Metabolic Brain Disease

, Volume 28, Issue 4, pp 523–540 | Cite as

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

Review Article

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.

Keywords

Chronic fatigue syndrome Inflammation Cytokines Depression Tryptophan Oxidative and nitrosative stress Mitochondria Autoimmune 

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

  1. 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):32–46PubMedGoogle Scholar
  2. Ak P, Levine AJ (2010) p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism. FASEB J 24(10):3643–3652PubMedGoogle Scholar
  3. Anderson G, Maes M, Berk M (2012) Biological underpinnings of the commonalities in depression, somatization, and Chronic Fatigue Syndrome. Med Hypotheses 78(6):752–756Google Scholar
  4. Aulak KS, Miyagi M, Yan L et al (2001) Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci USA 98:12056–12061PubMedGoogle Scholar
  5. 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 65:1547–1558PubMedGoogle Scholar
  6. 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 24:1302–1312PubMedGoogle Scholar
  7. 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 10:79–82PubMedGoogle Scholar
  8. 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 180:6457–6461Google Scholar
  9. 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 76:820–827PubMedGoogle Scholar
  10. Benarroch EE (2011) Clinical implications of neuroscience research. Neurology 77:1198–1204PubMedGoogle Scholar
  11. 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 17:160–166PubMedGoogle Scholar
  12. 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 31:1203–1212PubMedGoogle Scholar
  13. 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):804–817PubMedGoogle Scholar
  14. 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 301:9–11PubMedGoogle Scholar
  15. Blatteis CM, Sehic E (1997) Circulating pyrogen signaling of the brain. Ann NY Acad Sci 813:445–447PubMedGoogle Scholar
  16. Bodet D, Glaize G, Dabadie MP, Geffard M (2004) Immunological follow-up for multiple slerosis. Immuno-Analyse & Biol Specialise 19:138–147Google Scholar
  17. 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):341–350PubMedGoogle Scholar
  18. Boullerne A, Petry KG, Geffard M (1996) Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol 65:75–81PubMedGoogle Scholar
  19. Brasier AR (2006) The NF-kappaB regulatory network. Cardiovasc Toxicol 6(2):111–130PubMedGoogle Scholar
  20. 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 24:1209–1217PubMedGoogle Scholar
  21. Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355PubMedGoogle Scholar
  22. 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):372–376PubMedGoogle Scholar
  23. 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 28:1321–1328PubMedGoogle Scholar
  24. 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 17:253–261PubMedGoogle Scholar
  25. Carruthers BM, van de Sande MI, De Meirleir KL et al (2011) Myalgic encephalomyelitis: international consensus criteria. J Intern Med 270:327–338PubMedGoogle Scholar
  26. 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):1678–1683PubMedGoogle Scholar
  27. 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 104:12843–12848PubMedGoogle Scholar
  28. Chai LY, Netea MG, Vonk AG, Kullberg BJ (2009) Fungal strategies for overcoming host innate immune response. Med Mycol 47:227–236PubMedGoogle Scholar
  29. Chao CC, Janoff EN, Hu SX et al (1991) Altered cytokine release in PBMC cultures from patients with the chronic fatigue syndrome. Cytokine 3:292–298PubMedGoogle Scholar
  30. Chaudhuri A, Behan PO (2004) In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins Leukot Essent Fatty Acids 71:181–183PubMedGoogle Scholar
  31. 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 14:225–228Google Scholar
  32. 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 106:3988–3993PubMedGoogle Scholar
  33. Chernyak BV (1997) Redox regulation of the mitochondrial permeability transition pore. Biosci Rep 17(3):293–302PubMedGoogle Scholar
  34. 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 184:2377–2385PubMedGoogle Scholar
  35. 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 105:83–88PubMedGoogle Scholar
  36. 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 276:27296–27303PubMedGoogle Scholar
  37. De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K (2000) Exercise capacity in chronic fatigue syndrome. Arch Intern Med 160:3270–3277PubMedGoogle Scholar
  38. 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 10:52PubMedGoogle Scholar
  39. Del Rey A, Roggero E, Randolf A et al (2006) IL-1 resets glucose homeostasis at central levels. PNAS 103:16039–16044PubMedGoogle Scholar
  40. 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 840:684–697PubMedGoogle Scholar
  41. 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 73:1224–1234PubMedGoogle Scholar
  42. Duke RC (1989) Self recognition by T cells. I. Bystander killing of target cells bearing syngeneic MHC antigens. J Exp Med 170:59–71PubMedGoogle Scholar
  43. 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 55Google Scholar
  44. 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 18:9471–9479PubMedGoogle Scholar
  45. Engler H, Doenlen R, Engler A et al (2011) Acute amygdaloid response to systemic inflammation. Brain Behav Immun 25:1384–1392PubMedGoogle Scholar
  46. 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 17:7166–7179PubMedGoogle Scholar
  47. Ferrari CC, Tarelli R (2011) Parkinson's disease and systemic inflammation. Parkinsons Dis 2011:436813PubMedGoogle Scholar
  48. 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 10:165–169Google Scholar
  49. Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG (2009) Plasma cytokines in women with chronic fatigue syndrome. J Transl Med 7:96PubMedGoogle Scholar
  50. 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):e10817PubMedGoogle Scholar
  51. 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 126:92–101PubMedGoogle Scholar
  52. Fujinami RS, von Herrath MG, Christen U, Whitton JL (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19:80–94PubMedGoogle Scholar
  53. 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 121:953–959PubMedGoogle Scholar
  54. Fulton RJ, McDade RL, Smith PL, Kienker LJ, Kettman JR Jr (1997) Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 43:1749–1756PubMedGoogle Scholar
  55. Fulya I, Mehmet O, Handan A, Vedat B (2006) Cytokine measurements in lymphocyte culture supernatant of inactive lepromatous leprosy patients. Ind J Med Microbiol 24:121–123Google Scholar
  56. 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 513:31–36PubMedGoogle Scholar
  57. Gardner A, Boles RG (2008) Symptoms of solarization as a rapid screening tool for mitochondrial dysfunction in depression. Biopsychosoc Med 22(2):7Google Scholar
  58. Garrabou G, Sanjurjo E, Miró O et al (2006) Noninvasive diagnosis of mitochondrial dysfunction in HAART-related hyperlactatemia. Clin Infect Dis 42:584–585PubMedGoogle Scholar
  59. 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 17:302–310Google Scholar
  60. 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 21:404–412PubMedGoogle Scholar
  61. 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 2Google Scholar
  62. 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 43:357–364PubMedGoogle Scholar
  63. 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 19:334–344PubMedGoogle Scholar
  64. Goya R, Sun MGF, Morin RD et al (2010) SNVMix: predicting single nucleotide variants from next-generation sequencing of tumors. Bioinformatics 26:730–736PubMedGoogle Scholar
  65. Greco A, Tannock C, Brostoff J, Costa DC (1997) Brain MR in Chronic fatigue syndrome. Am J Neuroradiol 18:1265–1269PubMedGoogle Scholar
  66. Griffiths HR, Moller L, Bartosz G et al (2002) Biomarkers. Mol Aspects Med 23:101–208PubMedGoogle Scholar
  67. 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):169–175PubMedGoogle Scholar
  68. Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158PubMedGoogle Scholar
  69. Hahn S, Gehri R, Erb P (1995) Mechanism and biological significance of CD4-mediated cytotoxicity. Immunol Rev 146:57–79PubMedGoogle Scholar
  70. 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):R167PubMedGoogle Scholar
  71. Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford University Press, New YorkGoogle Scholar
  72. 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 97:240–243PubMedGoogle Scholar
  73. 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 77:34–39PubMedGoogle Scholar
  74. 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 400:175–196PubMedGoogle Scholar
  75. Herrod HG (1993) Management of the patient with IgG subclass deficiency and/or selective antibody deficiency. Ann Allergy 70:3–8PubMedGoogle Scholar
  76. Hilgers A, Frank J (1994) Chronic fatigue syndrome. Immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr 144:399–406PubMedGoogle Scholar
  77. Holley AK, St Clair DK (2009) Watching the watcher: regulation of p53 by mitochondria. Future Oncol 5(1):117–130PubMedGoogle Scholar
  78. Ingersoll MA, Platt AM, Potteaux S, Randolph GJ (2011) Monocyte trafficking in acute and chronic inflammation. Trends Immunol 32:470–477PubMedGoogle Scholar
  79. Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74:1–13PubMedGoogle Scholar
  80. 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 257:299–310PubMedGoogle Scholar
  81. 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):7995–8002PubMedGoogle Scholar
  82. Kantengwa S, Jornot L, Devenoges C, Nicod LP (2003) Superoxide anions induce the maturation of human dendritic cells. Am J Respir Crit Care Med 167:431–437PubMedGoogle Scholar
  83. Karchin R (2009) Next generation tools for the annotation of human SNPs. Brief Bioinform 10:35–52PubMedGoogle Scholar
  84. 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): P0182Google Scholar
  85. 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 39:584–589PubMedGoogle Scholar
  86. Kerkeni M, Addad F, Chauffert M et al (2006) Hyperhomocysteinemia, endothelial nitric oxide synthase polymorphism, and risk of coronary artery disease. Clin Chem 52:53–58PubMedGoogle Scholar
  87. Khalaf H, Jass J, Olsson PE (2010) Differential cytokine regulation by NF-kappaB and AP-1 in Jurkat T-cells. BMC Immunol 11:26PubMedGoogle Scholar
  88. 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 195:113–123PubMedGoogle Scholar
  89. Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313PubMedGoogle Scholar
  90. 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 1:21–26PubMedGoogle Scholar
  91. Klimas NG, Salvato FR, Morgan R, Fletcher MA (1990) Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol 28:1403–1410PubMedGoogle Scholar
  92. Komaroff AL, Cho TA (2011) Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol 31:325–337PubMedGoogle Scholar
  93. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517Google Scholar
  94. Kortekaas TR, Leenders KL, van Oostrom JCH et al (2005) Blood-brain barrier dysfunction in Parkinsonian midbrain in vivo. Ann Neurology 57:176–179Google Scholar
  95. Krueger JM, Majade JA (1987) Sleep and the immune response. Ann NY Acad Sci 496:510–516PubMedGoogle Scholar
  96. 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 179:2979–2988PubMedGoogle Scholar
  97. 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 11:203–214PubMedGoogle Scholar
  98. Landay AL, Jessop C, Lennette ET, Levy JA (1991) Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet 338:707–712PubMedGoogle Scholar
  99. 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 64:362–367PubMedGoogle Scholar
  100. 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 171:3–7PubMedGoogle Scholar
  101. Larsson HB, Tofts PS (1992) Measurement of blood-brain barrier permeability using dynamic Gd-DTPA scanning–a comparison of methods. Magn Reson Med 24:174–176PubMedGoogle Scholar
  102. Layser RB (1978) Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 312:1227–1230Google Scholar
  103. 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 144:267–275PubMedGoogle Scholar
  104. 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 36:764–785PubMedGoogle Scholar
  105. 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 26:1065–1071PubMedGoogle Scholar
  106. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795PubMedGoogle Scholar
  107. 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 15:2920–2934PubMedGoogle Scholar
  108. 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 8:2PubMedGoogle Scholar
  109. Maes M (2009) Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, solarization and psychosomatic symptoms. Curr Opin Psychiatry 22:75–83PubMedGoogle Scholar
  110. 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 35:784–794PubMedGoogle Scholar
  111. Maes M (2011b) Nooit meer moe: CVS ontmaskerd. Uitgever: Zorro Uitgeverij. Brugge. ISBN: 9461680015/9789461680013Google Scholar
  112. 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 30:677–693PubMedGoogle Scholar
  113. 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 8:35PubMedGoogle Scholar
  114. 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):487–492PubMedGoogle Scholar
  115. 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 26:745–751PubMedGoogle Scholar
  116. 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 90:141–147PubMedGoogle Scholar
  117. 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 27:615–621PubMedGoogle Scholar
  118. 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 28:456–462PubMedGoogle Scholar
  119. 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 28:463–469PubMedGoogle Scholar
  120. 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 30:462–469PubMedGoogle Scholar
  121. 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 30:715–722PubMedGoogle Scholar
  122. 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 35:769–783PubMedGoogle Scholar
  123. 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
  124. 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 136:933–939PubMedGoogle Scholar
  125. 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 136:909–917PubMedGoogle Scholar
  126. 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 99:907–912PubMedGoogle Scholar
  127. 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 19:374–382Google Scholar
  128. Manuel-y-Keenoy B, Moorkens G, Vertommen J, De Leeuw I (2001) Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome. Life Sci 68:2037–2049PubMedGoogle Scholar
  129. Martín P, Sánchez-Madrid F (2011) CD69: an unexpected regulator of TH17 cell-driven inflammatory responses. Sci Signal 4(165):pe14PubMedGoogle Scholar
  130. 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 22:251–258PubMedGoogle Scholar
  131. Matoba S, Kang JG, Patino WD et al (2006) p53 regulates mitochondrial respiration. Science 312:1650–1653PubMedGoogle Scholar
  132. Meeus M, Mistiaen W, Lambrecht L, Nijs J (2009) Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res 29:4717–4726PubMedGoogle Scholar
  133. 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 107:78–83PubMedGoogle Scholar
  134. 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):477–483PubMedGoogle Scholar
  135. Mohankumar PS, Thyagarajan S, Quadri SK (1991) Interleukin-1 stimulates the release of dopamine and dihydroxyphenylacetic acid from the hypothalamus in vivo. Life Sci 48:925–930PubMedGoogle Scholar
  136. 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 50:359–369PubMedGoogle Scholar
  137. Moss RB, Mercandetti A, Vojdani A (1999) TNF-alpha and chronic fatigue syndrome. J Clin Immunol 9:314–316Google Scholar
  138. 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):e1001311PubMedGoogle Scholar
  139. 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 23:643–650PubMedGoogle Scholar
  140. 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 62:1043–1050PubMedGoogle Scholar
  141. Myhill S, Booth NE, McLaren-Howard J (2009) Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med 2:1–16PubMedGoogle Scholar
  142. 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 24:185–188PubMedGoogle Scholar
  143. 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):582–587PubMedGoogle Scholar
  144. Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE (2007) Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 100:519–526PubMedGoogle Scholar
  145. Nijs J, Meeus M, McGregor NR et al (2005) Chronic fatigue syndrome: exercise performance related to immune dysfunction. Med Sci Sports Exerc 37:1647–1654PubMedGoogle Scholar
  146. 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 40:806–810PubMedGoogle Scholar
  147. Niu G, Wright KL, Ma Y et al (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440PubMedGoogle Scholar
  148. Obal F Jr, Krueger JM (2003) Biochemical regulation of non-rapid-eye-movement sleep. Front Biosci 8:d520–550PubMedGoogle Scholar
  149. 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 28:937–943PubMedGoogle Scholar
  150. Ortega-Hernandez OD, Shoenfeld Y (2009) Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Ann NY Acad Sci 1173:600–609PubMedGoogle Scholar
  151. Paradies G, Ruggiero FM, Petrosillo G, Quagliariello E (1998) Peroxidative damage to cardiac mitochondria: cytochrome oxidase and cardiolipin alterations. FEBS Lett 424:155–158PubMedGoogle Scholar
  152. 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 28:364–372Google Scholar
  153. Perrin R, Embleton K, Pentreath VW, Jackson A (2010) Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. Br J Radiol 83:419–423PubMedGoogle Scholar
  154. Perry VH, Newman TA, Cunningham C (2003) The impact of systemic infection on the progression of neurodegenerative disease. Nat Rev Neurosci 4:103–112PubMedGoogle Scholar
  155. Perry VH, Cunningham C, Holmes C (2007) Systemic infections and inflammation affect chronic neurodegeneration. Nature Reviews Immunol 7:161–167Google Scholar
  156. Perry VH, Nicoll JAR, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201PubMedGoogle Scholar
  157. 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):L551–559PubMedGoogle Scholar
  158. Pincus S (2005) Potential role of infections in chronic inflammatory diseases. ASM News 71:529–535Google Scholar
  159. 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
  160. 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
  161. Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462PubMedGoogle Scholar
  162. Radolf JD (1994) Role of outer membrane architecture in immune evasion by Treponema pallidum and Borrelia burgdorferi. Trends Microbiol 2:307–311PubMedGoogle Scholar
  163. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Ann Rev Immunol 27:119–145Google Scholar
  164. 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 105:17151–17156PubMedGoogle Scholar
  165. Rönnbäck L, Elisabeth Hansson E (2004) On the potential role of glutamate transport in mental fatigue. J Neuroinflamm 1:22Google Scholar
  166. 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 105:14023–14027PubMedGoogle Scholar
  167. 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 283:21134–21144PubMedGoogle Scholar
  168. Saper CB (1995) Central autonomic system. In: Paxinos G (ed) The rat nervous system, 2nd edn. Academic, San Diego, pp 107–135Google Scholar
  169. 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):e17287PubMedGoogle Scholar
  170. 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 162:943–951Google Scholar
  171. Schwid SR, Covington M, Segal BM, Goodman AD (2002) Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev 39:211–224PubMedGoogle Scholar
  172. 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):450–457PubMedGoogle Scholar
  173. 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 13:3574–3581PubMedGoogle Scholar
  174. 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
  175. Simmons WL, Dybvig K (2007) How some mycoplasmas evade host immune responses. Microbe 2:537–543Google Scholar
  176. Simopoulos A (2002) Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 21:495–505PubMedGoogle Scholar
  177. Smyth MJ, Sedgwick JD (1998) Delayed kinetics of tumor necrosis factor-mediated bystander lysis by peptide-specific CD8+ cytotoxic T lymphocytes. Eur J Immunol 28:4162–4169PubMedGoogle Scholar
  178. 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 26:10709–10716PubMedGoogle Scholar
  179. 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):561–566Google Scholar
  180. 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 38:180–190PubMedGoogle Scholar
  181. Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6:318–328PubMedGoogle Scholar
  182. 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 9:3–14Google Scholar
  183. Tirelli U, Marotta G, Improta S, Pinto A (1994) Immunological abnormalities in patients with chronic fatigue syndrome. Scand J Immunol 40:601–608PubMedGoogle Scholar
  184. Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859PubMedGoogle Scholar
  185. Trushina E, McMurray CT (2007) Oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Neuroscience 145:1233–1248PubMedGoogle Scholar
  186. 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 30:284–299PubMedGoogle Scholar
  187. 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 184:138Google Scholar
  188. Van Den Eede F, Moorkens G et al (2007) Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiol 55:112–120Google Scholar
  189. 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 268:265–278PubMedGoogle Scholar
  190. VanNess JM, Stevens SR, Bateman L et al (2010) Postexertional Malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt) 19:239–244Google Scholar
  191. 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 8:93PubMedGoogle Scholar
  192. 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 21:175–202PubMedGoogle Scholar
  193. 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 18:1313–1317PubMedGoogle Scholar
  194. 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
  195. 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 80:11852–11860PubMedGoogle Scholar
  196. Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol 150:963–976PubMedGoogle Scholar
  197. 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 56:179–183PubMedGoogle Scholar
  198. World Health Organization (1992) International statistical classification of diseases and related health problems, Tenth Revision. Volume 1, Geneva, WHO. G93.3Google Scholar
  199. 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):e13820Google Scholar
  200. Yamamoto S, Ouchi Y, Onoe H et al (2004) Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport 15:2571–2574PubMedGoogle Scholar
  201. Zhang L, Gough J, Christmas D et al (2010) Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol 63:156–164PubMedGoogle Scholar
  202. Zhong G (2009) Killing me softly: chlamydial use of proteolysis for evading host defenses. Trends Microbiol 17:467–474PubMedGoogle Scholar
  203. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Ann Rev Immunol 28:445–89Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Tir Na NogLlanelliUK
  2. 2.Maes Clinics @ TRIABangkokThailand
  3. 3.Piyavate HospitalBangkokThailand

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