Skip to main content

Advertisement

SpringerLink
Log in

The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs)

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses. A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies. The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

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

Similar content being viewed by others

References

  1. Morris G, Maes M (2012) A neuro‐immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis. 0885‐7490

  2. World Health Organisation (1992) ICD-10 classifications of mental and behavioural disorder: clinical descriptions and diagnostic guidelines. World Health Organisation, Geneva

    Google Scholar 

  3. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S (2011) Myalgic encephalomyelitis: international consensus criteria. J Intern Med 270:327–338

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Carruthers BM, Kumar Jain A, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI (2003) Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. JCFS 11:7–97

    Google Scholar 

  5. Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2011) Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit 17:SC11–SC15

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Morris G, Maes M (2012) Increased nuclear factor-κB and loss of p53 are key mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses 79:607–613

    CAS  PubMed  Google Scholar 

  7. Seishima M, Mizutani Y, Shibuya Y, Arakawa C (2008) Chronic fatigue syndrome after human parvovirus B19 infection without persistent viremia. Dermatology 216:341–346

    PubMed  Google Scholar 

  8. Chia JK, Chia AY (2008) Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol 61:43–48

    CAS  PubMed  Google Scholar 

  9. Nicolson GL, Nicolson NL, Haier J (2008) Chronic fatigue syndrome patients subsequently diagnosed with Lyme disease Borrelia burgdorferi: evidence for mycoplasma species co-infections. JCFS 14:5–17

    Google Scholar 

  10. Nicolson GL, Gan R, Haier J (2003) Multiple co-infections (Mycoplasma, Chlamydia, human herpesvirus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS 111:557–566

    CAS  PubMed  Google Scholar 

  11. Sleigh KM, Marra FH, Stiver HG (2002) Influenza vaccination: is it appropriate in chronic fatigue syndrome? Am J Respir Med 1:3–9

    PubMed  Google Scholar 

  12. Brenu EW, Staines DR, Baskurt OK, Ashton KJ, Ramos SB, Christy RM, Marshall-Gradisnik SM (2010) Immune and hemorheological changes in chronic fatigue syndrome. J Transl Med 8:1

    PubMed Central  PubMed  Google Scholar 

  13. Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, Klimas NG, Marshall-Gradisnik SM (2011) Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med 9:81

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, Tajouri L, Peterson D, Ramos SB, Marshall-Gradisnik SM (2012) Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med 10:88

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Hassan IS, Bannister BA, Akbar A, Weir W, Bofill M (1998) A study of the immunology of the chronic fatigue syndrome: correlation of immunologic markers to health dysfunction. Clin Immunol Immunopathol 87:60–67

    CAS  PubMed  Google Scholar 

  17. Maes M, Mihaylova I, Leunis JC (2006) 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

    CAS  PubMed  Google Scholar 

  18. Maes M, Mihaylova I, Leunis JC (2007) Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression. Neuro Endocrinol Lett 28:861–867

    PubMed  Google Scholar 

  19. Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed 25(9):1073–1087

    CAS  PubMed Central  PubMed  Google Scholar 

  20. 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

    CAS  PubMed  Google Scholar 

  21. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009) 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 30:470–476

    CAS  PubMed  Google Scholar 

  22. 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 

  23. Maes M, Twisk FNM, Kubera M, Ringel K (2011) Evidence for inflammation and activation of cell-mediated immunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord 136:933–939

    PubMed  Google Scholar 

  24. Maes M, Mihaylova I, Kubera M, Bosmans E (2007) 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

    CAS  PubMed  Google Scholar 

  25. Maes M, Mihaylova I, Bosmans E (2007) 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

    CAS  PubMed  Google Scholar 

  26. Meeus M, Mistiaen W, Lambrecht L, Nijs J (2011) Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res 29:4717–4726

    Google Scholar 

  27. Maes M, Mihaylova I, Kubera M, Leunis JC, Twisk FN, Geffard M (2012) IgM-mediated autoimmune responses directed against anchorage epitopes are greater in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) than in major depression. Metab Brain Dis 27(4):415–423

    CAS  PubMed  Google Scholar 

  28. Maes M, Twisk FN, Johnson C (2012) Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res 200:754–760

    PubMed  Google Scholar 

  29. Lombardi V, Hagen KS, Hunter KW, Diamond JW, Smith-Gagen J, Yang W, Mikovits JA (2011) Xenotropic murine leukemia virus-related virus-associated chronic fatigue syndrome reveals a distinct inflammatory signature. In Vivo 25:307–314

    CAS  PubMed  Google Scholar 

  30. Maes M, Twisk FN, Kubera M, Ringel K, Leunis JC, Geffard M (2012) 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

    CAS  PubMed  Google Scholar 

  31. Maes M, Mihaylova I, Leunis JC (2005) 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

    CAS  PubMed  Google Scholar 

  32. Vermuelen RCW, Kurt 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

    Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Booth NE, Myhill S, McLaren-Howard J (2012) Mitochondrial dysfunction and the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Clin Exp Med 5:208–220

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Wong R, Lopaschuk G, Zhu G, Walker D, Catellier D, Burton D, Teo K, Collins-Nakai R, Montague T (1992) Skeletal muscle metabolism in the chronic fatigue syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest 102:1716–1722

    CAS  PubMed  Google Scholar 

  36. Plioplys AV, Plioplys S (1995) Electron-microscopic Investigation of muscle mitochondria in chronic fatigue syndrome. Neuropsychobiol 32:175–181

    CAS  Google Scholar 

  37. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, McDonald EM, Mowbray JF, Pearson DJ, Peto TEA, Preedy VR, Smith AP, Smith DG, Taylor DJ, Tyrrell AJ, Wessely S, White PD (1991) A report—chronic fatigue syndrome: guidelines for research. JR Soc Med 84:118–121

    CAS  Google Scholar 

  38. Cleare AJ, O’Keane V, Miell J (2001) Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf) 55:113–119

    CAS  Google Scholar 

  39. Lu XY (2007) The leptin hypothesis of depression: a potential link between mood disorders and obesity? Curr Opin Pharmacol 7:648–652

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Pasco JA, Jacka FN, Williams LJ, Henry MJ, Nicholson GC, Kotowicz MA, Berk M (2008) Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study. J Affect Disord 107(1–3):221–225

    CAS  PubMed  Google Scholar 

  41. Nijs J, McGregor NR, De Becker P, Verhas M, Englebienne P, De Meirleir K (2003) Monitoring a hypothetical channelopathy in chronic fatigue syndrome: preliminary observations. JCFS 11:117–133

    Google Scholar 

  42. Nijs J, Coomans D, Nicolson GL, De Becker P, Christian D, De Meirleir K (2003) Immunophenotyping predictive of Mycoplasma infection in patients with chronic fatigue syndrome. JCFS 11:51–69

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. Bradley AS, Ford B, Bansal AS (2013) Altered functional B-cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. 172(1):73–80. doi:10.1111/cei.12043

  45. Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N (2003) Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med 12:225–230

    CAS  PubMed  Google Scholar 

  46. Buchwald MD, Wener MH, Komaroff AL (1991) Antineuronal antibody levels in chronic fatigue syndrome patients with neurologic abnormalities. Arthritis Rheum 34:1485–1486

    CAS  PubMed  Google Scholar 

  47. Plioplys AV (1997) Antimuscle and anti-CNS circulating antibodies in chronic fatigue syndrome. Neurology 48:1717–1719

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  49. Nishikai M (2007) Antinuclear antibodies in patients with chronic fatigue syndrome. Nippon Rinsho 65:1067–1070

    PubMed  Google Scholar 

  50. Maes M (2010) 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

    Google Scholar 

  51. 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

    CAS  PubMed  Google Scholar 

  52. Ljunggren HG, Karre K (1990) In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today 11:237–244

    CAS  PubMed  Google Scholar 

  53. Yokoyama WM, Kim S, French AR (2004) The dynamic life of natural killer cells. Annu Rev Immunol 22:405–429

    CAS  PubMed  Google Scholar 

  54. Lunemann A, Lunemann JD, Munz C (2009) Regulatory NK-cell functions in inflammation and autoimmunity. Mol Med 15:352–358

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Strowig T, Brilot F, Munz C (2008) Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity. J Immunol 180:7785–7791

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Zimmer J, Bausinger H, de la Salle H (2001) Autoimmunity mediated by innate immune effector cells. Trends Immunol 22:300–301

    CAS  PubMed  Google Scholar 

  57. Shi F, Ljunggren HG, Sarvetnick N (2001) Innate immunity and autoimmunity: from self-protection to self-destruction. Trends Immunol 22:97–101

    CAS  PubMed  Google Scholar 

  58. Smeltz RB, Wolf NA, Swanborg RH (1999) Inhibition of autoimmune T cell responses in the DA rat by bone marrow-derived NK cells in vitro: implications for autoimmunity. J Immunol 163:1390–1397

    CAS  PubMed  Google Scholar 

  59. Matsumoto Y, Kohyama K, Aikawa Y, Shin T, Kawazoe Y, Suzuki Y, Tanuma N (1998) Role of natural killer cells and TCRγδ T cells in acute autoimmune encephalomyelitis. Eur J Immunol 28:1681–1688

    CAS  PubMed  Google Scholar 

  60. Shi FD, Takeda K, Akira S, Sarvetnick N, Ljunggren HG (2000) IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-γ by NK cells. J Immunol 165:3099–3104

    CAS  PubMed  Google Scholar 

  61. Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, Van Kaer L, Ljunggren HG (2000) Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol 1:245–251

    CAS  PubMed  Google Scholar 

  62. Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376

    CAS  PubMed  Google Scholar 

  63. Liu R, Van Kaer L, La Cava A, Price M, Campagnolo DI, Collins M, Young DA, Vollmer TL, Shi FD (2006) Autoreactive T cells mediate NK cell degeneration in autoimmune disease. J Immunol 176:5247–5254

    CAS  PubMed  Google Scholar 

  64. Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B, Johnson KA, Witek JS, Senices M, Konz RF, Wurster AL, Donaldson DD, Collins M, Young DA, Grusby MJ (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16:559–569

    CAS  PubMed  Google Scholar 

  65. Vollmer TL, Liu R, Price M, Rhodes S, La Cava A, Shi FD (2005) Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen. J Immunol 174:2696–2701

    CAS  PubMed  Google Scholar 

  66. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA (2003) CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101:3052–3057

    CAS  PubMed  Google Scholar 

  67. Ferlazzo G, Pack M, Thomas D, Paludan C, Schmid D, Strowig T, Bougras G, Muller WA, Moretta L, Munz C (2004) Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci U S A 101:16606–16611

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL (2004) Cross-talk between activated human NK cells and CD4+ T cells via OX40–OX40 ligand interactions. J Immunol 173:3716–3724

    CAS  PubMed  Google Scholar 

  69. Vranes Z, Poljakovic Z, Marusic M (1989) Natural killer cell number and activity in multiple sclerosis. J Neurol Sci 94:115–123

    CAS  PubMed  Google Scholar 

  70. Infante-Duarte C, Weber A, Kratzschmar J, Prozorovski T, Pikol S, Hamann I, Bellmann-Strobl J, Aktas O, Dorr J, Wuerfel J, Sturzebecher CS, Zipp F (2005) Frequency of blood CX3CR1-positive natural killer cells correlates with disease activity in multiple sclerosis patients. FASEB J 19:1902–1904

    CAS  PubMed  Google Scholar 

  71. Schippling DS, Martin R (2008) Spotlight on anti-CD25: daclizumab in MS. Int MS J 15:94–98

    PubMed  Google Scholar 

  72. Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, Waldmann TA, McFarland H, Henkart PA, Martin R (2006) Regulatory CD56z(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 103:5941–5946

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220

    CAS  PubMed  Google Scholar 

  74. Su HC, Nguyen KB, Salazar-Mather TP, Ruzek MC, Dalod MY, Biron CA (2001) NK cell functions restrain T cell responses during viral infections. Eur J Immunol 31:3048–3055

    CAS  PubMed  Google Scholar 

  75. Fujinami RS, Oldstone MB, Wroblewska Z, Frankel ME, Koprowski H (1983) Molecular mimicry in virus infection: crossreaction of measles virus phosphoprotein or of herpes simplex virus protein with human intermediate filaments. Proc Natl Acad Sci U S A 80:2346–2350

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Li Y, Peng T, Yang Y, Niu C, Archard LC, Zhang H (2000) High prevalence of enteroviral genomic sequences in myocardium from cases of endemic cardiomyopathy (Keshan disease) in China. Heart 83:696–701

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Andersen O, Lygner PE, Bergstrom T, Andersson M, Vahlne A (1993) Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol 240:417–422

    CAS  PubMed  Google Scholar 

  79. Edwards S, Zvartau M, Clarke H, Irving W, Blumhardt LD (1998) Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis. J Neurol Neurosurg Psychiatry 64:736–741

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Johnson RT (1998) Chronic inflammatory and demyelinating diseases. In: Viral infections of the nervous system. 2nd Ed. Lippincott-Raven, Philadelphia, pp. 227–263

  81. Wucherpfennig KW, Ota K, Endo N, Seidman JG, Rosenzweig A, Weiner HL, Hafler DA (1990) Shared human T cell receptor Vb usage to immunodominant regions of myelin basic protein. Science 248:1016–1019

    CAS  PubMed  Google Scholar 

  82. McCoy L, Tsunoda I, Fujinami RS (2006) Multiple sclerosis and virus induced immune responses: autoimmunity can be primed by molecular mimicry and augmented by bystander activation. Autoimmunity 39:9–19

    CAS  PubMed  Google Scholar 

  83. Bangs SC, McMichael AJ, Xu XN (2006) Bystander T cell activation—implications for HIV infection and other diseases. Trends Immunol 27:518–524

    CAS  PubMed  Google Scholar 

  84. Bierer BE, Hahn WC (1993) T cell adhesion, avidity regulation and signaling: a molecular analysis of CD2. Semin Immunol 5:249–261

    CAS  PubMed  Google Scholar 

  85. Unutmaz D, Pilri P, Abrignani S (1994) Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med 180:1159–1164

    CAS  PubMed  Google Scholar 

  86. Mathew A, Kurane I, Green S, Vaughn DW, Kalayanarooj S, Suntayakorn S, Ennis FA, Rothman AL (1999) Impaired T cell proliferation in acute dengue infection. J Immunol 162:5609–5615

    CAS  PubMed  Google Scholar 

  87. Zivna I, Green S, Vaughn DW, Kalayanarooj S, Stephens HA, Chandanayingyong D, Nisalak A, Ennis FA, Rothman AL (2002) T cell responses to an HLA-B*07-restricted epitope on the dengue NS3 protein correlate with disease severity. J Immunol 168:5959–5965

    CAS  PubMed  Google Scholar 

  88. Rowland CA, Lertmemongkolchai G, Bancroft A, Haque A, Lever MS, Griffin KF, Jackson MC, Nelson M, O’Garra A, Grencis R, Bancroft GJ, Lukaszewski RA (2006) Critical role of type 1 cytokines in controlling initial infection with Burkholderia mallei. Infect Immun 74:5333–5340

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Douek DC, Picker LJ, Koup RA (2003) T cell dynamics in HIV-1 infection. Annu Rev Immunol 21:265–304

    CAS  PubMed  Google Scholar 

  90. Silvestri G, Feinberg MB (2003) Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest 112:821–824

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Fadok VA, Henson PM (1998) Apoptosis: getting rid of the bodies. Curr Biol 8:R693–R695

    CAS  PubMed  Google Scholar 

  92. Chung EY, Liu J, Homma Y, Zhang Y, Brendolan A, Saggese M, Han J, Silverstein R, Selleri L, Ma X (2007) Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. Immunity 27:952–964

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Cvetanovic M, Ucker DS (2004) Innate immune discrimination of apoptotic cells: repression of proinflammatory macrophage transcription is coupled directly to specific recognition. J Immunol 172:880–889

    CAS  PubMed  Google Scholar 

  94. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, Nagata S (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150

    CAS  PubMed  Google Scholar 

  95. Erwig LP, Henson PM (2007) Immunological consequences of apoptotic cell phagocytosis. Am J Pathol 171:2–8

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140:619–630

    CAS  PubMed  Google Scholar 

  97. Gaipl US, Franz S, Voll RE, Sheriff A, Kalden JR, Herrmann M (2004) Defects in the disposal of dying cells lead to autoimmunity. Curr Rheumatol Rep 6:401–407

    PubMed  Google Scholar 

  98. Arends MJ, Wyllie AH (1991) Apoptosis: mechanisms and roles in pathology. Int. Rev. Exp Pathol 32:223–254

    CAS  Google Scholar 

  99. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH, Peter ME (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 16:2794–2804

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Salvesen GS, Dixit VM (1997) Caspases: intracellular signaling by proteolysis. Cell 91:443–446

    CAS  PubMed  Google Scholar 

  102. Goonetilleke UR, Ward SA, Gordon SB (2009) Could proteomic research deliver the next generation of treatments for pneumococcal meningitis? Interdiscip Perspect Infect Dis 2009:214–216

    Google Scholar 

  103. Thornberry NA, Lazebnik Y (1998) Caspases: enemies within. Science 281:1312–1316

    CAS  PubMed  Google Scholar 

  104. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489

    CAS  PubMed  Google Scholar 

  105. Eguchi Y, Shimizu S, Tsujimoto Y (1997) Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57:1835–1840

    CAS  PubMed  Google Scholar 

  106. Melchior F, Gerace L (1995) Mechanisms of nuclear protein import. Curr Opin Cell Biol 7:310–318

    CAS  PubMed  Google Scholar 

  107. Yasuhara N, Eguchi Y, Tachibana T, Imamoto N, Yoneda Y, Tsujimoto Y (1997) Essential role of active nuclear transport in apoptosis. Genes Cells 2:55–64

    CAS  PubMed  Google Scholar 

  108. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20:1–15

    CAS  PubMed  Google Scholar 

  109. Proskuryakov SY, Konoplyannikov AG, Gabai VL (2003) Necrosis: a specific form of programmed cell death? Exp Cell Res 283:1–16

    CAS  PubMed  Google Scholar 

  110. Xu Y, Huang S, Liu ZG, Han J (2006) Poly(ADP-ribose) polymerase-1 signalling to mitochondria in necrotic cell death requires RIP1/TRAF2-mediated JNK1 activation. J Biol Chem 281:8788–8795

    CAS  PubMed  Google Scholar 

  111. Chen Y (2009) Necrosis: an energy-dependent programmed cell death? UTMJ 86:110–112

    Google Scholar 

  112. Blackwell TS, Christman JW (1997) The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 17:3–9

    CAS  PubMed  Google Scholar 

  113. Zhang G, Ghosh S (2000) Molecular mechanisms of NF-kappaB activation induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res 6:453–457

    CAS  PubMed  Google Scholar 

  114. Siebenlist U, Franzoso G, Brown K (1994) Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 10:405–455

    CAS  PubMed  Google Scholar 

  115. Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505

    CAS  PubMed  Google Scholar 

  116. Jones E, Adcock IM, Ahmed BY, Punchard NA (2007) Modulation of LPS stimulated NF-kappaB mediated nitric oxide production by PKCepsilon and JAK2 in RAW macrophages. J Inflamm (Lond) 4:23

    Google Scholar 

  117. Enzler T, Bonizzi G, Silverman GJ, Otero DC, Widhopf GF, Anzelon-Mills A, Rickert RC, Karin M (2006) Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity 25:403–415

    CAS  PubMed  Google Scholar 

  118. Wu Y, Bressette D, Carrell JA, Kaufman T, Feng P, Taylor K, Gan Y, Cho YH, Garcia AD, Gollatz E, Dimke D, LaFleur D, Migone TS, Nardelli B, Wei P, Ruben SM, Ullrich SJ, Olsen HS, Kanakaraj P, Moore PA, Baker KP (2000) Tumor necrosis factor (TNF) receptor superfamily member TACI is a high affinity receptor for TNF family members APRIL and BLyS. J Biol Chem 275:35478–35485

    CAS  PubMed  Google Scholar 

  119. Rahman ZS, Rao SP, Kalled SL, Manser T (2003) Normal induction but attenuated progression of germinal center responses in BAFF and BAFF-R signaling-deficient mice. J Exp Med 198:1157–1169

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Liu Z, Davidson A (2011) BAFF and selection of autoreactive B cells. Trends Immunol 32:388–394

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Senftleben U, Karin M (2002) The IKK/NF-kappa B pathway. Crit Care Med 30:S18–S26

    CAS  Google Scholar 

  122. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, Johnson R, Karin M (1999) The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189:1839–1845

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Karin M, Lin A (2002) NF-kappaB at the crossroads of life and death. Nat Immunol 3:221–227

    CAS  PubMed  Google Scholar 

  124. Karin M, Delhase M (2000) The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin Immunol 12:85–98

    CAS  PubMed  Google Scholar 

  125. Senftleben U, Cao Y, Xiao G, Greten FR, Krahn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499

    CAS  PubMed  Google Scholar 

  126. Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25:280–288

    CAS  PubMed  Google Scholar 

  127. Luo JL, Kamata H, Karin M (2005) IKK/NF-kappaB signaling: balancing life and death—a new approach to cancer therapy. J Clin Invest 115:2625–2632

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

    CAS  PubMed  Google Scholar 

  129. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    CAS  PubMed  Google Scholar 

  130. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170

    CAS  PubMed  Google Scholar 

  131. Doi TS, Marino MW, Takahashi T, Yoshida T, Sakakura T, Old LJ, Obata Y (1999) Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci U S A 96:2994–2999

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Kucharczak J, Simmons MJ, Fan Y, Gelinas C (2003) To be, or not to be: NF-kappaB is the answer—role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22:8961–8982

    CAS  PubMed  Google Scholar 

  133. Zhang Y, Chen F (2004) Reactive oxygen species (ROS), troublemakers between nuclear factor-kappaB (NF-kappaB) and c-Jun NH(2)-terminal kinase (JNK). Cancer Res 64:1902–1905

    CAS  PubMed  Google Scholar 

  134. Wullaert A, Heyninck K, Beyaert R (2006) Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes. Biochem Pharmacol 72:1090–1101

    CAS  PubMed  Google Scholar 

  135. Sakon S, Xue X, Takekawa M, Sasazuki T, Okazaki T, Kojima Y, Piao JH, Yagita H, Okumura K, Doi T, Nakano H (2003) NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22:3898–3909

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Gonzales-Garcia C, Martin-Saavedra FM, Ballestar A, Ballestar S (2009) The Th17 lineage: answers to some immunological questions. Inmunologia 28:32–45

    Google Scholar 

  137. Waite JC, Skokos D (2012) Th17 response and inflammatory autoimmune diseases. Int J Inflamm 2012:819467

    Google Scholar 

  138. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974

    CAS  PubMed  Google Scholar 

  139. Finckh A, Gabay C (2008) At the horizon of innovative therapy in rheumatology: new biologic agents. Curr Opin Rheumatol 20:269–275

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  141. Kryczek I, Wei S, Vatan L, Escara-Wilke J, Szeliga W, Keller ET, Zou W (2007) Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J Immunol 179:1423–1426

    CAS  PubMed  Google Scholar 

  142. Joosten LAB (2010) Excessive interleukin-1 signaling determines the development of Th1 and Th17 responses in chronic inflammation. Arthr Rheumatism 62:320–322

    CAS  Google Scholar 

  143. Deknuydt F, Bioley G, Valmon D, Ayyoub M (2009) IL-1β and IL-2 convert human Treg into TH17 cells. Clin Immunol 131:298–307

    CAS  PubMed  Google Scholar 

  144. Ziegler SF, Buckner JH (2009) FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect 11:594–598

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13:1173–1175

    CAS  PubMed  Google Scholar 

  146. McColl BW, Rothwell NJ, Allan SM (2008) Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 28:9451–9462

    CAS  PubMed  Google Scholar 

  147. Sharief MK, Ciardi M, Thompson EJ, Sorice F, Rossi F, Vullo V, Cirelli A (1992) Tumour necrosis factor-alpha mediates blood–brain barrier damage in HIV-1 infection of the central nervous system. Mediators Inflamm 1:191–196

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Ma TY, Iwamoto GK, Hoa NT, Akotia V, Pedram A, Boivin MA, Said HM (2004) TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation. Am J Physiol Gastrointest Liver Physiol 286:G367–G376

    CAS  PubMed  Google Scholar 

  149. Al-Sadi RM, Ma TY (2007) IL-1beta causes an increase in intestinal epithelial tight junction permeability. J Immunol 178:4641–4649

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Lakhan SE, Kirchgessner A (2010) Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond) 7:79

    Google Scholar 

  151. Wang H, Sun J, Goldstein H (2008) Human immunodeficiency virus type 1 infection increases the in vivo capacity of peripheral monocytes to cross the blood–brain barrier into the brain and the in vivo sensitivity of the blood–brain barrier to disruption by lipopolysaccharide. J Virol 82:7591–7600

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Xing B, Bachstetter AD, Eldik LJ (2011) Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα. Mol Neurodegener 6:84

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Chauhan VS, Marriott I (2007) Bacterial infections of the central nervous system: a critical role for resident glial cells in the initiation and progression of inflammation. Curr Immunol 3:133–143

    CAS  Google Scholar 

  154. Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Yu RK, Usuki S, Ariga T (2006) Ganglioside molecular mimicry and its pathological roles in Guillain–Barré syndrome and related diseases. Infect Immun 74:6517–6527

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Ang CW, Noordzij PG, de Klerk MA, Endtz HP, van Doorn PA, Laman JD (2002) Ganglioside mimicry of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity in rabbits. Infect Immun 70:5081–5085

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Wang YS, White TD (1999) The bacterial endotoxin lipopolysaccharide causes rapid inappropriate excitation in rat cortex. J Neurochem 72:652–660

    CAS  PubMed  Google Scholar 

  158. Sherbet G (2009) Bacterial infections and the pathogenesis of autoimmune conditions. BJMP 2:6–13

    Google Scholar 

  159. Tufekci KU, Genc S, Genc K (2011) The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinsons Dis 2011:487450

    PubMed Central  PubMed  Google Scholar 

  160. Yacyshyn B, Meddings J, Sadowski D, Bowen-Yacyshyn MB (1996) Multiple sclerosis patients have peripheral blood CD45RO + B cells and increased intestinal permeability. Dig Dis Sci 41:2493–2498

    CAS  PubMed  Google Scholar 

  161. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6:e28032

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Grune T, Michel P, Sitte N, Eggert W, Albrecht-Nebe H, Esterbauer H, Siems WG (1997) Increased levels of 4-hydroxynonenal modified proteins in plasma of children with autoimmune diseases. Free Radic Biol Med 23:357–360

    CAS  PubMed  Google Scholar 

  163. Kurien BT, Scofield RH (2008) Autoimmunity and oxidatively modified autoantigens. Autoimmun Rev 7:567–573

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Khan MF, Wu X, Kaphalia BS, Boor PJ, Ansari GA (1997) Acute hematopoietic toxicity of aniline in rats. Toxicol Lett 92:31–37

    CAS  PubMed  Google Scholar 

  165. Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, Pippen AM, Ruiz P, Wood ER, Gilkeson GS (1994) The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-l-arginine. J Exp Med 179:651–660

    CAS  PubMed  Google Scholar 

  166. Khan F, Siddiqui AA, Ali R (2006) Measurement and significance of 3-nitrotyrosine in systemic lupus erythematosus. Scand J Immunol 64:507–514

    CAS  PubMed  Google Scholar 

  167. Khan F, Ali R (2006) Antibodies against nitric oxide damaged poly l-tyrosine and 3-nitrotyrosine levels in systemic lupus erythematosus. J Biochem Mol Biol 39:189–196

    CAS  PubMed  Google Scholar 

  168. Kurien BT, Hensley K, Bachmann M, Scofield RH (2006) Oxidatively modified autoantigens in autoimmune diseases. Free Radic Biol Med 41:549–556

    CAS  PubMed  Google Scholar 

  169. Christensen B, Refsum H, Garras A, Ueland PM (1992) Homocysteine remethylation during nitrous oxide exposure of cells cultured in media containing various concentrations of folates. J Pharmacol Exp Ther 261:1096–1105

    CAS  PubMed  Google Scholar 

  170. Castro R, Rivera I, Struys EA, Jansen EE, Ravasco P, Camilo ME, Blom HJ, Jakobs C, Tavares de Almeida I (2003) Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 49:1292–1296

    CAS  PubMed  Google Scholar 

  171. Li Y, Liu Y, Strickland FM, Richardson B (2010) Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes. Exp Gerontol 45:312–322

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Zhao M, Tang J, Gao F, Wu X, Liang Y, Yin H, Lu Q (2010) Hypomethylation of IL10 and IL13 promoters in CD4+ T cells of patients with systemic lupus erythematosus. J Biomed Biotechnol 2010:931018

    PubMed Central  PubMed  Google Scholar 

  173. Xu X, Yang P, Shu Z, Bai Y, Wang CY (2012) DNA methylation in the pathogenesis of autoimmunity. In: Gu W, Wang Y (eds) Gene discovery for disease models. Wiley, Hoboken

    Google Scholar 

  174. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60:3613–3622

    CAS  PubMed  Google Scholar 

  175. Kim YI, Logan JW, Mason JB, Roubenoff R (1996) DNA hypomethylation in inflammatory arthritis: reversal with methotrexate. J Lab Clin Med 128:165–172

    CAS  PubMed  Google Scholar 

  176. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 33:1665–1673

    CAS  PubMed  Google Scholar 

  177. Richardson B (1986) Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Hum Immunol 17:456–470

    CAS  PubMed  Google Scholar 

  178. Beltran B, Quintero M, Garcia-Zaragoza E, O’Connor E, Esplugues JV, Moncada S (2002) Inhibition of mitochondrial respiration by endogenous nitric oxide: a critical step in Fas signaling. Proc Natl Acad Sci U S A 99:8892–8897

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Perl A, Telarico T, Singh R, Fernandez D (2010) Activation of the nitric oxide–mitochondrial hyperpolarization–mTOR–Rab4 signaling pathway precedes disease development in lupus T cells. J Immunol 184:93.36

    Google Scholar 

  180. Nagy G, Koncz A, Telarico T, Fernandez D, Ersek B, Buzas E, Perl A (2010) Central role of nitric oxide in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther 12:210

    PubMed Central  PubMed  Google Scholar 

  181. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945

    CAS  PubMed  Google Scholar 

  182. Pierdominici M, Vacirca D, Delunardo F, Ortona E (2011) mTOR signaling and metabolic regulation of T cells: new potential therapeutic targets in autoimmune diseases. Curr Pharm Des 17:3888–3897

    CAS  PubMed  Google Scholar 

  183. Fernandez-Riejos P, Najib S, Santos-Alvarez J, Martin-Romero C, Perez-Perez A, Gonzalez-Yanes C, Sanchez-Margalet V (2010) Role of leptin in the activation of immune cells. Mediators Inflamm 2010:568343

    PubMed Central  PubMed  Google Scholar 

  184. Delgoffe GM, Powell JD (2009) mTOR: taking cues from the immune microenvironment. Immunology 127:459–465

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Yurchenko E, Shio MT, Huang TC, Da Silva Martins M, Szyf M, Levings MK, Oliver M, Piccirillo CA (2012) Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS ONE 7:e35572

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Haxhinasto S, Mathis D, Benoist C (2008) The AKT-mTOR axis regulates de novo differentiation of CD4 + Foxp3+ cells. J Exp Med 205:565–574

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Fernandez D, Perl A (2010) mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov Med 9:173–178

    PubMed Central  PubMed  Google Scholar 

  188. Procaccini C, De Rosa V, Galgani M, Carbone F, Cassano S, Greco D, Qian K, Auvinen P, Calì G, Stallone G, Formisano L, La Cava A, Matarese G (2012) Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses. J Immunol 189:2941–2953

    CAS  PubMed  Google Scholar 

  189. Matarese G, Leiter EH, La Cava A (2007) Leptin in autoimmunity: many questions, some answers. Tissue Antigens 70:87–95

    CAS  PubMed  Google Scholar 

  190. Faggioni R, Feingold KR, Grunfeld C (2001) Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J 15:2565–2571

    CAS  PubMed  Google Scholar 

  191. Bettowski J, Wojcicka G, Jamroz A (2003) Stimulatory effect of leptin on nitric oxide production is impaired in dietary-induced obesity. Obes Res 11:1571–1580

    Google Scholar 

  192. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM (1998) Leptin regulates proinflammatory immune responses. FASEB J 12:57–65

    CAS  PubMed  Google Scholar 

  193. Napoleone E, DI Santo A, Amore C, Baccante G, di Febbo C, Porreca E, de Gaetano G, Donati MB, Lorenzet R (2007) Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk? J Thromb Haemost 5:1462–1468

    CAS  PubMed  Google Scholar 

  194. Martin-Romero C, Santos-Alvarez J, Goberna R, Sanchez-Margalet V (2000) Human leptin enhances activation and proliferation of human circulating T lymphocytes. Cell Immunol 199:15–24

    CAS  PubMed  Google Scholar 

  195. Fernandez-Riejos P, Goberna R, Sanchez-Margalet V (2008) Leptin promotes cell survival and activates Jurkat T lymphocytes by stimulation of mitogen-activated protein kinase. Clin Exp Immunol 151:505–518

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Sanchez-Margalet V, Martin-Romero C, Gonzalez-Yanes C, Goberna R, Rodriguez-Bano J, Muniain MA (2002) Leptin receptor (Ob-R) expression is induced in peripheral blood mononuclear cells by in vitro activation and in vivo in HIV-infected patients. Clin Exp Immunol 129:119–124

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Zarkesh-Esfahani H, Pockley G, Metcalfe RA, Bidlingmaier M, Wu Z, Ajami A, Weetman AP, Strasburger CJ, Ross RJ (2001) High-dose leptin activates human leukocytes via receptor expression on monocytes. J Immunol 167:4593–4599

    CAS  PubMed  Google Scholar 

  198. Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S (2009) Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem Biophys Res Commun 384:311–315

    CAS  PubMed  Google Scholar 

  199. Wong CK, Cheung PF, Lam CW (2007) Leptin-mediated cytokine release and migration of eosinophils: implications for immunopathophysiology of allergic inflammation. Eur J Immunol 37:2337–2348

    CAS  PubMed  Google Scholar 

  200. Mattioli B, Giordani L, Quaranta MG, Viora M (2009) Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K–Akt signaling pathway. FEBS Lett 583:1102–1106

    CAS  PubMed  Google Scholar 

  201. Lund FE (2008) Cytokine-producing B lymphocytes—key regulators of immunity. Curr Opin Immunol 20:332–338

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Pistoia V (1997) Production of cytokines by human B cells in health and disease. Immunol Today 18:343–350

    CAS  PubMed  Google Scholar 

  203. Mizoguchi A, Bhan AK (2006) A case for regulatory B cells. J Immunol 176:705–710

    CAS  PubMed  Google Scholar 

  204. Lund FE, Randall TD (2010) Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol 10:236–247

    CAS  PubMed Central  PubMed  Google Scholar 

  205. de Goer de Herve MG, Durali D, Dembele B, Giuliani M, Tran TA, Azzarone B, Eid P, Tardieu M, Delfraissy JF, Taoufik Y (2011) Interferon-alpha triggers B cell effector 1 (Be1) commitment. PLoS One 6:e19366

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Sanz I, Anolik JH, Looney RJ (2007) B cell depletion therapy in autoimmune diseases. Front Biosci 12:2546–2567

    CAS  PubMed  Google Scholar 

  207. Stasi R (2010) Rituximab in autoimmune hematologic diseases: not just a matter of B cells. Semin Hematol 47:170–179

    CAS  PubMed  Google Scholar 

  208. Harris DP, Goodrich S, Gerth AJ, Peng SL, Lund FE (2005) Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor. J Immunol 174:6781–6790

    CAS  PubMed  Google Scholar 

  209. Harris DP, Goodrich S, Mohrs K, Mohrs M, Lund FE (2005) Cutting edge: the development of IL-4-producing B cells (B effector 2 cells) is controlled by IL-4, IL-4 receptor alpha, and Th2 cells. J Immunol 175:7103–7107

    CAS  PubMed  Google Scholar 

  210. Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM, Johnson LL, Swain SL, Lund FE (2000) Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 1:475–482

    CAS  PubMed  Google Scholar 

  211. Duddy ME, Alter A, Bar-Or A (2004) Distinct profiles of human B cell effector cytokines: a role in immune regulation? J Immunol 172:3422–3427

    CAS  PubMed  Google Scholar 

  212. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C (2010) CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32:129–140

    CAS  PubMed  Google Scholar 

  213. Pers JO, Lemoine S, Morva A, Saraux A, Jamin C, Youinou P (2011) Impaired regulatory capacities of B lymphocytes in systemic lupus erytematosus. Ann Rheum Dis 70:A59

    Google Scholar 

  214. Gros MJ, Naquet P, Guinamard RR (2008) Intrinsic TGF-beta 1 regulation of B cells. J Immunol 180:8153–8158

    CAS  PubMed  Google Scholar 

  215. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF (2008) A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 28:639–650

    CAS  PubMed  Google Scholar 

  216. Mauri C, Ehrenstein MR (2008) The ‘short’ history of regulatory B cells. Trends Immunol 29:34–40

    CAS  PubMed  Google Scholar 

  217. Fluge O, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O (2011) Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS ONE 6:e26358

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Eisenberg R (2005) Update on rituximab. Ann Rheum Dis 64:iv55–iv57

    CAS  PubMed Central  PubMed  Google Scholar 

  219. Gurcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR (2009) A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 9:10–25

    PubMed  Google Scholar 

  220. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581

    CAS  PubMed  Google Scholar 

  221. Tokunaga M, Saito K, Kawabata D, Imura Y, Fujii T, Nakayamada S, Tsujimura S, Nawata M, Iwata S, Azuma T, Mimori T, Tanaka Y (2007) Efficacy of rituximab (anti-CD20) for refractory systemic lupus erythematosus involving the central nervous system. Ann Rheum Dis 66:470–475

    CAS  PubMed Central  PubMed  Google Scholar 

  222. Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roue IQ, Cochener B, Youinou P, Saraux A (2007) Improvement of Sjogren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum 57:310–317

    CAS  PubMed  Google Scholar 

  223. Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180:63–70

    CAS  PubMed Central  PubMed  Google Scholar 

  224. Petereit HF, Moeller-Hartmann W, Reske D, Rubbert A (2008) Rituximab in a patient with multiple sclerosis—effect on B cells, plasma cells and intrathecal IgG synthesis. Acta Neurol Scand 117:399–403

    CAS  PubMed  Google Scholar 

  225. Ireland S, Monson N (2011) Potential impact of B cells on T cell function in multiple sclerosis. Mult Scler Int 2011:423971

    PubMed Central  PubMed  Google Scholar 

  226. Lederer JA, Liou JS, Kim S, Rice N, Lichtman AH (1996) Regulation of NF-kappa B activation in T helper 1 and T helper 2 cells. J Immunol 156:56–63

    CAS  PubMed  Google Scholar 

  227. Jazirehi AR, Huerta-Yepez S, Cheng G, Bonavida B (2005) Rituximab (chimeric anti-CD20 monoclonal antibody) inhibits the constitutive nuclear factor-{kappa}B signaling pathway in non-Hodgkin’s lymphoma B-cell lines: role in sensitization to chemotherapeutic drug-induced apoptosis. Cancer Res 65:264–276

    CAS  PubMed  Google Scholar 

  228. Vigna-Perez M, Hernandez-Castro B, Paredes-Saharopulos O, Portales-Perez D, Baranda L, Abud-Mendoza C, Gonzalez-Amaro R (2006) Clinical and immunological effects of rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study. Arthritis Res Ther 8:R83

    PubMed Central  PubMed  Google Scholar 

  229. McFarland HF (2008) The B cell—old player, new position on the team. N Engl J Med 358:664–665

    CAS  PubMed  Google Scholar 

  230. Bar-Or A, Fawaz L, Fan B, Darlington PJ, Rieger A, Ghorayeb C, Calabresi PA, Waubant E, Hauser SL, Zhang J, Smith CH (2010) Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS? Ann Neurol 67:452–461

    CAS  PubMed  Google Scholar 

  231. Monson NL, Cravens PD, Frohman EM, Hawker K, Racke MK (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62:258–264

    PubMed  Google Scholar 

  232. Geffard M, Duleu S, Bessede A, Vigier V, Bodet D, Mangas A, Covenas R (2012) GEMSP: a new therapeutic approach to multiple sclerosis. Cent Nerv Syst Agents Med Chem 12:173–181

    CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

MB has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, MaynePharma, Servier, and Woolworths; has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, SanofiSynthelabo, Servier, Solvay, and Wyeth; and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck, and Servier. The other authors do not report any conflicts of interest.

Author information

Authors and Affiliations

  1. Mumbles Head, Pembrey, Llanelli, UK

    Gerwyn Morris

  2. Impact Strategic Research Center, School of Medicine, Deakin University, Geelong, Australia

    Michael Berk & Michael Maes

  3. Department of Psychiatry, Orygen Youth Health, Centre for Youth Mental Health and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Melbourne, Australia

    Michael Berk

  4. Department of Adult Psychiatry, Medical University of Łódź, Łódź, Poland

    Piotr Galecki

  5. Babinski Memorial Hospital, Łódź, Poland

    Piotr Galecki

  6. Department of Psychiatry, Chulalongkorn University, Por Bor Ror Building 12, Bangkok, Thailand

    Michael Maes

Authors
  1. Gerwyn Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Berk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Piotr Galecki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. 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., Berk, M., Galecki, P. et al. The Emerging Role of Autoimmunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/cfs). Mol Neurobiol 49, 741–756 (2014). https://doi.org/10.1007/s12035-013-8553-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8553-0

Keywords

Search

Navigation