sharkey KA, Pittman QJ (2008) Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation. Proc Natl Acad Sci USA 105:17151–17156

    PubMed  CAS  Google Scholar 

  • Rönnbäck L, Elisabeth Hansson E (2004) On the potential role of glutamate transport in mental fatigue. J Neuroinflamm 1:22

    Google Scholar 

  • Samanta A, Li B, Song X et al (2008) TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. PNAS 105:14023–14027

    PubMed  CAS  Google Scholar 

  • Samavati L, Lee I, Mathes I, Lottspeich F, Hüttemann M (2008) Tumor necrosis factor alpha inhibits oxidative phosphorylation through tyrosine phosphorylation at subunit I of cytochrome c oxidase. J Biol Chem 283:21134–21144

    PubMed  CAS  Google Scholar 

  • Saper CB (1995) Central autonomic system. In: Paxinos G (ed) The rat nervous system, 2nd edn. Academic, San Diego, pp 107–135

    Google Scholar 

  • Schutzer SE, Angel TE, Liu T et al (2011) Distinct Cerebrospinal fluid proteomes differentiate post-treatment Lyme disease from chronic fatigue syndrome. PLoS One 6(2):e17287

    PubMed  CAS  Google Scholar 

  • Schwartz RB, Komaroff AL, Garada BM et al (1994) SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. Am J Roentgenol 162:943–951

    CAS  Google Scholar 

  • Schwid SR, Covington M, Segal BM, Goodman AD (2002) Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev 39:211–224

    PubMed  Google Scholar 

  • Scott LV, Medbak S, Dinan TG (1998) Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand 97(6):450–457

    PubMed  CAS  Google Scholar 

  • Shintani F, Kanba S, Nakaki T et al (1993) Interleukin-1 beta augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus. J Neurosci 13:3574–3581

    PubMed  CAS  Google Scholar 

  • Shungu DC, Weiduschat N, Murrough JW et al (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. doi:10.1002/nbm.2772

  • Simmons WL, Dybvig K (2007) How some mycoplasmas evade host immune responses. Microbe 2:537–543

    Google Scholar 

  • Simopoulos A (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21:495–505

    PubMed  CAS  Google Scholar 

  • Smyth MJ, Sedgwick JD (1998) Delayed kinetics of tumor necrosis factor-mediated bystander lysis by peptide-specific CD8+ cytotoxic T lymphocytes. Eur J Immunol 28:4162–4169

    PubMed  CAS  Google Scholar 

  • Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW (2006) Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 26:10709–10716

    PubMed  CAS  Google Scholar 

  • Spence VA, Kennedy G, Belch JJ, Hill A, Khan F (2008) Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond) 114(8):561–566

    CAS  Google Scholar 

  • Stephensen CB, Marquis GS, Douglas SD, Wilson CM (2005) Immune activation and oxidative damage in HIV-positive and HIV-negative adolescents. J Acquir Immune Defic Syndr 38:180–190

    PubMed  CAS  Google Scholar 

  • Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6:318–328

    PubMed  CAS  Google Scholar 

  • Strickland PS, Levine PH, Peterson DL, O'Brien K, Fears T (2001) Neuromyasthenia and chronic fatigue syndrome (CFS) in Northern Nevada/California: a ten-year follow-up of an outbreak. J Chron Fatigue Syndr 9:3–14

    CAS  Google Scholar 

  • Tirelli U, Marotta G, Improta S, Pinto A (1994) Immunological abnormalities in patients with chronic fatigue syndrome. Scand J Immunol 40:601–608

    PubMed  CAS  Google Scholar 

  • Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859

    PubMed  CAS  Google Scholar 

  • Trushina E, McMurray CT (2007) Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145:1233–1248

    PubMed  CAS  Google Scholar 

  • Twisk FN, Maes M (2009) A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett 30:284–299

    PubMed  Google Scholar 

  • Valdes-Ferrer S, Rosas-Ballina M, Olofsson P, Chavan S, Tracey K (2010) Vagus nerve stimulation produces an anti-inflammatory monocyte phenotype in blood. J Immunol 184:138

    Google Scholar 

  • Van Den Eede F, Moorkens G et al (2007) Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiol 55:112–120

    Google Scholar 

  • Van Oosterwijck J, Nijs J, Meeus M et al (2010) Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med 268:265–278

    PubMed  Google Scholar 

  • VanNess JM, Stevens SR, Bateman L et al (2010) Postexertional Malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt) 19:239–244

    Google Scholar 

  • Vermeulen RCW, Kurk RM, Visser FC, Sluiter W, Scholte HR (2010) Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med 8:93

    PubMed  Google Scholar 

  • Vojdani A, Lapp CW (1999) Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol 21:175–202

    PubMed  CAS  Google Scholar 

  • Wang HH, Dai YQ, Qiu W et al (2011) Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse. J Clin Neurosci 18:1313–1317

    PubMed  CAS  Google Scholar 

  • Weismann D, Binder CJ (2012) The innate immune response to products of phospholipid peroxidation. Biochim Biophys Acta. doi:10.1016/j.bbamem.2012.01.018

  • Wessels E, Duijsings D, Lanke KHW et al (2006) Effects of picornavirus 3A proteins on protein transport and GBF1-dependent COP-I recruitment. J Virol 80:11852–11860

    PubMed  CAS  Google Scholar 

  • Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol 150:963–976

    PubMed  CAS  Google Scholar 

  • Winkler AS, Blair D, Marsden JT, Peters TJ, Wessely S, Cleare AJ (2004) Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. J Psychosom Res 56:179–183

    PubMed  Google Scholar 

  • World Health Organization (1992) International statistical classification of diseases and related health problems, Tenth Revision. Volume 1, Geneva, WHO. G93.3

  • Xiang Y, Xu G, Weigel-Van Aken KA (2010) Lactic Acid induces aberrant amyloid precursor protein processing by promoting its interaction with endoplasmic reticulum chaperone proteins. PLoS One 3;5(11):e13820

    Google Scholar 

  • Yamamoto S, Ouchi Y, Onoe H et al (2004) Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport 15:2571–2574

    PubMed  CAS  Google Scholar 

  • Zhang L, Gough J, Christmas D et al (2010) Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol 63:156–164

    PubMed  CAS  Google Scholar 

  • Zhong G (2009) Killing me softly: chlamydial use of proteolysis for evading host defenses. Trends Microbiol 17:467–474

    PubMed  CAS  Google Scholar 

  • Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Ann Rev Immunol 28:445–89

    CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Victoria Storey and Jane Clout for secretarial services. There was no specific financial support for this study. The authors declare that they do not have a conflict of interest.

Author information

Authors and Affiliations

  1. Tir Na Nog, Pembrey, Llanelli, UK

    Gerwyn Morris

  2. Maes Clinics @ TRIA, Bangkok, Thailand

    Michael Maes

  3. Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok, 10310, Thailand

    Michael Maes

Authors
  1. Gerwyn Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Maes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morris, G., Maes, M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis 28, 523–540 (2013). https://doi.org/10.1007/s11011-012-9324-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-012-9324-8

Keywords

Search

Navigation