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IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression

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Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and depression are considered to be neuro-immune disorders (Maes and Twisk, BMC Medicine 8:35, 2010). There is also evidence that depression and ME/CFS are accompanied by oxidative and nitrosative stress (O&NS) and by increased autoantibodies to a number of self-epitopes some of which have become immunogenic due to damage by O&NS. The aim of this study is to examine IgM-mediated autoimmune responses to different self-epitopes in ME/CFS versus depression. We examined serum IgM antibodies to three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine); acetylcholine; and conjugated NO-modified adducts in 26 patients with major depression; 16 patients with ME/CFS, 15 with chronic fatigue; and 17 normal controls. Severity of fatigue and physio-somatic (F&S) symptoms was measured with the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale. Serum IgM antibodies to the three anchorage molecules and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with F&S symptoms. The autoimmune activity directed against conjugated acetylcholine did not differ significantly between ME/CFS and depression, but was greater in the patients than controls. Partially overlapping pathways, i.e. increased IgM antibodies to a multitude of neo-epitopes, underpin both ME/CFS and depression, while greater autoimmune responses directed against anchorage molecules and oxidatively modified neo-epitopes discriminate patients with ME/CFS from those with depression. These autoimmune responses directed against neoantigenic determinants may play a role in the dysregulation of key cellular functions in both disorders, e.g. intracellular signal transduction, cellular differentiation and apoptosis, but their impact may be more important in ME/CFS than in depression.

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References

  • Alonso Fernandez F (2001) Somatoform depressive disorders. An R Acad Nac Med (Madr) 118(4):745–766

    CAS  Google Scholar 

  • Amara A, Chaugier C, Geffard M (1994) Circulating autoantibodies directed against conjugated fatty acids in sera of HIV-1-infected patients. Clin Exp Immunol 96:379–383

    Article  PubMed  CAS  Google Scholar 

  • American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. Text Revision (DSM-IV-TR), Washington

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

    Article  PubMed  Google Scholar 

  • Behan WM, More IA, Behan PO (1991) Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol 83(1):61–65

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Boguski MS, McCormick F (1993) Proteins regulating Ras and its relatives. Nature 366(6456):643–654

    Article  PubMed  CAS  Google Scholar 

  • Boullerne A, Petry KG, Geffard M (1996) Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. J Neuroimmunol 65(1):75–81

    Article  PubMed  CAS  Google Scholar 

  • Burridge S (2011) Myristic acid. Linkage of this saturated fatty acid to a wide variety of proteins has a key role in processes such as protein membrane localization and ceramide biosynthesis. Lipid Maps—Nat Lipidomics Gatew. doi:10.1038/lipidmaps.2011.3

  • Cantor F (2010) Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis. Phys Med Rehabil 2(5):399–405

    Google Scholar 

  • Elad G, Paz A, Haklai R, Marciano D, Cox A, Kloog Y (1999) Targeting of K-Ras 4B by S-trans, trans-farnesyl thiosalicylic acid. Biochim Biophys Acta 1452(3):228–242

    Article  PubMed  CAS  Google Scholar 

  • Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Int Med 121(12):953–959

    PubMed  CAS  Google Scholar 

  • Galecki P, Kedziora J, Florkowski A, Galecka E (2007) Lipid peroxidation and copper-zinc superoxide dismutase activity in patients treated with fluoxetine during the first episode of depression. Psychiatr Pol 41(5):615–624

    PubMed  Google Scholar 

  • Galecki P, Szemraj J, Bieckiewicz M, Zboralski K, Galecka E (2009) Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol 24:277–286

    Article  PubMed  CAS  Google Scholar 

  • Gardner A, Boles RG (2011) Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry 35(3):730–743

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Geffard M, Bodet D, Dabadie MP, Arnould L (2003) Identification of antibodies in sera of breast cancer patients. Immuno-Analyse Biol Spec 18:248–253

    Article  Google Scholar 

  • Gow JW, Hagan S, Herzyk P, Cannon C, Behan PO, Chaudhuri A (2009) A gene signature for post-infectious chronic fatigue syndrome. BMC Med Gen 2:38

    Article  Google Scholar 

  • Hawk C, Jason LA, Torres-Harding S (2006) Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med 13(3):244–251

    Article  PubMed  Google Scholar 

  • Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K (2009) Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal 23(4):210–212

    Article  PubMed  CAS  Google Scholar 

  • Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S (2005) Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Int Med 257(3):299–310

    Article  CAS  Google Scholar 

  • Janowsky DS, Overstreet DH (1990) Cholinergic dysfunction in depression. Pharmacol Toxicol 66(Suppl 3):100–111

    Article  PubMed  CAS  Google Scholar 

  • Joseph M, Nagaraj R (1997) Is the role of fatty acids only to provide membrane-anchor in fatty acylated proteins? Ind J Biochem Biophys 34(1–2):1–5

    CAS  Google Scholar 

  • Kapadia M, Sakic B (2011) Autoimmune and inflammatory mechanisms of CNS damage. Prog Neurobiol 95(3):301–333

    Article  PubMed  CAS  Google Scholar 

  • 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 Rad Biol Med 39(5):584–589

    Article  PubMed  CAS  Google Scholar 

  • Kerr JR, Petty R, Burke B, Gough J, Fear D, Sinclair LI, Mattey DL, Richards SC, Montgomery J, Baldwin DA, Kellam P, Harrison TJ, Griffin GE, Main J, Enlander D, Nutt DJ, Holgate ST (2008) Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis 197(8):1171–1184

    Article  PubMed  CAS  Google Scholar 

  • Khan F, Kennedy G, Spence VA, Newton DJ, Belch JJ (2004) Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure. Clin Sci (London) 106(2):183–189

    Article  CAS  Google Scholar 

  • Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M (2011) In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry 35(3):744–759

    Article  PubMed  CAS  Google Scholar 

  • Leonard BE (2010) The concept of depression as a dysfunction of the immune system. Curr Immunol Rev 6(3):205–212

    Article  PubMed  CAS  Google Scholar 

  • Lowy DR, Willumsen BM (1993) Function and regulation of ras. Annu Rev Biochem 62:851–891

    Article  PubMed  CAS  Google Scholar 

  • Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 19(1):11–38

    Article  PubMed  CAS  Google Scholar 

  • Maes M (2009) “Functional” or “psychosomatic” symptoms, e.g. a flu-like malaise, aches and pain and fatigue, are major features of major and in particular of melancholic depression. Neuro Endocrinol Lett 30(5):564–573

    PubMed  Google Scholar 

  • Maes M (2011a) An intriguing and hitherto unexplained co-occurrence: depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry 35(3):784–794

    Article  PubMed  CAS  Google Scholar 

  • Maes M (2011b) Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 35(3):664–675

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Maes M, De Vos N, Pioli R, Demedts P, Wauters A, Neels H, Christophe A (2000) Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness. J Affect Disord 58(3):241–246

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, De Ruyter M (2006a) Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord 90(2–3):141–147

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Leunis JC (2006b) Chronic fatigue syndrome is accompanied by an IgM-related immune response directed against neopitopes formed by oxidative or nitrosative damage to lipids and proteins. Neuro Endocrinol Lett 27(5):615–621

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Bosmans E (2007a) 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(4):463–469

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Leunis JC (2007b) 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(6):861–867

    PubMed  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009a) Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett 30(4):470–476

    PubMed  CAS  Google Scholar 

  • Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009b) Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett 30(6):715–722

    PubMed  CAS  Google Scholar 

  • Maes M, Galecki P, Chang YS, Berk M (2011a) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35(3):676–692

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2011b) Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monitor 17(4):SC11–SC15

    CAS  Google Scholar 

  • Maes M, Twisk F, Kubera M, Ringel C (2012) Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increases in interleukin-1, tumor necrosis factor-α, neopterin, lysozyme and PMN-elastase. J Affect Disord 136(3):933–939

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O (2004) Antioxidant enzyme activities and oxidative stress in affective disorders. Int Clin Psychopharmacol 19(2):89–95

    Article  PubMed  Google Scholar 

  • Roy-Byrne P, Afari N, Ashton S, Fischer M, Goldberg J, Buchwald D (2002) Chronic fatigue and anxiety/depression: a twin study. Br J Psychiatry 180:29–34

    Article  PubMed  Google Scholar 

  • Silverman RH (2007) Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J Virol 81(23):12720–12729

    Article  PubMed  CAS  Google Scholar 

  • Skapinakis P, Lewis G, Mavreas V (2003) Unexplained fatigue syndromes in a multinational primary care sample: specificity of definition and prevalence and distinctiveness from depression and generalized anxiety. Am J Psychiatry 160(4):785–787

    Article  PubMed  Google Scholar 

  • Skapinakis P, Lewis G, Mavreas V (2004) Temporal relations between unexplained fatigue and depression: longitudinal data from an international study in primary care. Psychosom Med 66(3):330–335

    Article  PubMed  Google Scholar 

  • Smirnova IV, Pall ML (2003) Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Mol Cell Biochem 248(1–2):93–95

    Article  PubMed  CAS  Google Scholar 

  • Souan ML, Geffard M, Lebrun-Grandie P, Orgogozo JM (1986) Detection of anti-acetylcholine antibodies in myasthenic patients. Neurosci Lett 64(1):23–28

    Article  PubMed  CAS  Google Scholar 

  • Suhadolnik RJ, Reichenbach NL, Hitzges P, Sobol RW, Peterson DL, Henry B, Ablashi DV, Moller WE, Schroder HC, Carter WA et al (1994) Upregulation of the 2-5A synthetase/RNase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis Suppl 1:S96–S104

    Article  Google Scholar 

  • Szewczyk B, Kubera M, Nowak G (2011) The role of zinc in neurodegenerative inflammatory pathways in depression. Prog Neuropsychopharmacol Biol Psychiatry 35(3):693–701

    Article  PubMed  CAS  Google Scholar 

  • Underwood CK, Reid K, May LM, Bartlett PF, Coulson EJ (2008) Palmitoylation of the C-terminal fragment of p75(NTR) regulates death signaling and is required for subsequent cleavage by gamma-secretase. Mol Cell Neurosci 37(2):346–358

    Article  PubMed  CAS  Google Scholar 

  • Vecchiet J, Cipollone F, Falasca K, Mezzetti A, Pizzigallo E, Bucciarelli T, De Laurentis S, Affaitati G, De Cesare D, Giamberardino MA (2003) Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett 335(3):151–154

    Article  PubMed  CAS  Google Scholar 

  • Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A (2006) Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis 31:6–15

    Google Scholar 

  • Yellamma K, Saraswathamma S, Kumari BN (2010) Cholinergic system under aluminium toxicity in rat brain. Toxicol Int 17(2):106–112

    Article  PubMed  CAS  Google Scholar 

  • Zachrisson O, Regland B, Jahreskog M, Kron M, Gottfries CG (2002) A rating scale for fibromyalgia and chronic fatigue syndrome (the FibroFatigue scale). J Psychosom Res 52(6):501–509

    Article  PubMed  Google Scholar 

  • Zameer A, Hoffman SA (2001) Immunoglobulin binding to brain autoimmune mice. J Neurobiol 120:10–18

    CAS  Google Scholar 

  • Zhang C, Baumer A, Mackay IR, Linnane AW, Nagley P (1995) Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome. Hum Mol Genet 4:751–754

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Lee YC, Kim SJ, Choi MS, Tsai PC, Xu Y, Xiao YJ, Zhang P, Heffer A, Mukherjee AB (2006) Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. Hum Mol Genet 15(2):337–346

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Gough J, Christmas D, Mattey DL, Richards SC, Main J, Enlander D, Honeybourne D, Ayres JG, Nutt DJ, Kerr JR (2010) Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis. J Clin Pathol 63(2):156–164

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Maes Clinics @ TRIA, Piyavate Hospital, 998 Rimklongsamsen Road, Bangkok, 10310, Thailand

    Michael Maes

  2. CRC-MH, Antwerp, Belgium

    Ivana Mihaylova

  3. Department of Experimental Endocrinology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Marta Kubera

  4. Laboratoire Ategis, Wavre, Belgium

    Jean-Claude Leunis

  5. Me-de-patienten Foundation, Limmen, the Netherlands

    Frank N. M. Twisk

  6. Association Institute for Research & Development in Human Pathology and Therapy, Talence, France

    Michel Geffard

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  1. Michael Maes
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  2. Ivana Mihaylova
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  3. Marta Kubera
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  4. Jean-Claude Leunis
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  5. Frank N. M. Twisk
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Correspondence to Michael Maes.

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Maes, M., Mihaylova, I., Kubera, M. et al. 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, 415–423 (2012). https://doi.org/10.1007/s11011-012-9316-8

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  • DOI: https://doi.org/10.1007/s11011-012-9316-8

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