Neuro-immune Model

<p>From: <a href="https://www.researchgate.net/publication/227710342_A_neuro-immune_model_of_Myalgic_EncephalomyelitisChronic_fatigue_syndrome">https://www.researchgate.net/publication/227710342_A_neuro-immune_model_of_Myalgic_EncephalomyelitisChronic_fatigue_syndrome</a></p>

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<div class="nova-l-flex__item"><a class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-silent" href="topic/Chronic-Fatigue-Syndrome"><span class="nova-e-badge nova-e-badge--color-grey nova-e-badge--display-inline nova-e-badge--luminosity-medium nova-e-badge--size-l nova-e-badge--theme-ghost nova-e-badge--radius-full">Chronic Fatigue Syndrome</span></a></div>

<div class="nova-l-flex__item"><a class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-silent" href="topic/Stress"><span class="nova-e-badge nova-e-badge--color-grey nova-e-badge--display-inline nova-e-badge--luminosity-medium nova-e-badge--size-l nova-e-badge--theme-ghost nova-e-badge--radius-full">Stress</span></a></div>

<div class="nova-l-flex__item"><a class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-silent" href="topic/Depression"><span class="nova-e-badge nova-e-badge--color-grey nova-e-badge--display-inline nova-e-badge--luminosity-medium nova-e-badge--size-l nova-e-badge--theme-ghost nova-e-badge--radius-full">Depression</span></a></div>

<div class="nova-l-flex__item"><a class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-silent" href="topic/Major-Depressive-Disorder"><span class="nova-e-badge nova-e-badge--color-grey nova-e-badge--display-inline nova-e-badge--luminosity-medium nova-e-badge--size-l nova-e-badge--theme-ghost nova-e-badge--radius-full">Major Depressive Disorder</span></a></div>

<div class="nova-l-flex__item"><a class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-silent" href="topic/Depressive-Disorder"><span class="nova-e-badge nova-e-badge--color-grey nova-e-badge--display-inline nova-e-badge--luminosity-medium nova-e-badge--size-l nova-e-badge--theme-ghost nova-e-badge--radius-full">Depressive Disorder</span></a></div>

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<h1 class="nova-e-text nova-e-text--size-xxxl nova-e-text--family-sans-serif nova-e-text--spacing-l nova-e-text--color-grey-900 title-font-reduced">A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome</h1>

<div class="publication-meta-text"><strong class="publication-meta-type">Article · Literature Review (PDF Available) </strong><span class="publication-meta-journal">&ensp;<span class="publication-meta-separator">in</span>&ensp;<span class="publication-meta-journal"><a class="text-color-grey ga-journal-name" href="journal/1573-7365_Metabolic_Brain_Disease">Metabolic Brain Disease</a> 28(4)</span></span><span class="publication-meta-date"> · June 2012</span>&ensp;<span class="publication-meta-separator">with</span>&ensp;<span class="publication-meta-stats">157 ReadsDOI</span>

<div class="publication-meta-secondary">: 10.1007/s11011-012-9324-8 · Source: <a class="text-color-gray-lighter" href="deref/http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F22718491" target="_blank" rel="noopener">PubMed</a>

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<div class="nova-e-text nova-e-text--size-m nova-e-text--family-sans-serif nova-e-text--spacing-auto nova-e-text--color-inherit">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.</div>

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<div>Effects of pathogens on the immune system leading to immunoinflammatory<span class="nova-e-expandable-text__diff"> cascades. Different pathogens in ME/CFS may activate the immuno-inflammatory pathways, reactive oxygen and nitrogen species (ROS/RNS), oxidative and nitrosative stress (O&NS) pathways, and nuclear factor κB (NF-κB) through the Toll-like receptor (TLR) complex, and consequently inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2). Consequently, pro…</span> <button class="nova-e-link nova-e-link--color-inherit nova-e-link--theme-decorated" type="button"></button></div>

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<div class="nova-e-text nova-e-text--size-s nova-e-text--family-sans-serif nova-e-text--spacing-none nova-e-text--color-inherit">Available from: <a class="nova-e-link nova-e-link--color-blue nova-e-link--theme-bare js-name name" href="profile/Gerwyn_Morris">Gerwyn Morris</a>, Nov 17, 2017</div>

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<div class="t m0 x1 h2 y1 ff1 fs0 fc0 sc0 ls10 ws0">REVIEW ARTICLEA</div>

<div class="t m0 x0 h3 y2 ff2 fs1 fc0 sc0 ls10 ws1">neuro-immune model of MyalgicEncephalomyelitis/Chronicfatigue</div>

<div class="t m0 x0 h3 y3 ff2 fs1 fc0 sc0 ls10 ws2">syndromeGerwyn</div>

<div class="t m0 x0 h4 y4 ff2 fs2 fc0 sc0 ls10 ws3">Morris <span class="ff3 fs3 ls0">&</span><span class="ws4">Michael MaesReceived</span></div>

<div class="t m0 x0 h5 y5 ff1 fs4 fc0 sc0 ls10 ws5">: 18 April 2012 /Accepted: 7 June 2012 / Published online: 21 June 2012</div>

<div class="t m0 x0 h6 y6 ff4 fs4 fc0 sc0 ls1">#<span class="ff1 ls10 ws6 v1">Springer Science+Business Media, LLC 2012Abstract</span></div>

<div class="t m0 x0 h7 y7 ff2 fs2 fc0 sc0 ls10 ws7"><span class="ff1 ws8">This paper proposes a neuro-immune model forMyalgic</span></div>

<div class="t m0 x0 h7 y8 ff1 fs2 fc0 sc0 ls10 ws9">Encephalomyelitis/Chronic fatigue syndrome (ME/</div>

<div class="t m0 x0 h7 y9 ff1 fs2 fc0 sc0 ls11 wsa">CFS). A wide range of immunological and neurologicalabnormalities</div>

<div class="t m0 x0 h7 ya ff1 fs2 fc0 sc0 ls10 wsb">have been reported in people suffering fromME</div>

<div class="t m0 x0 h7 yb ff1 fs2 fc0 sc0 ls10 wsc">/CFS. They include abnormalities in proinflammatorycytokines</div>

<div class="t m0 x0 h8 yc ff1 fs2 fc0 sc0 ls2 wsd">, raised production of nuclear factor-κB<span class="ls4 wse">, mito-chondrial</span></div>

<div class="t m0 x0 h7 yd ff1 fs2 fc0 sc0 ls10 wsf">dysfunctions, autoimmune responses, autonomicdisturbances</div>

<div class="t m0 x0 h7 ye ff1 fs2 fc0 sc0 ls10 ws10">and brain pathology. Raised levels of oxidativeand</div>

<div class="t m0 x0 h7 yf ff1 fs2 fc0 sc0 ls10 ws11">nitrosative stress (O&NS), together with reduced levelsof</div>

<div class="t m0 x0 h7 y10 ff1 fs2 fc0 sc0 ls10 ws12">antioxidants are indicative of an immuno-inflammatorypathology.</div>

<div class="t m0 x0 h7 y11 ff1 fs2 fc0 sc0 ls5 ws13">A number of different pathogens have beenreported</div>

<div class="t m0 x0 h7 y12 ff1 fs2 fc0 sc0 ls6 ws14">either as triggering or maintaining factors. Ourmodel</div>

<div class="t m0 x0 h7 y13 ff1 fs2 fc0 sc0 ls10 ws15">proposes that initial infection and immune activationcaused</div>

<div class="t m0 x0 h7 y14 ff1 fs2 fc0 sc0 ls10 ws16">by a number of possible pathogens leads to a state ofchronic</div>

<div class="t m0 x0 h7 y15 ff1 fs2 fc0 sc0 ls10 ws17">peripheral immune activation driven by activatedO</div>

<div class="t m0 x0 h7 y16 ff1 fs2 fc0 sc0 ls10 ws18">&NS pathways that lead to progressive damage of selfepitopes</div>

<div class="t m0 x0 h7 y17 ff1 fs2 fc0 sc0 ls10 ws19">even when the initial infection has been cleared.Subsequent</div>

<div class="t m0 x0 h7 y18 ff1 fs2 fc0 sc0 ls12 ws1a">activation of autoreactive<span class="ls4 ws1b"> T cells conspiringwith</span></div>

<div class="t m0 x0 h7 y19 ff1 fs2 fc0 sc0 ls10 ws1c">O&NS pathways cause further damage and provokechronic</div>

<div class="t m0 x0 h7 y1a ff1 fs2 fc0 sc0 ls10 ws1d">activation of immuno-inflammatory pathways. Thesubsequent</div>

<div class="t m0 x0 h7 y1b ff1 fs2 fc0 sc0 ls7 ws1e">upregulation of proinflammatorycompoundsmay</div>

<div class="t m0 x2 h7 y1c ff1 fs2 fc0 sc0 ls10 ws1f">activate microglia via the vagus nerve. Elevated proin-flammatory</div>

<div class="t m0 x2 h7 y1d ff1 fs2 fc0 sc0 ls10 ws20">cytokines together with raised O&NS conspireto</div>

<div class="t m0 x2 h7 y1e ff1 fs2 fc0 sc0 ls8 ws21">produce mitochondrial damage. The subsequent ATPdeficit</div>

<div class="t m0 x2 h7 y1f ff1 fs2 fc0 sc0 ls10 ws22">together with inflammation and O&NS are responsi-ble</div>

<div class="t m0 x2 h7 y20 ff1 fs2 fc0 sc0 ls10 ws23">for the landmark symptoms of ME/CFS, including post-exertional</div>

<div class="t m0 x2 h7 y21 ff1 fs2 fc0 sc0 ls10 ws24">malaise. Raised levels of O&NS subsequentlycause</div>

<div class="t m0 x2 h7 y22 ff1 fs2 fc0 sc0 ls10 ws25">progressive elevation of autoimmune activity facili-tated</div>

<div class="t m0 x2 h7 y23 ff1 fs2 fc0 sc0 ls10 ws26">by molecular mimicry, bystander activation or epitopespreading.</div>

<div class="t m0 x2 h7 y24 ff1 fs2 fc0 sc0 ls10 ws27">These processes provoke central nervous system</div>

<div class="t m0 x2 h7 y25 ff1 fs2 fc0 sc0 ls10 ws28">(CNS) activation in an attempt to restore immune homeo-statsis.</div>

<div class="t m0 x2 h7 y26 ff1 fs2 fc0 sc0 ls10 ws29">This model proposes that the antagonistic activitiesof</div>

<div class="t m0 x2 h7 y27 ff1 fs2 fc0 sc0 ls10 ws2a">the CNS response to peripheral inflammation, O&NS andchronic</div>

<div class="t m0 x2 h7 y28 ff1 fs2 fc0 sc0 ls10 ws16">immune activation are responsible for the remitting-</div>

<div class="t m0 x2 h7 y29 ff1 fs2 fc0 sc0 ls10 ws2b">relapsing nature of ME/CFS. Leads for future research aresuggested</div>

<div class="t m0 x2 h7 y2a ff1 fs2 fc0 sc0 ls10 ws2c">based on this neuro-immune model.Keywords</div>

<div class="t m0 x2 h9 y2b ff2 fs2 fc0 sc0 ls10 ws2d"><span class="ff1 ws2e">Chronic fatigue syndrome <span class="ls9 v2">.Inflammation</span><span class="ws2f"> <span class="v2">.Cytokines</span></span></span></div>

<div class="t m0 x2 ha y2c ff1 fs2 fc0 sc0 ls10 ws30"><span class="lsa v2">.Depression</span><span class="ws31"> <span class="ls9 v2">.Tryptophan</span><span class="ws32"> <span class="lsa v2">.Oxidative</span><span class="ws33"> andnitrosative</span></span></span></div>

<div class="t m0 x2 h9 y2d ff1 fs2 fc0 sc0 ls10 ws34">stress <span class="ls9 v2">.Mitochondria</span><span class="ws35"> <span class="ls9 v2">.AutoimmuneAbbreviationsME</span></span></div>

<div class="t m0 x2 h7 y2f ff1 fs2 fc0 sc0 ls10 ws37">MyalgicEncephalomyelitisWHO</div>

<div class="t m0 x2 h7 y30 ff1 fs2 fc0 sc0 ls10 ws38">World Health OrganizationCFS</div>

<div class="t m0 x2 h7 y31 ff1 fs2 fc0 sc0 ls10 ws39">Chronic fatigue syndromePICs</div>

<div class="t m0 x2 h7 y32 ff1 fs2 fc0 sc0 ls10 ws3a">Pro-inflammatory cytokinesTNFαTumor</div>

<div class="t m0 x2 h8 y33 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws3b"> necrosis factorIL-6</span></div>

<div class="t m0 x2 h7 y34 ff1 fs2 fc0 sc0 ls10 ws3c">Interleukin-6NK</div>

<div class="t m0 x2 h7 y35 ff1 fs2 fc0 sc0 ls10 ws3d">Natural killerO</div>

<div class="t m0 x2 h7 y36 ff1 fs2 fc0 sc0 ls10 ws2c">&NS Oxidative and nitrosative stressNF-κB</div>

<div class="t m0 x2 h8 y37 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws3e"> Nuclear factor </span><span class="ff5">κB2-5A</span></div>

<div class="t m0 x2 h7 y38 ff1 fs2 fc0 sc0 ls10 ws3f">2′-5′-oligoadenylateRNaseL</div>

<div class="t m0 x2 h7 y39 ff1 fs2 fc0 sc0 ls10 ws39">2-5A-dependentribonucleaseLPKR</div>

<div class="t m0 x2 h7 y3a ff1 fs2 fc0 sc0 ls10 ws40">Protein kinase RCOX-2</div>

<div class="t m0 x2 h7 y3b ff1 fs2 fc0 sc0 ls10 ws41">Cyclo-oxygenase2IFNγInterferon</div>

<div class="t m0 x0 h5 y3d ff1 fs4 fc0 sc0 ls10 ws42">MorrisTir</div>

<div class="t m0 x0 h5 y3f ff1 fs4 fc0 sc0 ls10 ws44">Pembrey,</div>

<div class="t m0 x0 h5 y40 ff1 fs4 fc0 sc0 ls10 ws45">Llanelli, UKM.</div>

<div class="t m0 x0 h5 y41 ff1 fs4 fc0 sc0 ls10 ws46">MaesMaes</div>

<div class="t m0 x0 h5 y42 ff1 fs4 fc0 sc0 ls10 ws47">Clinics @ TRIA,</div>

<div class="t m0 x0 h5 y43 ff1 fs4 fc0 sc0 ls10 ws48">Bangkok, ThailandM.</div>

<div class="t m0 x0 h5 y45 ff1 fs4 fc0 sc0 ls10 ws4a">Piyavate Hospital,</div>

<div class="t m0 x0 h5 y46 ff1 fs4 fc0 sc0 ls10 ws4b">998 Rimklongsamsen Road,</div>

<div class="t m0 x0 h5 y47 ff1 fs4 fc0 sc0 ls10 ws4c">Bangkok 10310, Thailande-mail</div>

<div class="t m0 x0 h5 y48 ff1 fs4 fc0 sc0 ls10 ws4d">: dr.michaelmaes@hotmail.comURL</div>

<div class="t m0 x0 h5 y49 ff1 fs4 fc0 sc0 ls10 ws4e">: <span class="fc1 ws44">http://scholar.google.co.th/citations?</span></div>

<div class="t m0 x0 h5 y4a ff1 fs4 fc1 sc0 ls10 ws44">hl0en&user01wzMZ7UAAAAJ&oi0sraMetab</div>

<div class="t m0 x0 h5 y4b ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540DOI</div>

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<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws51">Th T helperTGF-β1</div>

<div class="t m0 x0 h8 y4e ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws52"> Transforming growth factorTreg</span></div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws53">T regulatoryATP</div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws41">AdenosinetriphosphateLPS</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws54">LipopolysaccharideTLR</div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls10 ws55">Toll-like receptorBBB</div>

<div class="t m0 x0 h7 y53 ff1 fs2 fc0 sc0 ls10 ws56">Blood brain barrierSPECT</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls10 ws2c">Single-photon emission computed tomographyPET</div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 ws57">Positron emission tomographyT</div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc0 sc0 ls10 ws58">MRI Tesla magnetic-resonance imagingHPA</div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws59">Hypothalamic-pituitary-adrenalMS</div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws40">Multiple sclerosisIDO</div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10 ws5a">2,3-dioxygenaseTRYCAT</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls10 ws5b">TryptophancataboliteNMDA</div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls10 ws5c">N-methyl-D-aspartateNADP</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10 ws5d">Nicotinamide adenine dinucleotidephosphateSTAT3</div>

<div class="t m0 x0 h7 y5d ff1 fs2 fc0 sc0 ls10 ws3e">Signal Transducer and Activatorof</div>

<div class="t m0 x3 h7 y5e ff1 fs2 fc0 sc0 ls10 ws5e">Transcription 3Foxp3</div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws38">Forkhead box P3PBMCs</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc0 sc0 ls10 ws5f">Peripheral blood mononuclear cellsSNPs</div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 ls10 ws60">Single nucleotide polymorphismsIntroductionMyalgic</div>

<div class="t m0 x0 h7 y63 ff1 fs2 fc0 sc0 ls10 ws3a">Encephalomyelitis (ME) has been described in themedical</div>

<div class="t m0 x0 h7 y64 ff1 fs2 fc0 sc0 ls10 ws61">literature since the <span class="ff6 ls14">‘30s.</span><span class="ws62"> Characteristics of ME arepost-exertional</span></div>

<div class="t m0 x0 h7 y65 ff1 fs2 fc0 sc0 ls10 ws63">malaise, chronic fatigue, autonomic symp-toms</div>

<div class="t m0 x0 h7 y66 ff1 fs2 fc0 sc0 ls10 ws64">, hyperalgesia, malaise, neurocognitive dysfunctions,</div>

<div class="t m0 x0 h7 y67 ff1 fs2 fc0 sc0 ls10 ws65">and a chronic and relapsing-remitting course. The WorldHealth</div>

<div class="t m0 x0 h7 y68 ff1 fs2 fc0 sc0 ls10 ws66">Organization (WHO) acknowledges ME as a diseaseof</div>

<div class="t m0 x0 h7 y69 ff1 fs2 fc0 sc0 ls10 ws67">the nervous system (World Health Organization <span class="fc1 ws36">1992</span>).Much</div>

<div class="t m0 x0 h7 y6a ff1 fs2 fc0 sc0 ls10 ws68">later, in the <span class="ff6 ws36">‘80s</span><span class="ws28"> and <span class="ff6 ls14">‘90s</span><span class="ws69">, the diagnosis of chronicfatigue</span></span></div>

<div class="t m0 x0 h7 y6b ff1 fs2 fc0 sc0 ls10 ws6a">syndrome (CFS) was introduced. The definition ofCFS</div>

<div class="t m0 x0 h7 y6c ff1 fs2 fc0 sc0 ls10 ws6b">is primarily based upon the presence of chronic fatiguelasting</div>

<div class="t m0 x0 h7 y6d ff1 fs2 fc0 sc0 ls10 ws6c">more than 6 months. According to a commonly useddiagnostic</div>

<div class="t m0 x0 h7 y6e ff1 fs2 fc0 sc0 ls10 ws6d">classification of CFS (Fukuda et al. <span class="fc1 ws36">1994</span><span class="ws6e">), chron-ic</span></div>

<div class="t m0 x0 h7 y6f ff1 fs2 fc0 sc0 ls15 ws6f">fatigue must be accompanied by four or more of thefollowing</div>

<div class="t m0 x0 h7 y70 ff1 fs2 fc0 sc0 ls10 ws70">symptoms: substantial impairment in short-termmemory</div>

<div class="t m0 x0 h7 y71 ff1 fs2 fc0 sc0 ls10 ws71">or concentration; sore throat; tender lymph nodes;</div>

<div class="t m0 x0 h7 y72 ff1 fs2 fc0 sc0 ls10 ws72">muscle pain; multi-joint pain without swelling or redness;</div>

<div class="t m0 x0 h7 y73 ff1 fs2 fc0 sc0 ls10 ws73">headache of a new type, pattern or severity; unrefreshingsleep</div>

<div class="t m0 x0 h7 y74 ff1 fs2 fc0 sc0 ls10 ws74">; and post-exertional malaise lasting more than 24 h.ME</div>

<div class="t m0 x0 h7 y75 ff1 fs2 fc0 sc0 ls16 ws75">and CFS are therefore different diagnostic concepts</div>

<div class="t m0 x0 h7 y76 ff1 fs2 fc0 sc0 ls10 ws3e">(Maes et al. <span class="fc1 ws36">2012a</span><span class="ws76">; Twisk and Maes <span class="fc1 ws36">2009</span>).In</span></div>

<div class="t m0 x4 h7 y77 ff1 fs2 fc0 sc0 ls10 ws39">an attempt to define a more homogenous patient pop-ulation</div>

<div class="t m0 x0 h7 y78 ff1 fs2 fc0 sc0 ls10 ws77">, a panel of ME/CFS experts has published consensuscriteria</div>

<div class="t m0 x0 h7 y79 ff1 fs2 fc0 sc0 ls10 ws61">for ME (Carruthers et al. <span class="fc1 ws36">2011</span><span class="ws78">). Using multivariatestatistical</span></div>

<div class="t m0 x0 h7 y7a ff1 fs2 fc0 sc0 ls17 ws79">analyses, Maesetal. (<span class="fc1 ls18 ws7a">2012a</span><span class="ls11 ws7b">) showed that thediagnosis</span></div>

<div class="t m0 x0 h7 y7b ff1 fs2 fc0 sc0 ls10 ws3a">of CFS according to Fukuda’s<span class="ws39"> criteria (Fukuda etal.</span></div>

<div class="t m0 x0 h7 y7c ff1 fs2 fc0 sc0 ls10 ws3e"><span class="fc1 ws36">1994</span><span class="ws7c">) defines a heterogeneous population of individualswith</span></div>

<div class="t m0 x0 h7 y7d ff1 fs2 fc0 sc0 ls10 ws7d">chronic fatigue, of whom individuals with ME are asubset</div>

<div class="t m0 x2 h7 y7e ff1 fs2 fc0 sc0 ls10 ws7e">(Maes et al. <span class="fc1 ws36">2012a</span><span class="ws7f">). Moreover, the data show thatpost-exertional</span></div>

<div class="t m0 x2 h7 y7f ff1 fs2 fc0 sc0 ls19 ws80">malaise is a key component of ME anddifferentiates</div>

<div class="t m0 x2 h7 y80 ff1 fs2 fc0 sc0 ls10 ws81">ME from CFS (Maes et al. <span class="fc1 ws36">2012a</span><span class="ws78">). Thus, thediagnosis</span></div>

<div class="t m0 x2 h7 y81 ff1 fs2 fc0 sc0 ls10 ws82">of ME, CFS and ME/CFS refer to different con-cepts</div>

<div class="t m0 x2 h7 y82 ff1 fs2 fc0 sc0 ls10 ws83">, ranging from chronic fatigue together with physio-</div>

<div class="t m0 x2 h7 y83 ff1 fs2 fc0 sc0 ls1a ws84">somatic symptoms (Fukuda et al. <span class="fc1 ls21 ws85">1994</span><span class="ls22 ws86">), to a symptomcomplex</span></div>

<div class="t m0 x2 h7 y84 ff1 fs2 fc0 sc0 ls10 ws87">where post-exertional malaise is a key factor (Maeset</div>

<div class="t m0 x2 h7 y85 ff1 fs2 fc0 sc0 ls10 ws88">al.<span class="fc1 ws36">2012a</span><span class="ws89">). Patients with ME display the unique charac-teristic</span></div>

<div class="t m0 x2 h7 y86 ff1 fs2 fc0 sc0 ls10 ws8a">of producing a range of objectively measurable ab-</div>

<div class="t m0 x2 h7 y87 ff1 fs2 fc0 sc0 ls15 ws8b">normal physiological responses to exercise and a globalworsening</div>

<div class="t m0 x2 h7 y88 ff1 fs2 fc0 sc0 ls10 ws8c">of symptoms following even trivial increases incognitive</div>

<div class="t m0 x2 h7 y89 ff1 fs2 fc0 sc0 ls10 ws9">or physical activity (De Becker et al. <span class="fc1 ws36">2000</span><span class="ls23 ws8d">;Nijsetal.</span></div>

<div class="t m0 x2 h7 y8a ff1 fs2 fc0 sc0 ls10 ws8e"><span class="fc1 ws36">2005</span><span class="ws8f">; Lane et al. <span class="fc1 ws36">1998</span><span class="ws90">). Obviously these differences indiagnostic</span></span></div>

<div class="t m0 x2 h7 y8b ff1 fs2 fc0 sc0 ls1b ws91">classifications and criteria have blurred theresults</div>

<div class="t m0 x2 h7 y8c ff1 fs2 fc0 sc0 ls10 ws69">of scientific research. In this paper we will use theterm</div>

<div class="t m0 x2 h7 y8d ff1 fs2 fc0 sc0 ls1c ws92">ME/CFS, since most research until now has beenperformed</div>

<div class="t m0 x2 h7 y8e ff1 fs2 fc0 sc0 ls10 ws31">on ME/CFS and not on ME as defined recently</div>

<div class="t m0 x2 h7 y8f ff1 fs2 fc0 sc0 ls10 ws3e">(Maes et al. <span class="fc1 ws36">2012a</span><span class="ws93">; Carruthers et al. <span class="fc1 ws36">2011</span>).Recently</span></div>

<div class="t m0 x5 h7 y90 ff1 fs2 fc0 sc0 ls10 ws94">an explanatory model has been developed insupport</div>

<div class="t m0 x2 h7 y91 ff1 fs2 fc0 sc0 ls10 ws95">of the WHO<span class="ff6 ws36">’</span><span class="ws96 v0">s classification that considers ME to bea</span></div>

<div class="t m0 x2 h7 y92 ff1 fs2 fc0 sc0 ls1d ws97">neuro-immune disorder (Maes<span class="fc1 ls1e ws98">2009<span class="fc0 ws99">; Maes and Twisk2010</span></span></div>

<div class="t m0 x2 h7 y93 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws9a">; Maes et al. </span>2012b<span class="fc0 ws9b">). This model provides considerableevidence</span></div>

<div class="t m0 x2 h7 y94 ff1 fs2 fc0 sc0 ls10 ws9c">that the pathophysiology of ME/CFS is associatedwith</div>

<div class="t m0 x2 h7 y95 ff1 fs2 fc0 sc0 ls10 ws9d">immuno-inflammatory pathways, which lead to neuro-logical</div>

<div class="t m0 x2 h7 y96 ff1 fs2 fc0 sc0 ls1f ws9e">aberrations, includi<span class="ls20 ws9f">ng behavioral responses, andneuro-endocrine</span></div>

<div class="t m0 x2 h7 y97 ff1 fs2 fc0 sc0 ls10 wsa0">, autonomic and brain dysfunctions.The</div>

<div class="t m0 x5 h7 y98 ff1 fs2 fc0 sc0 ls24 wsa1">presence of raised levels of the pro-inflammatory cyto-kines</div>

<div class="t m0 x2 h8 y99 ff1 fs2 fc0 sc0 ls25 ws39">(PICs), tumor necrosis factor (TNF)<span class="ff5 ls10 ws36">α</span><span class="ls26 wsa2">, interleukin-6 (IL-6</span></div>

<div class="t m0 x2 h8 y9a ff1 fs2 fc0 sc0 ls27 wsa3">) and IL-1β<span class="ls28 wsa4">, is a consistent finding in patients with ME/CFSwho</span></div>

<div class="t m0 x2 h7 y9b ff1 fs2 fc0 sc0 ls29 wsa5">show signs of a chronically activated and highly disregu-lated</div>

<div class="t m0 x2 h7 y9c ff1 fs2 fc0 sc0 ls2a wsa6">immune system. These inc<span class="ls2b ws69">lude the presence of autoim-mune</span></div>

<div class="t m0 x2 h7 y9d ff1 fs2 fc0 sc0 ls2c wsa7">responses, loss of natural killer (NK) function and raisedlevels</div>

<div class="t m0 x2 h7 y9e ff1 fs2 fc0 sc0 ls2d wsa8">of the anti-inflammatory cytokines.<span class="ls2e wsa9"> Studies investigatingthe</span></div>

<div class="t m0 x2 h7 y9f ff1 fs2 fc0 sc0 ls2f wsaa">pathophysiology of ME/CFS ha<span class="ls30 wsab">ve consistently revealed awide</span></div>

<div class="t m0 x2 h7 ya0 ff1 fs2 fc0 sc0 ls31 wsac">range of aberrations in oxidative and nitrosative stress</div>

<div class="t m0 x2 h7 ya1 ff1 fs2 fc0 sc0 ls27 wsad">(O&NS) pathways and lowered antioxidant defenses. Perhapsunsurprisingly</div>

<div class="t m0 x2 h7 ya2 ff1 fs2 fc0 sc0 ls10 wsae">then evidence of mitochondrial damage hasbeen</div>

<div class="t m0 x2 h7 ya3 ff1 fs2 fc0 sc0 ls32 wsaf">reported in patients with <span class="ls33 wsb0">ME/CFS. Studies have reportedactivation</span></div>

<div class="t m0 x2 h7 ya4 ff1 fs2 fc0 sc0 ls10 wsb1">of intracellular signaling molecules, e.g. nuclearfactor</div>

<div class="t m0 x2 h8 ya5 ff1 fs2 fc0 sc0 ls34 wsb2"><span class="ff5 ls10 ws36">κB</span><span class="ls35 wsb3">(NF-κB<span class="ff5 ls10 ws36"><span class="ff1 ls36 wsb4">) and the 2′-5′-oligoadenylate</span><span class="ff6"><span class="ff1 ls38 wsb6"> (2-5A)/2-5A-dependent</span></span></span></span></div>

<div class="t m0 x2 h7 ya6 ff1 fs2 fc0 sc0 ls26 wsaa">ribonuclease L (RNaseL) and the protein kinase R</div>

<div class="t m0 x2 h7 ya7 ff1 fs2 fc0 sc0 ls39 wsb7">(PKR) pathways. A new immuno-inflammatory pathway inME</div>

<div class="t m0 x2 h7 ya8 ff1 fs2 fc0 sc0 ls2c wsb8">/CFS that may cause neuro-immune dysfunctions and evenneurological</div>

<div class="t m0 x2 h7 ya9 ff1 fs2 fc0 sc0 ls2c wsb9">disease is bacterial translocation.Here</div>

<div class="t m0 x5 h7 yaa ff1 fs2 fc0 sc0 ls3a wsba">we propose a key role for changes in immuno-inflammatory</div>

<div class="t m0 x2 h7 yab ff1 fs2 fc0 sc0 ls10 wsbb">pathways and resultant neuro-inflammation, inconjunction</div>

<div class="t m0 x2 h7 yac ff1 fs2 fc0 sc0 ls10 wsbc">with aberrations in O&NS pathways, in produc-ing</div>

<div class="t m0 x2 h7 yad ff1 fs2 fc0 sc0 ls10 wsbd">the wide range of symptoms reported and abnormalitiesidentified</div>

<div class="t m0 x2 h7 yae ff1 fs2 fc0 sc0 ls10 wsbe">in people with ME/CFS. This paper proposes that aninteraction</div>

<div class="t m0 x2 h7 yaf ff1 fs2 fc0 sc0 ls10 wsbf">between an activated immune system, O&NS, andmitochondrial</div>

<div class="t m0 x2 h7 yb0 ff1 fs2 fc0 sc0 ls10 wsc0">damage, explains the symptoms of ME/CFS.This</div>

<div class="t m0 x2 h7 yb1 ff1 fs2 fc0 sc0 ls10 ws94">is an area of active research and much needs to beconfirmed</div>

<div class="t m0 x2 h7 yb2 ff1 fs2 fc0 sc0 ls10 ws39">by new results. As such there are gaps, which we524</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 wsc1">have filled with established knowledge on immune and neuro-immune</div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 wsc2">mechanisms and directions for future research.Pathophysiological</div>

<div class="t m0 x0 h4 yb4 ff2 fs2 fc0 sc0 ls10 ws7c">findings in ME/CFSImmuno-inflammatory</div>

<div class="t m0 x0 h7 yb5 ff1 fs2 fc0 sc0 ls10 ws3a">pathways in ME/CFSActivation</div>

<div class="t m0 x0 h7 yb6 ff1 fs2 fc0 sc0 ls34 wsc3">of immuno-inflammatory<span class="ls36 wsc4"> pathways is a consistentfindinginME</span></div>

<div class="t m0 x0 h7 yb7 ff1 fs2 fc0 sc0 ls43 wsc5">/CFS(Mossetal.1999<span class="ls44 wsc7">; Cannon et al. <span class="fc1 ls34 wsc6">1997</span><span class="ls37">).Increased</span></span></div>

<div class="t m0 x0 h8 yb8 ff1 fs2 fc0 sc0 ls44 wsc8">levels of PICs, such as IL-1β<span class="ls45 wsc9">,TNFαandIL-6havebeen</span></div>

<div class="t m0 x0 h7 yb9 ff1 fs2 fc0 sc0 ls47 wscb">reported in people with ME/CFS (Maes et al. <span class="fc1 ls10 ws36">2012a<span class="fc0">;</span></span></div>

<div class="t m0 x0 h8 yba ff1 fs2 fc0 sc0 ls48 wsb2">Broderick et al. <span class="fc1 ls34 wsc6">2010</span><span class="ls31 wscc">). The levels of IL-1 and TNFαshow<span class="ls39 wscd"> apositive</span></span></div>

<div class="t m0 x0 h7 ybb ff1 fs2 fc0 sc0 ls27 wsce">significant correlatio<span class="ls2c wscf">n with fatigue, autonomic symp-toms</span></div>

<div class="t m0 x0 h7 ybc ff1 fs2 fc0 sc0 ls49 wsd0">and flu like symptoms (Maes et al. <span class="fc1 ls34 wsc6">2012b</span><span class="ls2c wsd1">). Other markersof</span></div>

<div class="t m0 x0 h7 ybd ff1 fs2 fc0 sc0 ls27 wsb8">inflammation, e.g. lysozyme and polymorph nuclear neutro-phil</div>

<div class="t m0 x0 h7 ybe ff1 fs2 fc0 sc0 ls2b wsd2">elastase, are also elevated (Maesetal.<span class="fc1 ls34 wsc6">2012b</span><span class="ls4a wsd3">). The levelsof</span></div>

<div class="t m0 x0 h7 ybf ff1 fs2 fc0 sc0 ls4b wsd4">the latter correlate significantly and positively with levels ofmemory</div>

<div class="t m0 x0 h7 yc0 ff1 fs2 fc0 sc0 ls25 wsd5">and cognitive impairment and phenomenological ex-perience</div>

<div class="t m0 x0 h7 yc1 ff1 fs2 fc0 sc0 ls25 wsd6">of infection. Increased levels of acute phase reactants,</div>

<div class="t m0 x0 h8 yc2 ff1 fs2 fc0 sc0 ls2f wsd7">e.g. C-reactive protein and the <span class="ff5 ls10 ws36">α2</span><span class="ls4c wsd8"> protein fraction obtainedduring</span></div>

<div class="t m0 x0 h7 yc3 ff1 fs2 fc0 sc0 ls25 wsd9">protein electrophoresis, further underscore the presenceof</div>

<div class="t m0 x0 h7 yc4 ff1 fs2 fc0 sc0 ls25 wsd1">an inflammatory response (Buchwald et al. <span class="fc1 ls34 wsc6">1997</span><span class="ls4d wsda">;Maesetal.2005a</span></div>

<div class="t m0 x0 h7 yc5 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ls4e wsdb">;Spenceetal.2008<span class="fc1 ls10 ws36"><span class="fc0 wsdc">). Also the production of cyclo-oxygenase</span></span></span></div>

<div class="t m0 x0 h7 y62 ff1 fs2 fc0 sc0 ls25 wsdd">2 (COX-2) is significantly elevated in patients suf-fering</div>

<div class="t m0 x0 h7 yc6 ff1 fs2 fc0 sc0 ls4c ws5b">from ME/CFS (Maes et al. <span class="fc1 ls34 wsc6">2007b</span><span class="ls2e wsde">). The elevated levelsof</span></div>

<div class="t m0 x0 h7 yc7 ff1 fs2 fc0 sc0 ls44 wsdf">COX-2 are additionally related to key symptoms of ME/</div>

<div class="t m0 x0 h7 yc8 ff1 fs2 fc0 sc0 ls24 wse0">CFS, such as a subjective experience of infection, hyperalgesia,</div>

<div class="t m0 x0 h7 yc9 ff1 fs2 fc0 sc0 ls2c wse1">fatigue, and neurocognitive disorders (Maes et al. <span class="fc1 ls34 wsc6">2007b</span><span class="ls4f">).Neopterin</span></div>

<div class="t m0 x4 h7 yca ff1 fs2 fc0 sc0 ls10 wse2">, an indicant of cell-mediated immune activa-tion</div>

<div class="t m0 x0 h7 ycb ff1 fs2 fc0 sc0 ls10 ws37">is significantly increased in ME/CFS patients (Maes etal.</div>

<div class="t m0 x0 h7 ycc ff1 fs2 fc0 sc0 ls10 ws3e"><span class="fc1 ws36">2012b</span><span class="wse3">). The same study showed that severity of fatigue,</span></div>

<div class="t m0 x0 h7 ycd ff1 fs2 fc0 sc0 ls10 wse4">autonomic and flu like symptoms also correlate positivelywith</div>

<div class="t m0 x0 h7 yce ff1 fs2 fc0 sc0 ls10 wse5">serum neopterin concentrations. Some but not all stud-ies</div>

<div class="t m0 x0 h8 ycf ff1 fs2 fc0 sc0 ls10 ws27">found increased production of interferon (IFN)<span class="ff5 ls3d">γin</span><span class="wse6"> ME/</span></div>

<div class="t m0 x0 h7 yd0 ff1 fs2 fc0 sc0 ls10 wse7">CFS (review: Maes and Twisk <span class="fc1 ws36">2010</span><span class="wse8">). Increased levels of IL-12</span></div>

<div class="t m0 x0 h7 yd1 ff1 fs2 fc0 sc0 ls10 wse9">were detected by Fletcher et al. (<span class="fc1 ls50 wsea">2009</span><span class="wseb">), suggesting aThelper</span></div>

<div class="t m0 x0 h7 yd2 ff1 fs2 fc0 sc0 ls10 wsec">(Th)1-like response in some patients. No significantdifferences</div>

<div class="t m0 x0 h7 yd3 ff1 fs2 fc0 sc0 ls10 ws19">in the Th17 cytokines, IL-17 and IL-23, wereobserved</div>

<div class="t m0 x0 h7 yd4 ff1 fs2 fc0 sc0 ls10 wsb">in patients with ME/CFS as compared with con-trols</div>

<div class="t m0 x0 h7 yd5 ff1 fs2 fc0 sc0 ls10 wsed">(Fletcher et al. <span class="fc1 ws36">2009</span><span class="wsee">). Nevertheless, associations be-</span></div>

<div class="t m0 x0 h7 yd6 ff1 fs2 fc0 sc0 ls10 wsef">tween fatigue scores and IL-17 levels were established in</div>

<div class="t m0 x0 h7 yd7 ff1 fs2 fc0 sc0 ls10 ws61">patients with primary Sjögren's syndrome (Haldorsen et al.2011</div>

<div class="t m0 x0 h7 yd8 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 wsf0">). This finding together with increased levels of PICs,</span></div>

<div class="t m0 x0 h8 yd9 ff1 fs2 fc0 sc0 ls10 wsf1">including IL-1, IL-6 and TNFα<span class="wsf2">, further suggest that a Th17response</span></div>

<div class="t m0 x0 h7 yda ff1 fs2 fc0 sc0 ls10 wsf3">may occur in some patients with chronic fatigue. Inaddition</div>

<div class="t m0 x0 h7 ydb ff1 fs2 fc0 sc0 ls3e wsf4">, the lowered expression of CD69 activationmarkers</div>

<div class="t m0 x0 h7 ydc ff1 fs2 fc0 sc0 ls51 wsf5">on CD4+ T cells in ME/CFS (Mihaylova et al.2007</div>

<div class="t m0 x0 h7 ydd ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 wsf6">) may further skew towards Th17 responses. Indeed,</span></div>

<div class="t m0 x0 h7 yde ff1 fs2 fc0 sc0 ls10 wsf7">CD69 promotes some pathways that inhibit Th17 cell dif-ferentiation</div>

<div class="t m0 x0 h7 ydf ff1 fs2 fc0 sc0 ls10 wsf8">(Martín and Sánchez-Madrid <span class="fc1 ws36">2011</span>).A</div>

<div class="t m0 x4 h7 ye0 ff1 fs2 fc0 sc0 ls10 wsf9">state of immune activation is further evidenced by ele-vated</div>

<div class="t m0 x0 h7 ye1 ff1 fs2 fc0 sc0 ls10 wsfa">expression of surface markers CD38+, HLA-DR onCD8</div>

<div class="t m0 x2 h7 ye2 ff1 fs2 fc0 sc0 ls10 wsfb">+T cells (Landay et al. <span class="fc1 ws36">1991</span><span class="wsfc">), and higher percentages ofCD8</span></div>

<div class="t m0 x2 h7 ye3 ff1 fs2 fc0 sc0 ls10 wsfd">+T cells and higher numbers of CD8+T cell class 11activation</div>

<div class="t m0 x2 h7 ye4 ff1 fs2 fc0 sc0 ls10 wsfe">markers (Klimas et al. <span class="fc1 ws36">1990</span><span class="wsff">). We have reviewedthat</span></div>

<div class="t m0 x2 h7 ye5 ff1 fs2 fc0 sc0 ls10 ws100">a Th2 response with increased levels of IL-4 or IL-5 mayoccur</div>

<div class="t m0 x2 h7 ye6 ff1 fs2 fc0 sc0 ls10 wsf3">in part of the patients (Maes et al. <span class="fc1 ws36">2012b</span><span class="ws101">; Fletcher et al.2009</span></div>

<div class="t m0 x2 h7 ye7 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 wscd v0">). Other studies show signs of immunosuppression, in-cluding</span></div>

<div class="t m0 x2 h7 ye8 ff1 fs2 fc0 sc0 ls10 ws102">lowered NK cell activity and raised levels of immu-noregulatory</div>

<div class="t m0 x2 h7 ye9 ff1 fs2 fc0 sc0 ls10 ws103">cytokines, IL-10 and transforming growth factor</div>

<div class="t m0 x2 h8 yea ff1 fs2 fc0 sc0 ls10 ws36">(TGF)-β1<span class="ws104"> (Chao et al. <span class="fc1 ws36">1991</span><span class="ws105">; Ogawa et al. <span class="fc1 ws36">1998</span><span class="ls52 ws106">;Fletcheretal.2010</span></span></span></div>

<div class="t m0 x2 h7 yeb ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws107">; Bennett et al. <span class="fc1 ws36">1997</span>; Nakamura et al. <span class="fc1 ws36">2010</span><span class="ws108">). All in all,</span></span></div>

<div class="t m0 x2 h7 yec ff1 fs2 fc0 sc0 ls10 ws109">while a chronic, low-grade inflammatory response accompa-nies</div>

<div class="t m0 x2 h7 yed ff1 fs2 fc0 sc0 ls10 ws10a">ME/CFS, some patient groups feature elevations of Th1,</div>

<div class="t m0 x2 h7 yee ff1 fs2 fc0 sc0 ls10 ws10b">Th2, Treg and maybe Th17 cytokines. Some ME/CFS patientsshow</div>

<div class="t m0 x2 h7 yef ff1 fs2 fc0 sc0 ls3f ws10c">a mixed response with activation of Th1 and Th2cytokines.</div>

<div class="t m0 x2 h7 yf0 ff1 fs2 fc0 sc0 ls10 ws10d">Th1 and Th2 subsets are indeed not mutuallyexclusive</div>

<div class="t m0 x2 h7 yf1 ff1 fs2 fc0 sc0 ls10 ws10e">, as Th17 and Treg subsets, but together facilitaterecovery</div>

<div class="t m0 x2 h7 yf2 ff1 fs2 fc0 sc0 ls10 ws10f">from infection (Bot et al. <span class="fc1 ws36">2004<span class="fc0 ls53 ws110">;Afzalietal.2007<span class="fc1 ls10 ws36"><span class="fc0">).For</span></span></span></span></div>

<div class="t m0 x2 h7 yf3 ff1 fs2 fc0 sc0 ls10 ws71">example, IL-4 and Th2 immune responses monitor Th1responses</div>

<div class="t m0 x2 h7 yf4 ff1 fs2 fc0 sc0 ls10 ws111">and maintain homeostasis (Bot et al. <span class="fc1 ws36">2004</span><span class="ws112">). It may</span></div>

<div class="t m0 x2 h7 yf5 ff1 fs2 fc0 sc0 ls10 ws113">be that the different cytokine profiles in ME/CFS depend onsubgroups</div>

<div class="t m0 x2 h7 yf6 ff1 fs2 fc0 sc0 ls10 ws114">or staging of the disease, e.g. acute flares versuspartial</div>

<div class="t m0 x2 h7 yf7 ff1 fs2 fc0 sc0 ls10 ws115">remission. In <span class="ff6 ws36">‘Mechanistic</span><span class="fc1 ws116"> explanations for the chronicand</span></div>

<div class="t m0 x2 h7 yf8 ff1 fs2 fc1 sc0 ls10 ws90">relapsing<span class="ff6 ws36">–</span><span class="ws117">remitting nature of ME/CFS’we<span class="fc0 ws118"> will discusshow</span></span></div>

<div class="t m0 x2 h7 yf9 ff1 fs2 fc0 sc0 ls10 ws119">Th1 versus Th2 dominance and Treg functions may playa</div>

<div class="t m0 x2 h7 yfa ff1 fs2 fc0 sc0 ls10 ws11a">role in the relapsing<span class="ff6 ws36">–<span class="ff1 ws10">remitting nature of ME/CFS.A</span></span></div>

<div class="t m0 x5 h7 yfb ff1 fs2 fc0 sc0 ls54 ws11b">number of factors predispose to chronic inflammation.IgG1</div>

<div class="t m0 x2 h7 yfc ff1 fs2 fc0 sc0 ls2c ws11c">deficiencies often result i<span class="ls55 ws11d">n a decreased level of total IgG</span></div>

<div class="t m0 x2 h7 yfd ff1 fs2 fc0 sc0 ls32 ws11e">(hypogammaglobulinemia). Along with IgG1, the IgG3 sub-</div>

<div class="t m0 x2 h7 yfe ff1 fs2 fc0 sc0 ls54 ws11f">class is most frequently present in the antibody response toprotein</div>

<div class="t m0 x2 h7 yff ff1 fs2 fc0 sc0 ls36 ws120">antigens. Decreased IgG3 <span class="ls38 ws121">levels are frequently associ-ated</span></div>

<div class="t m0 x2 h7 y100 ff1 fs2 fc0 sc0 ls10 ws122">with IgG1 deficiency (Herrod <span class="fc1 ws36">1993</span><span class="ws123">). IgG1 and IgG3deficiency</span></div>

<div class="t m0 x2 h7 y101 ff1 fs2 fc0 sc0 ls10 ws10c">has been associated with a history of recurrentinfectious.</div>

<div class="t m0 x2 h7 y102 ff1 fs2 fc0 sc0 ls2c ws124">IgG1 and IgG3 levels are reduced in ME/CFS (Bassiet</div>

<div class="t m0 x2 h7 y103 ff1 fs2 fc0 sc0 ls2c ws125">al.<span class="fc1 ls34 wsc6">2008</span><span class="ls2e ws126">; Hilgers and Frank <span class="fc1 ls34 wsc6">1994</span><span class="ls32 ws127">). Another feature whichpredisposes</span></span></div>

<div class="t m0 x2 h7 y104 ff1 fs2 fc0 sc0 ls28 ws128">to chroni<span class="ls34 ws129">c inflammation is the decreased ratio ofω3</span></div>

<div class="t m0 x2 h8 y105 ff5 fs2 fc0 sc0 ls10 ws36"><span class="ff1 ls34 wsc6">/</span>ω6<span class="ff1 ls56 ws12a"> polyunsaturated fatty acids (PUFAs) in patients withME</span></div>

<div class="t m0 x2 h7 y106 ff1 fs2 fc0 sc0 ls57 ws12b">/CFS (Maes et al. <span class="fc1 ls34 wsc6">2005b</span><span class="ls58 ws12c">). Omega-3 fatty acids have anti-</span></div>

<div class="t m0 x2 h7 y107 ff1 fs2 fc0 sc0 ls10 ws12d">inflammatory properties, whereas omega-6 fatty acids havepro-inflammatory</div>

<div class="t m0 x2 h7 y108 ff1 fs2 fc0 sc0 ls25 ws12e">effects (Simopoulos <span class="fc1 ls34 wsc6">2002</span><span class="ws12f">). A genetic predis-position</span></div>

<div class="t m0 x2 h7 y109 ff1 fs2 fc0 sc0 ls59 ws130">is repeatedly observed in patients with ME/CFS. Forexample</div>

<div class="t m0 x2 h7 y10a ff1 fs2 fc0 sc0 ls2c ws102">, a significant increase in TNF<span class="ff6 ls10 ws36">–</span><span class="ls5a ws131">857 TT and CT geno-types</span></div>

<div class="t m0 x2 h7 y10b ff1 fs2 fc0 sc0 ls10 ws19">, likely to be associated with increased production ofTNFαand</div>

<div class="t m0 x2 h8 y10c ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws132"> IFNγ</span><span class="ws133">; human leucocyte antigen class II alleleHLA-DQA1</span></div>

<div class="t m0 x2 h7 y10d ff1 fs2 fc0 sc0 ls10 ws19">*01; C/T polymorphism leading to His161Argsubstitution</div>

<div class="t m0 x2 h7 y10f ff1 fs2 fc0 sc0 ls36 ws136">A polymorphisms (review: Maes and Twisk <span class="fc1 ls34 wsc6">2010</span><span class="ls37">).O</span></div>

<div class="t m0 x2 h7 y110 ff1 fs2 fc0 sc0 ls10 ws3a">&NS pathways in ME/CFSME</div>

<div class="t m0 x2 h7 y111 ff1 fs2 fc0 sc0 ls10 ws137">/CFS is accompanied by increased reactive oxygen andnitrogen</div>

<div class="t m0 x2 h7 y112 ff1 fs2 fc0 sc0 ls10 ws138">species (ROS/RNS) and activated O&NS pathways</div>

<div class="t m0 x2 h7 y113 ff1 fs2 fc0 sc0 ls10 ws139">(Jammes et al. <span class="fc1 ws36">2005</span><span class="ws7c">; Meeus et al. <span class="fc1 ws36">2009</span>; Maes et al. <span class="fc1 ws36">2006b</span>,</span></div>

<div class="t m0 x2 h7 y114 ff1 fs2 fc1 sc0 ls10 ws36">2009b<span class="fc0 ws13a">). Frequently reported abnormalities include O&NSMetab</span></div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span><span class="ws13b">540 525</span></div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws13c">damage to proteins, lipids and DNA (Maes et al. <span class="fc1 ws36">2009b</span>;</div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 wsf8">Maes and Twisk <span class="fc1 ws36">2010</span>). Patients with ME/CFS additionallyshow</div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws13d">increased IgM-mediated responses to different NO-adducts</div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws13e">, indicating chronically increased nitric oxide (NO)</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws13f">production (Maes et al. <span class="fc1 ws36">2006b</span><span class="ws140">), and increased production ofinducible</span></div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls2 ws13">NO synthase (iNOS) (Maes et al. <span class="fc1 ls18 ws7a">2007b</span><span class="ls5b ws141">). In-</span></div>

<div class="t m0 x0 h7 y53 ff1 fs2 fc0 sc0 ls10 ws142">creased IgM-mediated responses directed to palmitic andmyristic</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls10 ws143">acid and the NO-adducts show that O&NS havemodified</div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 ws144">the structure of fatty acids and proteins (Maes et al.2006b</div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws145">). Reduced levels of the antioxidants zinc, coenzymeQ10</span></div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws146">, dehydroepiandrosterone sulfate and glutathione havealso</div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws147">been reported (Manuel-y-Keenoy et al. <span class="fc1 ls50 wsea">2000</span><span class="ls5c">,</span><span class="fc1 ws36">2001</span>;</div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls5 ws148">Kennedy et al. <span class="fc1 ls5d ws149">2003</span><span class="ls5e">,<span class="fc1 ls5d ws149">2005</span><span class="ls79 ws1a">; Maes et al. <span class="fc1 ls5d ws149">2005a</span></span>,<span class="fc1 ls5d ws149">2006a</span><span class="ls10">,</span></span></div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc1 sc0 ls50 wsea">2009a<span class="fc0 ls7a ws14a">;Maes2011a<span class="fc1 ls10 ws36"><span class="fc0 ws24">). Low grade inflammation, activatedO</span></span></span></div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls11 ws14b">&NS pathways and impaired oxidative defenses likelyinteract</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10 ws14c">to increase the magnitude of abnormality in eachleading</div>

<div class="t m0 x0 h7 y5d ff1 fs2 fc0 sc0 ls5f ws14d">to a vicious cycle (Maes and Twisk <span class="fc1 ls18 ws7a">2010</span><span class="ls60 ws84">). Thesymptoms</span></div>

<div class="t m0 x0 h7 y5e ff1 fs2 fc0 sc0 ls10 ws114">of fatigue, malaise and pain, positively and sig-nificantly</div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws14e">correlate with markers of lipid peroxidation andprotein</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc0 sc0 ls10 ws14f">oxidation/nitrosylation (Kennedy et al. <span class="fc1 ws36">2003</span><span class="ls61">,</span><span class="fc1 ws36">2005</span>;</div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 ls10 ws150">Maes et al. <span class="fc1 ws36">2006b</span><span class="ws151">; Maes and Twisk <span class="fc1 ws36">2010</span><span class="ws152">; Maes <span class="fc1 ws36">2011a</span>).Studies</span></span></div>

<div class="t m0 x0 h7 y115 ff1 fs2 fc0 sc0 ls10 ws12d">have demonstrated increased ventricular lactate inME</div>

<div class="t m0 x0 h7 y116 ff1 fs2 fc0 sc0 ls10 ws153">/CFS using 3 Tesla proton magnetic-resonance spectros-copy</div>

<div class="t m0 x0 h7 y117 ff1 fs2 fc0 sc0 ls10 ws154">(Murrough et al. <span class="fc1 ws36">2010</span><span class="ws155">; Mathew et al. <span class="fc1 ws36">2009</span>; Shungu etal.</span></div>

<div class="t m0 x0 h7 y118 ff1 fs2 fc0 sc0 ls62 ws156"><span class="fc1 ls5d ws149">2012<span class="fc0 ws157">). Ventricular CSF lactate was significantly in-</span></span></div>

<div class="t m0 x0 h7 y119 ff1 fs2 fc0 sc0 ls63 ws158">creased in ME/CFS as comp<span class="ls64 ws18">ared to normal volunteers</span></div>

<div class="t m0 x0 h7 y11a ff1 fs2 fc0 sc0 ls10 ws159">(Murrough et al. <span class="fc1 ws36">2010</span><span class="ws15a">). During exercise lactate is associatedwith</span></div>

<div class="t m0 x0 h7 y11b ff1 fs2 fc0 sc0 ls10 ws15b">the production of radical oxygen species and acidosis</div>

<div class="t m0 x0 h7 y11c ff1 fs2 fc0 sc0 ls10 ws15c">(Groussard et al. <span class="fc1 ws36">2000</span><span class="ws15d">). Lactate is an antioxidant that scav-enges</span></div>

<div class="t m0 x0 h7 y11d ff1 fs2 fc0 sc0 ls10 ws9b">free radicals and attenuates lipid peroxidation, where-</div>

<div class="t m0 x0 h7 y11e ff1 fs2 fc0 sc0 ls10 ws15e">as acidosis is a potent oxidative condition (Groussard et al.2000</div>

<div class="t m0 x4 h7 y120 ff1 fs2 fc0 sc0 ls10 ws15f">presence of O&NS is known to lead to mitochondrialdamage</div>

<div class="t m0 x0 h7 y121 ff1 fs2 fc0 sc0 ls10 ws160">in neurological diseases (Lin and Beal <span class="fc1 ws36">2006</span><span class="ws161">; Trushinaand</span></div>

<div class="t m0 x0 h7 y122 ff1 fs2 fc0 sc0 ls10 ws162">McMurray<span class="fc1 ws36">2007<span class="fc0 ws163">) and is likely the source of mitochondrialdysfunction</span></span></div>

<div class="t m0 x0 h7 y123 ff1 fs2 fc0 sc0 ls10 ws62">seen in people with ME/CFS (Maes and Twisk2010</div>

<div class="t m0 x0 h7 y124 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws164">). Specific and highly sensitive alterations in the avail-</span></div>

<div class="t m0 x0 h7 y125 ff1 fs2 fc0 sc0 ls10 ws15e">ability of adenosine triphosphate (ATP), inadequate suppliesof</div>

<div class="t m0 x0 h7 y126 ff1 fs2 fc0 sc0 ls10 ws111">ATP, and oxidative phosphorylation have been reported inneutrophil</div>

<div class="t m0 x0 h7 y127 ff1 fs2 fc0 sc0 ls10 ws165">mitochondria of individuals with ME/CFS (Myhillet</div>

<div class="t m0 x0 h7 y128 ff1 fs2 fc0 sc0 ls10 ws166">al.<span class="fc1 ws36">2009</span>; Vermeulen et al. <span class="fc1 ws36">2010</span><span class="ws167">). Another study reportedthat</span></div>

<div class="t m0 x0 h7 y129 ff1 fs2 fc0 sc0 ls10 ws168">all individuals with physio-somatic symptoms in depres-sion</div>

<div class="t m0 x0 h7 y12a ff1 fs2 fc0 sc0 ls10 ws13a">had a significantly lower ATP production in musclebiopsies</div>

<div class="t m0 x0 h7 y12b ff1 fs2 fc0 sc0 ls10 ws11a">compared to controls (Gardner and Boles <span class="fc1 ws36">2008</span>).Intracellular</div>

<div class="t m0 x0 h7 yda ff1 fs2 fc0 sc0 ls10 ws41">signaling networksA</div>

<div class="t m0 x0 h7 ydc ff1 fs2 fc0 sc0 ls10 ws169">number of different signaling networks are upregulated inME</div>

<div class="t m0 x0 h7 ydd ff1 fs2 fc0 sc0 ls10 ws16a">/CFS. Studies have demonstrated higher production ofunstimulated</div>

<div class="t m0 x0 h8 y12c ff1 fs2 fc0 sc0 ls65 ws79">, and TNFα-<span class="ls7b ws16b"> and PMA-stimulated NF-κB<span class="ls64">,</span></span></div>

<div class="t m0 x0 h7 y12d ff1 fs2 fc0 sc0 ls10 ws15e">cyclo-oxygenase-2 and inducible iNOS (Maes et al. <span class="fc1 ws36">2007a</span>,</div>

<div class="t m0 x0 h8 y12e ff1 fs2 fc1 sc0 ls68">b<span class="fc0 ls10 ws16c">). NF-κβ <span class="ws1b">is a major upstream molecule, which regulatesimmuno-inflammatory</span></span></div>

<div class="t m0 x0 h7 y12f ff1 fs2 fc0 sc0 ls69 ws16e">an<span class="ls6a ws16f">d O&NS responses. Uponactivation</span></div>

<div class="t m0 x2 h7 y130 ff1 fs2 fc0 sc0 ls17 ws79">by viral products, lipopolysaccharide (LPS), aconstituent</div>

<div class="t m0 x2 h7 y131 ff1 fs2 fc0 sc0 ls10 ws62">of the outer membrane of gram negative bacte-ria</div>

<div class="t m0 x2 h8 y132 ff1 fs2 fc0 sc0 ls10 ws170">, PICs and free radicals, NF-κβ <span class="ws8c">is translocated from thecytoplasma</span></div>

<div class="t m0 x2 h7 y133 ff1 fs2 fc0 sc0 ls10 ws13a">to the nucleus where it binds DNA promotersequences</div>

<div class="t m0 x2 h7 y134 ff1 fs2 fc0 sc0 ls10 ws172">and induces transcriptional activation of PICs,</div>

<div class="t m0 x2 h8 y135 ff1 fs2 fc0 sc0 ls10 ws173">such as IL-1, IL-6, and TNFα<span class="ws11c">, COX-2 and inducible iNOS</span></div>

<div class="t m0 x2 h8 y136 ff1 fs2 fc0 sc0 ls10 ws174">(Brasier <span class="fc1 ws36">2006</span><span class="ws175">). Upon activation, the inhibitory IκB<span class="ws176"> proteins,</span></span></div>

<div class="t m0 x2 h8 y137 ff1 fs2 fc0 sc0 ls10 ws177">that hold NF-κB<span class="ws178"> in an inactive state, are tagged from pro-teosomal</span></div>

<div class="t m0 x2 h8 y138 ff1 fs2 fc0 sc0 ls6b ws179">degradation following phosphorylation by IκBkinases.</div>

<div class="t m0 x2 h8 y139 ff1 fs2 fc0 sc0 ls10 ws17a">In many inflammatory disorders, NF-κB<span class="ws14f"> in chron-ically</span></div>

<div class="t m0 x2 h7 y13a ff1 fs2 fc0 sc0 ls10 ws11c">upregulated. In ME/CFS, the increased production ofNF-κB</div>

<div class="t m0 x2 h8 y13b ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws17b"> is associated with fatigue and a subjective feeling ofinfection</span></div>

<div class="t m0 x2 h7 y13c ff1 fs2 fc0 sc0 ls10 ws61">(Maes et al. <span class="fc1 ws36">2007a</span><span class="ws78">). Moreover, there were signif-icant</span></div>

<div class="t m0 x2 h7 y13d ff1 fs2 fc0 sc0 ls10 ws17c">and positive intercorrelations between the productionof</div>

<div class="t m0 x2 h8 y13e ff1 fs2 fc0 sc0 ls10 ws17d">NF-κB<span class="ws17e">, COX-2, and inducible iNOS, suggesting that theincreased</span></div>

<div class="t m0 x2 h7 y13f ff1 fs2 fc0 sc0 ls10 ws17f">production of COX-2 and iNOS is driven by thetranscription</div>

<div class="t m0 x2 h8 y140 ff1 fs2 fc0 sc0 ls10 ws180">factor NF-κB.<span class="ws181"> Thus, increased production ofNF-κB</span></div>

<div class="t m0 x2 h8 y141 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws182"> is response to viral and bacterial infections may beone</span></div>

<div class="t m0 x2 h7 y142 ff1 fs2 fc0 sc0 ls10 ws17c">key mechanism modulating the immuno-inflammatoryand</div>

<div class="t m0 x2 h7 y143 ff1 fs2 fc0 sc0 ls10 ws3a">O&NS pathways in ME/CFS.The</div>

<div class="t m0 x5 h7 y144 ff1 fs2 fc0 sc0 ls3a ws21">2-5A/RNaseL and PKR pathways are also upre-gulated</div>

<div class="t m0 x2 h7 y145 ff1 fs2 fc0 sc0 ls3 ws10d">in individuals with ME/CFS (Vojdani and Lapp1999</div>

<div class="t m0 x2 h7 y146 ff1 fs2 fc1 sc0 ls1e ws98"><span class="fc0 ws183">). Importantly, the latter pathways have antiprolifer-ative</span></div>

<div class="t m0 x2 h7 y147 ff1 fs2 fc0 sc0 ls6d ws184">and antiviral effects and are induced by interferonsin</div>

<div class="t m0 x2 h7 y148 ff1 fs2 fc0 sc0 ls6e ws185">response to viral infections. Moreover, the enzymethat</div>

<div class="t m0 x2 h7 y149 ff1 fs2 fc0 sc0 ls6f ws186">synthesizes 2-5A, i.e. 2′-5′-oligoadenylate<span class="ls5b ws187"><span class="ls71 ws188"> synthe-tase</span></span></div>

<div class="t m0 x2 h7 y14a ff1 fs2 fc0 sc0 ls6d ws189">, is activated during bacterial infections. PKR is alsoactivated</div>

<div class="t m0 x2 h7 y14b ff1 fs2 fc0 sc0 ls72 ws18a">by bacterial LPS and PICs, including IL-1 andTNFα.Bacterial</div>

<div class="t m0 x2 h7 y14d ff1 fs2 fc0 sc0 ls10 ws139">translocationThe</div>

<div class="t m0 x2 h7 y14e ff1 fs2 fc0 sc0 ls10 ws18c">presence of intestinal permeability and resultant bacte-rial</div>

<div class="t m0 x2 h7 y14f ff1 fs2 fc0 sc0 ls10 ws18d">translocation into the lamina propina, the lymph nodesand</div>

<div class="t m0 x2 h7 y150 ff1 fs2 fc0 sc0 ls10 ws18e">possibly the systemic circulation, is evidenced by thepresence</div>

<div class="t m0 x2 h7 y151 ff1 fs2 fc0 sc0 ls75 ws9f">of IgM and IgA mediated immune responsesagainst</div>

<div class="t m0 x2 h7 y152 ff1 fs2 fc0 sc0 ls10 ws18f">LPS of different gram negative bacteria in up to40</div>

<div class="t m0 x2 h7 y153 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ff6 ls68">–</span><span class="ws190">60 % of people with ME/CFS (Maes et al. </span><span class="fc1">2012c</span><span class="ws136">). Thismay</span></div>

<div class="t m0 x2 h7 y154 ff1 fs2 fc0 sc0 ls10 ws191">be due to the presence of systemic inflammation, whichcan</div>

<div class="t m0 x2 h7 y155 ff1 fs2 fc0 sc0 ls10 wsf3">reduce the integrity of epithelial tight junctions. The IgAresponses</div>

<div class="t m0 x2 h7 y156 ff1 fs2 fc0 sc0 ls21 ws148">positively and significantly correlate with thelevels</div>

<div class="t m0 x2 h8 y157 ff1 fs2 fc0 sc0 ls10 ws179">of PICs, such as IL-1βand<span class="ws192"> TNFα<span class="ws24">, and neopterin</span></span></div>

<div class="t m0 x2 h7 y158 ff1 fs2 fc0 sc0 ls7c ws193">(Maes et al. <span class="fc1 ls21 ws85">2012c</span><span class="ls77 ws194">). LPS from translocated commensalbacteria</span></div>

<div class="t m0 x2 h7 y159 ff1 fs2 fc0 sc0 ls10 ws65">may provoke a peripheral immuno-inflammatoryresponse</div>

<div class="t m0 x2 h7 y15a ff1 fs2 fc0 sc0 ls7d ws195">by binding to the To<span class="ls78 ws196">ll-like receptor-4 (TLR4)</span></div>

<div class="t m0 x2 h7 y15b ff1 fs2 fc0 sc0 ls20 ws197">complex, which in turn activates intracellular signalingpathways</div>

<div class="t m0 x2 h8 y15c ff1 fs2 fc0 sc0 ls10 ws198">, such as NF-κB<span class="ws118">, which subsequently will inducegenes</span></div>

<div class="t m0 x2 h7 y15d ff1 fs2 fc0 sc0 ls7e ws148">of PICs, iNOS and COX-2 (Maes et al. <span class="fc1 ls5d ws149">2012c</span><span class="ls7f">).Increased</span></div>

<div class="t m0 x2 h7 y15e ff1 fs2 fc0 sc0 ls80 ws86">LPS may also explain other immuno-inflammatory</div>

<div class="t m0 x2 h7 y15f ff1 fs2 fc0 sc0 ls10 ws10">signs in ME/CFS, such as increased neopterinand</div>

<div class="t m0 x2 h7 y160 ff1 fs2 fc0 sc0 ls10 ws199">elastase levels. Indeed, LPS may stimulate the produc-tion</div>

<div class="t m0 x2 h7 y161 ff1 fs2 fc0 sc0 ls10 ws19a">of neopterin by monocytes/macrophages and elastaseby</div>

<div class="t m0 x2 h7 y162 ff1 fs2 fc0 sc0 ls10 ws56">neutrophils and monocytes (Maesetal.<span class="fc1 ws36">2012c</span>).526</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws19b">Autoimmune responsesIncreased</div>

<div class="t m0 x0 h7 y163 ff1 fs2 fc0 sc0 ls10 ws161">levels of B cells such as CD19+, CD 20+ and CD21</div>

<div class="t m0 x0 h7 y164 ff1 fs2 fc0 sc0 ls10 ws94">+ have been reported (Tirelli et al. <span class="fc1 ws36">1994</span><span class="ws13c">). IgM mediatedautoimmune</span></div>

<div class="t m0 x0 h7 yb4 ff1 fs2 fc0 sc0 ls10 wsfc">responses towards self antigens whose structurehas</div>

<div class="t m0 x0 h7 y165 ff1 fs2 fc0 sc0 ls10 ws19c">been damaged by O&NS also occurs in ME/CFS (Maes etal.</div>

<div class="t m0 x0 h7 yb5 ff1 fs2 fc0 sc0 ls10 ws19d"><span class="fc1 ws36">2006b</span><span class="ws19e">). These involve autoantibodies to anchorage mole-cules</span></div>

<div class="t m0 x0 h7 y166 ff1 fs2 fc0 sc0 ls10 ws19f">, palmitic and myristinic acid, which are essential fornormal</div>

<div class="t m0 x0 h7 yb6 ff1 fs2 fc0 sc0 ls10 ws1a0">cellular function (Maes et al. <span class="fc1 ws36">2006b</span><span class="wsbb">). Other autoanti-bodies</span></div>

<div class="t m0 x0 h7 yb7 ff1 fs2 fc0 sc0 ls10 ws1a1">towards Sa antigen, cell nucleus, and cardiolopin andserotonin</div>

<div class="t m0 x0 h7 yb8 ff1 fs2 fc0 sc0 ls10 ws1a2">, gangliosides, vasoactive neuropeptides, and cholin-ergic</div>

<div class="t m0 x0 h7 yb9 ff1 fs2 fc0 sc0 ls10 ws1a3">receptors have all been reported in large groups of ME/</div>

<div class="t m0 x0 h7 yba ff1 fs2 fc0 sc0 ls10 ws133">CFS patients (review: Maes. <span class="fc1 ws36">2011b</span><span class="ws1a4">; Nishikai et al. <span class="fc1 ws36">2001</span>;</span></div>

<div class="t m0 x0 h7 ybb ff1 fs2 fc0 sc0 ls10 ws1a5">Ortega-Hernandez and Shoenfeld <span class="fc1 ws36">2009</span><span class="ws1a6">). In the next sectionswe</span></div>

<div class="t m0 x0 h7 ybc ff1 fs2 fc0 sc0 ls10 ws1a7">will further explain the mechanisms that may cause auto-</div>

<div class="t m0 x0 h7 ybd ff1 fs2 fc0 sc0 ls10 ws1a3">immune responses in ME/CFS.Role</div>

<div class="t m0 x0 h4 y167 ff2 fs2 fc0 sc0 ls10 ws7c">of pathogens in ME/CFSViral</div>

<div class="t m0 x0 h7 y168 ff1 fs2 fc0 sc0 ls10 ws18f">and bacterial infections probably play an importantrole</div>

<div class="t m0 x0 h7 y169 ff1 fs2 fc0 sc0 ls10 ws1a8">in ME/CFS, either as trigger or maintaining factors</div>

<div class="t m0 x0 h7 y16a ff1 fs2 fc0 sc0 ls10 ws13c">(Maes and Twisk <span class="fc1 ws36">2010</span><span class="ws152">; Maes <span class="fc1 ws36">2011a<span class="fc0 ws152">; Komaroff and Cho2011</span></span></span></div>

<div class="t m0 x0 h7 y16b ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws87">; Broderick et al. </span>2010<span class="fc0 wsf3">). The overall picture of activatedimmuno-inflammatory</span></div>

<div class="t m0 x0 h7 y16c ff1 fs2 fc0 sc0 ls10 ws1a9">pathways in ME/CFS, e.g. increasedNF-κB</div>

<div class="t m0 x0 h8 y16d ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws1aa">, 2-5A/RNaseL and PKR pathways, PICs and bacte-rial</span></div>

<div class="t m0 x0 h7 y63 ff1 fs2 fc0 sc0 ls10 ws1ab">translocation, support the hypothesis that viral and bac-terial</div>

<div class="t m0 x0 h7 y64 ff1 fs2 fc0 sc0 ls10 ws1ac">infections play a major role in the onset of ME/CFS</div>

<div class="t m0 x0 h7 y65 ff1 fs2 fc0 sc0 ls81 ws1ad">(Maes and Twisk <span class="fc1 ls82 ws1ae">2010</span><span class="ls83 ws1af">). Not only the immunologicalanomalies</span></div>

<div class="t m0 x0 h7 y66 ff1 fs2 fc0 sc0 ls10 ws1b0">but also the distinctive gene expression are inaccordance</div>

<div class="t m0 x0 h7 y67 ff1 fs2 fc0 sc0 ls84 ws21">with viral or bacterial infections (Maes andTwi</div>

<div class="t m0 x0 h7 y68 ff1 fs2 fc0 sc0 ls8b ws1b1">s k <span class="fc1 ls10 ws36">2010<span class="fc0 ws1b2">; Broderick et al. </span>2010<span class="fc0 ws1b3">). ME/CFS often beginswith</span></span></div>

<div class="t m0 x0 h7 y69 ff1 fs2 fc0 sc0 ls7 ws1b4">a severe flu-like infection (Naess et al. <span class="fc1 ws1b5">2010</span><span class="ls8c ws1b6">)andepidemics</span></div>

<div class="t m0 x0 h7 y6a ff1 fs2 fc0 sc0 ls10 ws1b7">of ME/CFS have repeatedly been described inthe</div>

<div class="t m0 x0 h7 y6b ff1 fs2 fc0 sc0 ls10 ws1b8">literature (Strickland et al. <span class="fc1 ws36">2001</span><span class="ws1b9">). A number of patho-gens</span></div>

<div class="t m0 x0 h7 y6c ff1 fs2 fc0 sc0 ls10 ws1ba">have been associated with ME/CFS such as Borreliaburgdorferi</div>

<div class="t m0 x0 h7 y6d ff1 fs2 fc0 sc0 ls10 ws1bb">, P. aeruginosa, Mycoplasma, Chlamydia, Cyto-megalovirus</div>

<div class="t m0 x0 h7 y6e ff1 fs2 fc0 sc0 ls10 ws1bc">, HHV-6, and EBV, Coxsackie and Aspergillus</div>

<div class="t m0 x0 h7 y6f ff1 fs2 fc0 sc0 ls10 wsf8">(review: Maes and Twisk <span class="fc1 ws36">2010</span>).A</div>

<div class="t m0 x4 h7 y70 ff1 fs2 fc0 sc0 ls10 ws1bd">wide range of pathogens commonly found infectingpeople</div>

<div class="t m0 x0 h7 y71 ff1 fs2 fc0 sc0 ls10 ws1be">with ME/CFS are capable of establishing prolongedinfections</div>

<div class="t m0 x0 h7 y72 ff1 fs2 fc0 sc0 ls10 ws190">as a result of developing sophisticated adaptationsto</div>

<div class="t m0 x0 h7 y73 ff1 fs2 fc0 sc0 ls10 ws190">avoid or mitigate the effects of the host immune response</div>

<div class="t m0 x0 h7 y74 ff1 fs2 fc0 sc0 ls10 ws1bf">(Hilgers and Frank <span class="fc1 ws36">1994</span>; Zhang et al. <span class="fc1 ws36">2010<span class="fc0 ls8d ws1c0">;Stephensenetal.2005</span></span></div>

<div class="t m0 x0 h7 y75 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws1c1">). Borrelia burgdorferi, for example, persists in the hostand</span></div>

<div class="t m0 x0 h7 y76 ff1 fs2 fc0 sc0 ls10 ws1a1">has strategies for immune evasion that include immuno-genic</div>

<div class="t m0 x0 h7 y77 ff1 fs2 fc0 sc0 ls10 ws1c2">surface-exposed proteins as potential virulence determi-nants</div>

<div class="t m0 x0 h7 y78 ff1 fs2 fc0 sc0 ls10 ws1c3">(Radolf <span class="fc1 ws36">1994</span><span class="ws1c4">). Borrelia burgdorferi undergoes antigenicvariation</span></div>

<div class="t m0 x0 h7 y79 ff1 fs2 fc0 sc0 ls10 ws1c5">, so that the configuration of the exposed proteinsalso</div>

<div class="t m0 x0 h7 y7a ff1 fs2 fc0 sc0 ls10 ws1c6">changes in the host over time (Bankhead and Chaconas2007</div>

<div class="t m0 x0 h7 y7b ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 wsae">). P. aeruginosa evades human complement attack bybinding</span></div>

<div class="t m0 x0 h7 y7c ff1 fs2 fc0 sc0 ls10 ws107">human regulators to its surface (Kunert et al. <span class="fc1 ws36">2007<span class="fc0">).Mycoplasma</span></span></div>

<div class="t m0 x0 h7 y7d ff1 fs2 fc0 sc0 ls3a wsba">can evade the host response by generatingvariable</div>

<div class="t m0 x2 h7 y7e ff1 fs2 fc0 sc0 ls10 ws1c7">surface antigen proteins, which continually changetheir</div>

<div class="t m0 x2 h7 y7f ff1 fs2 fc0 sc0 ls10 ws1c8">antigenicity (Simmons and Dybvig <span class="fc1 ws36">2007</span><span class="ws1c9">; Le Grand et al.1996</span></div>

<div class="t m0 x2 h7 y80 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws1ca">). Chlamydiae hijack signaling pathways that prevent thehost</span></div>

<div class="t m0 x2 h7 y81 ff1 fs2 fc0 sc0 ls10 ws1cb">cells from undergoing apoptosis and protect the infectedcells</div>

<div class="t m0 x2 h7 y82 ff1 fs2 fc0 sc0 ls48 ws1cc">from attack by host defenses (Zhong <span class="fc1 ls10 ws36">2009<span class="fc0 ws1c3">). Each humanherpes</span></span></div>

<div class="t m0 x2 h7 y83 ff1 fs2 fc0 sc0 ls10 ws1cd">virus studied has evolved cell biological solutions toavoid</div>

<div class="t m0 x2 h7 y84 ff1 fs2 fc0 sc0 ls10 ws151">or mitigate problems posed by the human immuneresponse</div>

<div class="t m0 x2 h7 y85 ff1 fs2 fc0 sc0 ls10 ws1ce">(Gewurz et al. <span class="fc1 ws36">2007</span><span class="ws12">). Herpes virus evasion of T-</span></div>

<div class="t m0 x2 h7 y86 ff1 fs2 fc0 sc0 ls10 ws1cf">cell immunity includes latency, restriction of viral gene ex-pression</div>

<div class="t m0 x2 h7 y87 ff1 fs2 fc0 sc0 ls10 ws1d0">to immuno-privileged sites (CNS), interference withcomplement</div>

<div class="t m0 x2 h7 y88 ff1 fs2 fc0 sc0 ls10 ws1d1">, cytokines, apoptosis and NK cell activity, andexpression</div>

<div class="t m0 x2 h7 y89 ff1 fs2 fc0 sc0 ls10 ws1d2">of immuno-evasins, i.e. molecules that disruptnormal</div>

<div class="t m0 x2 h7 y8a ff1 fs2 fc0 sc0 ls8e ws1d3">immune physiology. Coxsackie B3 employs avirally-encoded</div>

<div class="t m0 x2 h7 y8b ff1 fs2 fc0 sc0 ls10 ws1d4">protein, i.e. 3Cpro, to degrade molecules,</div>

<div class="t m0 x2 h7 y16e ff1 fs2 fc0 sc0 ls10 ws1d5">which function downstream of pattern recognition receptorsignaling</div>

<div class="t m0 x2 h7 y16f ff1 fs2 fc0 sc0 ls10 ws1d6">(Mukherjee et al. <span class="fc1 ws36">2011<span class="fc0 ws1d6">; Wessels et al. </span>2006<span class="fc0 ws1d7">). Asper-gillus</span></span></div>

<div class="t m0 x2 h7 y170 ff1 fs2 fc0 sc0 ls10 ws1d2">species employ the following strategies: binding tocomplement</div>

<div class="t m0 x2 h7 y171 ff1 fs2 fc0 sc0 ls10 ws12a">regulators, which avoids the host complementattack</div>

<div class="t m0 x2 h7 y172 ff1 fs2 fc0 sc0 ls10 ws111">(Behnsen et al. <span class="fc1 ws36">2008</span><span class="ls8f ws1d8">;Radolf1994<span class="fc1 ls10 ws36"><span class="fc0 ws66">); shielding of stim-ulatory</span></span></span></div>

<div class="t m0 x2 h7 y173 ff1 fs2 fc0 sc0 ls5f ws1d9">surface recognition molecules; induction of anti-</div>

<div class="t m0 x2 h7 y174 ff1 fs2 fc0 sc0 ls10 ws7c">inflammatory signals; complement evasion; and shedding ofdecoy</div>

<div class="t m0 x2 h7 y175 ff1 fs2 fc0 sc0 ls10 ws9">components (Chai et al. <span class="fc1 ws36">2009</span>).Environmental</div>

<div class="t m0 x5 h7 y176 ff1 fs2 fc0 sc0 ls10 ws1da">signals at the inflammatory site inducemonocytic</div>

<div class="t m0 x2 h7 y177 ff1 fs2 fc0 sc0 ls11 ws7b">mobilization and differentiate these cells intomacrophages</div>

<div class="t m0 x2 h7 y178 ff1 fs2 fc0 sc0 ls10 wscd">or dendritic cells (Ingersoll et al. <span class="fc1 ws36">2011</span><span class="ws1db">). Cel-lular</span></div>

<div class="t m0 x2 h7 y179 ff1 fs2 fc0 sc0 ls10 ws1dc">immune activation leads to the upregulation of PICs,</div>

<div class="t m0 x2 h8 y17a ff1 fs2 fc0 sc0 ls10 ws1dd">e.g. TNFα<span class="ws1de">, IL-1βand<span class="ws1df"> IL-6, and initially Th1 cytokines, e.g.IL-12</span></span></div>

<div class="t m0 x2 h8 y17b ff1 fs2 fc0 sc0 ls10 ws1e0">and IFNγ<span class="wsf7">(Halliwell and Gutteridge <span class="fc1 ws36">1999</span></span>). Chronicand</div>

<div class="t m0 x2 h7 y17c ff1 fs2 fc0 sc0 ls84 ws1e1">persistent infections ca<span class="ls87 ws1e2">n induce prolonged immunesystem</span></div>

<div class="t m0 x2 h7 y17d ff1 fs2 fc0 sc0 ls88 ws1e3">activation, leading to high levels of localized orsystemic</div>

<div class="t m0 x2 h7 y17e ff1 fs2 fc0 sc0 ls10 ws1e4">O&NS, which leads to oxidative damage to pro-teins</div>

<div class="t m0 x2 h7 y17f ff1 fs2 fc0 sc0 ls10 ws25">lipids and nucleic acids. Prolonged activation of theimmune</div>

<div class="t m0 x2 h7 y180 ff1 fs2 fc0 sc0 ls10 ws17">system leads to damage to antioxidant defenses.Figure</div>

<div class="t m0 x2 h7 y181 ff1 fs2 fc0 sc0 ls10 wse9"><span class="fc1 ls89">1shows</span><span class="ws65"> the effects of pathogens on the immunesystem</span></div>

<div class="t m0 x2 h7 y182 ff1 fs2 fc0 sc0 ls10 ws1e5">leading to immuno-inflammatory cascades.Transition</div>

<div class="t m0 x2 h4 y183 ff2 fs2 fc0 sc0 ls10 ws1e6">to a chronic inflammatory stateNot</div>

<div class="t m0 x2 h7 y184 ff1 fs2 fc0 sc0 ls28 ws1e7">only persistent infections can create a chronic inflammato-ry</div>

<div class="t m0 x2 h7 y185 ff1 fs2 fc0 sc0 ls44 ws1e8">state, but also acute microbia<span class="ls32 ws1e9">l infections can lead to chronicsystemic</span></div>

<div class="t m0 x2 h7 y186 ff1 fs2 fc0 sc0 ls54 ws1ea">inflammation, whether the infection becomes chronicor</div>

<div class="t m0 x2 h7 y187 ff1 fs2 fc0 sc0 ls25 ws1eb">is cleared by the immune system (Pincus <span class="fc1 ls34 wsc6">2005</span><span class="ls90 ws1ec">). Processesthat</span></div>

<div class="t m0 x2 h7 y188 ff1 fs2 fc0 sc0 ls44 ws112">may explain chronic systemic inflammation are, for exam-ple</div>

<div class="t m0 x2 h7 y189 ff1 fs2 fc0 sc0 ls32 ws1ed">, damage by O&NS and autoimmune responses generatedby</div>

<div class="t m0 x2 h7 y18a ff1 fs2 fc0 sc0 ls34 ws1ee">infections or mounted against self-antigens that have beenmodified</div>

<div class="t m0 x2 h7 y18b ff1 fs2 fc0 sc0 ls2c ws1ef">by O&NS (Maes et al. <span class="fc1 ls34 wsc6">2006b</span><span class="ls36 ws1f0">). Thus, activation ofO</span></div>

<div class="t m0 x2 h7 y18c ff1 fs2 fc0 sc0 ls34 ws1f1">&NS pathways may cause O&NS damage depending on thestate</div>

<div class="t m0 x2 h7 y18d ff1 fs2 fc0 sc0 ls2c ws1f2">of the antioxidant defenses, and lead to elevations of NF-κB</div>

<div class="t m0 x2 h8 y18e ff5 fs2 fc0 sc0 ls10 ws36"><span class="ff1 ls32 ws11e"> levels. O&NS damage to lipids and proteins can changetheir</span></div>

<div class="t m0 x2 h7 y18f ff1 fs2 fc0 sc0 ls44 ws1f3">structure so that they are regarded as 'non self', leading tothe</div>

<div class="t m0 x2 h7 y190 ff1 fs2 fc0 sc0 ls32 ws1f4">generation of auto-immune responses and autoreactive Tcells</div>

<div class="t m0 x2 h7 y191 ff1 fs2 fc0 sc0 ls32 ws1f5">(Maes et al. <span class="fc1 ls34 wsc6">2006a</span><span class="ls8a">,<span class="fc1 ls10 ws36">b</span><span class="ls37">).Metab</span></span></div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span><span class="ws13b">540 527</span></div>

</div>

</div>

<div class="t m0 x4 h7 y192 ff1 fs2 fc0 sc0 ls95 ws72">Different infections can initiate or exacerbate a chronic in-flammatory</div>

<div class="t m0 x0 h7 y193 ff1 fs2 fc0 sc0 ls96 ws8e">condition and cause au<span class="ls97 ws1f6">toimmune responses, usingprocesses</span></div>

<div class="t m0 x0 h7 y194 ff1 fs2 fc0 sc0 ls98 ws1f7">described as molecu<span class="ls99 ws1f8">lar mimicry, bystander damageand</span></div>

<div class="t m0 x0 h7 y195 ff1 fs2 fc0 sc0 ls9a ws1f9">epitope spreading (Fujinamietal.<span class="fc1 ls9b ws1fa">2006</span><span class="ls9c ws1fb">). Autoreactive Tcells</span></div>

<div class="t m0 x0 h7 y196 ff1 fs2 fc0 sc0 ls9d ws1fc">can be formed when the pathogen contains epitopes, whichare</div>

<div class="t m0 x0 h7 y197 ff1 fs2 fc0 sc0 ls9e ws1fd">cross reactive to host molecules, leading to autoimmunetargeting</div>

<div class="t m0 x0 h7 y198 ff1 fs2 fc0 sc0 ls9f ws1fe">of both pathogen and self epitopes. Epitope spreadingand</div>

<div class="t m0 x0 h7 y199 ff1 fs2 fc0 sc0 lsa0 ws1ff">bystander damage are other sources of chronic immuneactivation</div>

<div class="t m0 x0 h7 y19a ff1 fs2 fc0 sc0 ls99 ws200">, inflammation and autoimmune responses. Bystandercell</div>

<div class="t m0 x0 h7 y19b ff1 fs2 fc0 sc0 lsa1 ws201">death, which is caused by pathogen specific T cells, mayincrease</div>

<div class="t m0 x0 h7 y19c ff1 fs2 fc0 sc0 ls9d ws202">the release of self-epitopes that induce de novo T cellresponses.</div>

<div class="t m0 x0 h7 y19d ff1 fs2 fc0 sc0 ls95 ws203">Pathogen-specific T <span class="ls9a ws204">cells may initiate bystander acti-vation</span></div>

<div class="t m0 x0 h7 y19e ff1 fs2 fc0 sc0 lsa2 ws205">by migrating to areas of infection, where they encounterpathogen-infected</div>

<div class="t m0 x0 h7 y19f ff1 fs2 fc0 sc0 ls99 ws1ff">cells that present pathogen peptides in thecontext</div>

<div class="t m0 x0 h7 y1a0 ff1 fs2 fc0 sc0 ls99 ws206">of MHC human leukocyte antigen class I molecules toT</div>

<div class="t m0 x0 h7 y1a1 ff1 fs2 fc0 sc0 ls98 ws207">cells. The CD8+ T cells recogni<span class="ls9f ws208">ze these infected cells and willrelease</span></div>

<div class="t m0 x0 h7 y1a2 ff1 fs2 fc0 sc0 lsa3 ws155">cytotoxic granules which may result in the killing of theinfected</div>

<div class="t m0 x0 h7 y1a3 ff1 fs2 fc0 sc0 ls97 ws209">cell. Consequently, the dying cells, the CD8+ T cellsand</div>

<div class="t m0 x0 h7 y1a4 ff1 fs2 fc0 sc0 ls9f ws20a">macrophages within the inflammatory focus, release PICsand</div>

<div class="t m0 x0 h7 y1a5 ff1 fs2 fc0 sc0 ls9f ws20b">ROS/RNS, which may cause bystander damage of unin-fected</div>

<div class="t m0 x0 h7 y1a6 ff1 fs2 fc0 sc0 ls9f ws20c">but neighbouring cells (Fujinami et al. <span class="fc1 ls9b ws1fa">2006</span><span class="lsa4 ws20d">). This mayresult</span></div>

<div class="t m0 x0 h7 y1a7 ff1 fs2 fc0 sc0 ls9f ws20d">in additional immunopathology (Duke <span class="fc1 ls9b ws1fa">1989</span><span class="lsa5 ws20e">;SmythandSedgwick</span></div>

<div class="t m0 x0 h7 y1a8 ff1 fs2 fc0 sc0 lsa6 ws20f"><span class="fc1 ls9b ws1fa">1998</span><span class="lsa3 ws1b7">), because self proteins may be released andengulfed</span></div>

<div class="t m0 x0 h7 y1a9 ff1 fs2 fc0 sc0 ls9d ws210">by dendritic cells, macrophages and antigen presentingcells</div>

<div class="t m0 x2 h7 y1aa ff1 fs2 fc0 sc0 ls97 ws211">(Fujinami et al. <span class="fc1 ls9b ws1fa">2006</span><span class="lsa7 ws212">). The latter cells are subsequentlylysed</span></div>

<div class="t m0 x2 h7 y1ab ff1 fs2 fc0 sc0 lsa8 wsb0">by cytotoxic CD4+T cells (Hahn et al. <span class="fc1 ls9b ws1fa">1995<span class="fc0 ls4f">).It</span></span></div>

<div class="t m0 x5 h7 y1ac ff1 fs2 fc0 sc0 lsa9 ws213">is also possible that the initial infection may create autor-eactive</div>

<div class="t m0 x2 h7 y1ad ff1 fs2 fc0 sc0 lsaa ws214">T cells, but insufficien<span class="lsa4 ws215">t inflammation to induce overtpathology</span></div>

<div class="t m0 x2 h7 y1ae ff1 fs2 fc0 sc0 ls9e ws216">(Hahn et al. <span class="fc1 ws217">1995</span><span class="ls9d ws218">). Nevertheless, autoreactive T cellscan</span></div>

<div class="t m0 x2 h7 y1af ff1 fs2 fc0 sc0 ls9d ws219">be activated by subsequent infections with a broad range ofpathogens</div>

<div class="t m0 x2 h7 y1b0 ff1 fs2 fc0 sc0 ls9d ws21a">leading to overt inflammatory damage (Hahn et al.1995</div>

<div class="t m0 x2 h7 y1b1 ff1 fs2 fc1 sc0 ls9b ws1fa"><span class="fc0 lsa3 ws1b7">). This fertile field, induced by the interaction with theprimary</span></div>

<div class="t m0 x2 h7 y1b2 ff1 fs2 fc0 sc0 lsab ws1ee">infecting agent, can change with time (Fujinami et al.2006</div>

<div class="t m0 x2 h7 y1b3 ff1 fs2 fc1 sc0 ls9b ws1fa"><span class="fc0 lsac ws21b">). The initial priming infection and subsequent challengesthat</span></div>

<div class="t m0 x2 h7 y1b4 ff1 fs2 fc0 sc0 lsab ws68">produce symptoms may be separated by many years andsometimes</div>

<div class="t m0 x2 h7 y1b5 ff1 fs2 fc0 sc0 lsad ws21c">more than one challenge is needed to induce symp-toms.</div>

<div class="t m0 x2 h7 y1b6 ff1 fs2 fc0 sc0 ls9f ws21d">A fertile field can also be generated when an infectionwith</div>

<div class="t m0 x2 h7 y1b7 ff1 fs2 fc0 sc0 ls9e wsd2">a pathogen, which shows m<span class="lsae ws120">olecular mimicry to self CNSmolecules</span></div>

<div class="t m0 x2 h7 y1b8 ff1 fs2 fc0 sc0 lsa9 ws21e">, primes autoreactive T cells without initiating auto-</div>

<div class="t m0 x2 h7 y1b9 ff1 fs2 fc0 sc0 lsaf ws21f">immune inflammatory disease. La<span class="ls4f ws220">ter challenges may then trig-ger</span></div>

<div class="t m0 x2 h7 y1ba ff1 fs2 fc0 sc0 lsad ws108">these autoimmune cells to cause overt symptoms (Fujinamiet</div>

<div class="t m0 x2 h4 y1bc ff2 fs2 fc0 sc0 ls10 ws107">peripheral inflammation to neuro-inflammationIt</div>

<div class="t m0 x2 h7 y1bd ff1 fs2 fc0 sc0 ls10 ws222">is well known that peripheral inflammation may induce abehavioral</div>

<div class="t m0 x2 h7 y1be ff1 fs2 fc0 sc0 ls10 ws223">complex characterized by fever, anorexia, weightFig.</div>

<div class="t m0 x0 h5 y1bf ff2 fs4 fc0 sc0 ls10 ws224">1 <span class="ff1 ws225">Effects of pathogens on the immune system leading to immuno-inflammatory</span></div>

<div class="t m0 x0 h5 y1c0 ff1 fs4 fc0 sc0 ls10 ws226">cascades. Different pathogens in ME/CFS may activatethe</div>

<div class="t m0 x0 h5 y1c1 ff1 fs4 fc0 sc0 ls10 ws227">immuno-inflammatory pathways, reactive oxygen and nitrogenspecies</div>

<div class="t m0 x0 h5 y1c2 ff1 fs4 fc0 sc0 ls10 ws228">(ROS/RNS), oxidative and nitrosative stress (O&NS) path-</div>

<div class="t m0 x0 hd y1c3 ff1 fs4 fc0 sc0 ls10 ws229">ways, and nuclear factor <span class="ff5 ls91">κB</span><span class="ws22a"> (NF-κB<span class="ws22b">) through the Toll-like receptor</span></span></div>

<div class="t m0 x0 h5 y1c4 ff1 fs4 fc0 sc0 lsb0 ws22c">(TLR) complex, and consequently inducible nitric oxide synthase</div>

<div class="t m0 x0 h5 y1c5 ff1 fs4 fc0 sc0 ls92 ws22d">(iNOS) and cyclo-oxygenase-2 (COX-2). Consequently, pro-</div>

<div class="t m0 x2 hd y1c6 ff1 fs4 fc0 sc0 ls10 ws22e">inflammatory cytokines (PICs), e.g. tumor necrosis factor-α<span class="ws44">(TNFα),</span></div>

<div class="t m0 x2 h5 y1c7 ff1 fs4 fc0 sc0 ls10 ws229">interleukin-1 (IL-1) and IL-6, are increased in individuals with ME/</div>

<div class="t m0 x2 h5 y1c8 ff1 fs4 fc0 sc0 ls10 ws22f">CFS. This disease can feature elevations of Thelper (Th)1, Th17, Th2and</div>

<div class="t m0 x2 h5 y1c9 ff1 fs4 fc0 sc0 ls10 ws230">Tregulatory (Treg) cytokines. Increased O&NS, through the for-mation</div>

<div class="t m0 x2 h5 y1ca ff1 fs4 fc0 sc0 ls10 ws231">of neoepitopes, and enhanced Th17 and Th1 responses increasethe</div>

<div class="t m0 x2 h5 y1cb ff1 fs4 fc0 sc0 ls10 ws232">risk to develop autoimmune reactions528</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws233">loss, and behavior inhibition, including reduced locomotoractivity</div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 ws132">and listlessness (Goehler et al. <span class="fc1 ws36">2005</span><span class="ws234">). CirculatingPICs</span></div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws235">and other inflammatory and O&NS molecules mayaffect</div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 wsad">brain function through several routes, mainly humoraland</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls54 ws1d9">neural pathways (Ferrari and Tarelli <span class="fc1 ls10 ws36">2011<span class="fc0 ws236">). The bloodbrain</span></span></div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls10 ws237">barrier (BBB) controls the passage of inflammatorycompounds</div>

<div class="t m0 x0 h7 y53 ff1 fs2 fc0 sc0 ls10 ws238">from the plasma to the brain. There are severalways</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls10 ws66">by which these substances can cross the BBB (Perry etal.</div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 ws239"><span class="fc1 ws36">2010</span><span class="ws1d7">). Firstly, these substances can enter the brain throughthe</span></div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc0 sc0 ls10 ws1d">areas that lack a BBB, e.g. the circumventricular organs</div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws23a">(Whitton <span class="fc1 ws36">2007</span><span class="ws23b">). Secondly, cytokines may cross the BBBusing</span></div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws23c">specific transporters (Kim and de Vellis <span class="fc1 ws36">2005</span><span class="ws10a">). Thirdly,</span></div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10 ws23d">BBB permeability may be increased as a consequence ofimmuno-inflammatory</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls10 ws23e">stimuli. For example, Th17 T cellscan</div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls10 ws23f">infiltrate the brain through the BBB via loosening of theendothelial</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10 ws240">tight junctions by increased secretion of IL-17 andIL-22</div>

<div class="t m0 x0 h7 y5d ff1 fs2 fc0 sc0 ls10 ws241">(Jadidi-Niaragh and Mirshafiey <span class="fc1 ws36">2011<span class="fc0 ls2e ws242">). Fourthly, periph-eral</span></span></div>

<div class="t m0 x0 h7 y5e ff1 fs2 fc0 sc0 ls10 ws1a1">stimuli may activate endothelial cells which in turn mayinduce</div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws243">immune signals in the CNS (Ransohoff and Perry2009</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 lsb8 ws244">). For example, Parkinson</span><span class="ff6 fc0">’<span class="ff1 ws2c">s Disease is accompanied bybreakdown</span></span></div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 ls10 ws245">of the BBB which allows noxious blood-bornesubstances</div>

<div class="t m0 x0 h7 y115 ff1 fs2 fc0 sc0 ls10 ws246">to penetrate in the CNS (Kortekaas et al. <span class="fc1 ws36">2005</span>).Likewise</div>

<div class="t m0 x0 h7 y116 ff1 fs2 fc0 sc0 ls10 ws247">, disruption of the BBB allows the extravasation ofPICs</div>

<div class="t m0 x0 h7 y117 ff1 fs2 fc0 sc0 ls10 ws248">and immune cells, which can activate microglia and,</div>

<div class="t m0 x0 h7 y118 ff1 fs2 fc0 sc0 ls10 ws249">therefore, induce neuroprogression (Leonard and Maes <span class="fc1 ws36">2012</span>).Neuroprogression</div>

<div class="t m0 x0 h7 y119 ff1 fs2 fc0 sc0 ls10 ws60">is a progressive process, which is inducedby</div>

<div class="t m0 x0 h7 y11a ff1 fs2 fc0 sc0 ls10 ws24a">inflammatory and O&NS processes, and that is character-ized</div>

<div class="t m0 x0 h7 y11b ff1 fs2 fc0 sc0 ls10 ws216">by neurodegeneration, reduced neurogenesis and neuro-nal</div>

<div class="t m0 x0 h7 y11c ff1 fs2 fc0 sc0 ls10 ws24b">plasticity, and/or neuronal apoptosis (Berk et al. <span class="fc1 ws36">2011<span class="fc0">).The</span></span></div>

<div class="t m0 x4 h7 y11d ff1 fs2 fc0 sc0 ls10 ws1d5">second route of immune-to-brain communication isthe</div>

<div class="t m0 x0 h7 y11e ff1 fs2 fc0 sc0 ls10 ws24c">neural pathway, which transmits peripheral inflammatorysignals</div>

<div class="t m0 x0 h7 y11f ff1 fs2 fc0 sc0 ls10 ws24d">to the CNS via the autonomic nervous system. Themost</div>

<div class="t m0 x0 h7 y120 ff1 fs2 fc0 sc0 ls10 ws1ce">important afferent pathway that signals peripheral in-flammation</div>

<div class="t m0 x0 h7 y121 ff1 fs2 fc0 sc0 ls10 ws1fd">to the CNS is the vagus nerve. These neuralpathways</div>

<div class="t m0 x0 h7 y122 ff1 fs2 fc0 sc0 ls10 ws1c3">are stimulated by inflammatory signals that increasethe</div>

<div class="t m0 x0 h7 y123 ff1 fs2 fc0 sc0 ls10 ws155">levels of brain cytokines (Perry et al. <span class="fc1 ws36">2003</span><span class="lsb1">,</span><span class="fc1 ws36">2010<span class="fc0 ws24e">; Tracey2002</span></span></div>

<div class="t m0 x0 h7 y124 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws24f">). The role of the vagus nerve is crucial in inducingneuro-inflammation</span></div>

<div class="t m0 x0 h7 y125 ff1 fs2 fc0 sc0 ls10 ws250">and activation of microglia (Goehler etal.</div>

<div class="t m0 x0 h7 y126 ff1 fs2 fc0 sc0 ls10 ws251"><span class="fc1 ws36">1997</span><span class="lsb2">,</span><span class="fc1 ws36">2005<span class="fc0 ws1a0">; Herkenham et al. <span class="fc1 ws36">1998<span class="fc0 ws252">; Ericsson et al. <span class="fc1 ws36">1997<span class="fc0">;</span></span></span></span></span></span></div>

<div class="t m0 x0 h7 y127 ff1 fs2 fc0 sc0 ls10 ws253">Benarroch <span class="fc1 ws36">2011<span class="fc0 ws254">; Blatteis and Sehic </span>1997<span class="fc0 ws255">; Ek et al. </span>1998<span class="fc0">;</span></span></div>

<div class="t m0 x0 h7 y128 ff1 fs2 fc0 sc0 lsb9 ws256">Saper <span class="fc1 ls10 ws36">1995</span><span class="lsba ws257">;Gallaheretal.2012<span class="fc1 ls10 ws36"><span class="fc0 ws24e">; Riazi et al. <span class="fc1 ws36">2008</span><span class="lsba ws257">;Engleretal.</span></span></span></span></div>

<div class="t m0 x0 h7 y129 ff1 fs2 fc0 sc0 ls10 ws258"><span class="fc1 ws36">2011<span class="fc0 ws1d7">). Not only PICs, but also prostaglandins and comple-ment</span></span></div>

<div class="t m0 x0 h7 y12a ff1 fs2 fc0 sc0 ls51 ws259">factors may activate the vagal nerve pathways, viachemoreceptors</div>

<div class="t m0 x0 h7 y12b ff1 fs2 fc0 sc0 ls10 ws25a">situated on glomus cells in the vagal para-</div>

<div class="t m0 x0 h7 y1cc ff1 fs2 fc0 sc0 ls10 ws1d6">ganglia (Goehler et al. <span class="fc1 ws36">1997</span><span class="ws25b">). The latter serve as a monitoringsystem</span></div>

<div class="t m0 x0 h7 y1cd ff1 fs2 fc0 sc0 ls1d ws25c">that detects immuno-inflammatory stimuli in thelymph</div>

<div class="t m0 x0 h7 y1ce ff1 fs2 fc0 sc0 ls10 ws25d">and spleen. Vagal afferents terminate in the dorsalvagal</div>

<div class="t m0 x0 h7 y1cf ff1 fs2 fc0 sc0 ls10 ws60">complex of the caudal medulla, the area postrema, thenucleus</div>

<div class="t m0 x0 h7 y1d0 ff1 fs2 fc0 sc0 ls10 ws25e">of the solitary tract and the dorsal motor nucleus of thevagus</div>

<div class="t m0 x0 h7 y1d1 ff1 fs2 fc0 sc0 ls10 ws25f">(Saper <span class="fc1 ws36">1995<span class="fc0 ws253">). Ascending immuno-inflammatory sig-nals</span></span></div>

<div class="t m0 x0 h7 y1d2 ff1 fs2 fc0 sc0 ls10 ws260">activate microglia in the nucleus of the solitary tract andthe</div>

<div class="t m0 x0 h7 y1d3 ff1 fs2 fc0 sc0 ls10 ws261">doral motor nucleus of the vagus (Gallaheretal.<span class="fc1 ws36">2012</span><span class="lsbb ws262">)andthe</span></div>

<div class="t m0 x0 h7 y1d4 ff1 fs2 fc0 sc0 ls10 ws263">hippocampus (Riazietal.<span class="fc1 ws36">2008</span><span class="ws23b">). Subsequently, theseperipheral</span></div>

<div class="t m0 x2 h7 y1d5 ff1 fs2 fc0 sc0 ls10 ws101">immuno-inflammatory signals activate the produc-tion</div>

<div class="t m0 x2 h7 y1d6 ff1 fs2 fc0 sc0 ls11 ws2d">of PICs in the amygadala, which acts to coordinatebehavioral</div>

<div class="t m0 x2 h7 y1d7 ff1 fs2 fc0 sc0 ls17 ws264">, CNS and autonomic responses (Engler et al.2011</div>

<div class="t m0 x2 h7 y1d8 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws219">). These bottom-up pathways may explain that systemicinflammation</span></div>

<div class="t m0 x2 h7 y1d9 ff1 fs2 fc0 sc0 ls10 ws265">is accompanied by neuro-inflammation and be-havioral</div>

<div class="t m0 x2 h7 y1da ff1 fs2 fc0 sc0 ls10 ws10f">changes. For example, systemic LPS administrationmay</div>

<div class="t m0 x2 h8 y1db ff1 fs2 fc0 sc0 ls10 ws1d5">elicit neuro-inflammation with increased brain TNFα,</div>

<div class="t m0 x2 h7 y1dc ff1 fs2 fc0 sc0 ls10 ws253">which remains elevated for months and is associated withbehavior</div>

<div class="t m0 x2 h7 y1dd ff1 fs2 fc0 sc0 ls10 ws248">symptoms, including fatigue, malaise, and hyper-alagesia</div>

<div class="t m0 x2 h7 y1de ff1 fs2 fc0 sc0 ls11 ws266">(Qin et al. <span class="fc1 ls18 ws7a">2007</span><span class="lsb3 ws267">). Moreover, once the immuno-inflammatory</span></div>

<div class="t m0 x2 h7 y1df ff1 fs2 fc0 sc0 ls10 wsbd">signals have arrived in the CNS via the vagalafferents</div>

<div class="t m0 x2 h7 y1e0 ff1 fs2 fc0 sc0 ls10 ws268">, a counter-regulatory anti-inflammatory reflex re-sponse</div>

<div class="t m0 x2 h7 y1e1 ff1 fs2 fc0 sc0 ls10 ws15c">is mounted that tends to downregulate the peripheralimmuno-inflammatory</div>

<div class="t m0 x2 h7 y1e2 ff1 fs2 fc0 sc0 ls10 ws269">response (Perry et al. <span class="fc1 ws36">2007</span><span class="ws26a">; Tracey2002</span></div>

<div class="t m0 x2 h7 y1e3 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws26b">). These counter-regulatory responses will be discussedin</span></div>

<div class="t m0 x2 h7 y1e4 ff1 fs2 fc0 sc0 ls10 ws26c"><span class="ff6 ws36">‘Mechanistic</span><span class="fc1 ws238"> explanations for the chronic and relapsing<span class="ff6">–</span></span></div>

<div class="t m0 x2 h7 y1e5 ff1 fs2 fc1 sc0 ls10 wsec">remitting nature of ME/CFS’.Neurological</div>

<div class="t m0 x2 h4 y1e6 ff2 fs2 fc0 sc0 ls10 ws7c">dysfunctions in ME/CFSSingle-photon</div>

<div class="t m0 x2 h7 y1e7 ff1 fs2 fc0 sc0 ls7d ws26d">emission computed tomography (SPECT)</div>

<div class="t m0 x2 h7 y1e8 ff1 fs2 fc0 sc0 ls10 ws1c7">scans may reveal significantly lower cortical/cerebellar re-gional</div>

<div class="t m0 x2 h7 y1e9 ff1 fs2 fc0 sc0 ls10 ws10">cerebral blood flow frequently in the frontal, parietal,</div>

<div class="t m0 x2 h7 y1ea ff1 fs2 fc0 sc0 ls10 ws198">temporal, occipital, brain stem and throughout the cerebralcortex</div>

<div class="t m0 x2 h7 y1eb ff1 fs2 fc0 sc0 ls10 ws26e">(Schwartz et al. <span class="fc1 ws36">1994</span><span class="ws26f">; Biswal et al. <span class="fc1 ws36">2011</span><span class="ws117">; Patrick etal.</span></span></div>

<div class="t m0 x2 h7 y1ec ff1 fs2 fc0 sc0 ls10 ws1bd"><span class="fc1 ws36">2008</span><span class="ws270">). Positron emission tomography (PET) scans mayreveal</span></div>

<div class="t m0 x2 h7 y1ed ff1 fs2 fc0 sc0 ls10 ws13a">decreased density of 5-HT transporter in the brain</div>

<div class="t m0 x2 h7 y1ee ff1 fs2 fc0 sc0 ls10 ws271">(Yamamoto et al. <span class="fc1 ws36">2004</span><span class="ws272">). Proton magnetic resonance spec-troscopy</span></div>

<div class="t m0 x2 h7 y1ef ff1 fs2 fc0 sc0 ls10 ws273">has revealed various abnormalities in metabolicpathways</div>

<div class="t m0 x2 h7 y1f0 ff1 fs2 fc0 sc0 ls10 ws13a">in the brain (Chaudhuri et al. <span class="fc1 ws36">2003</span><span class="ws151">; Chaudhuriand</span></div>

<div class="t m0 x2 h7 y1f1 ff1 fs2 fc0 sc0 ls10 wsf8">Behan <span class="fc1 ws36">2004</span><span class="ws173">). Barnden et al. (<span class="fc1 ws36">2011</span><span class="ws274">) detected that whitematter</span></span></div>

<div class="t m0 x2 h7 y1f2 ff1 fs2 fc0 sc0 lsb4 ws1ff">volume decreased with fatigue duration and theyfound</div>

<div class="t m0 x2 h7 y1f3 ff1 fs2 fc0 sc0 lsb5 ws275">signs of impaired cerebrovascular autoregulation.The</div>

<div class="t m0 x2 h7 y1f4 ff1 fs2 fc0 sc0 ls10 ws276">findings suggest that fatigue onset is accompanied byan</div>

<div class="t m0 x2 h7 y1f5 ff1 fs2 fc0 sc0 ls10 ws277">insult that suppresses cognitive activity and modulatesthe</div>

<div class="t m0 x2 h7 y1f6 ff1 fs2 fc0 sc0 ls10 ws278">autonomic system (Barnden et al. <span class="fc1 ws36">2011</span><span class="ws279">). Elevated numb-ers</span></div>

<div class="t m0 x2 h7 y1f7 ff1 fs2 fc0 sc0 lsb6 ws27a">of punctuate lesions have been detected in ME/CFSwithout</div>

<div class="t m0 x2 h7 y1f8 ff1 fs2 fc0 sc0 ls10 ws27b">psychiatric comorbidity in the frontal lobes as com-</div>

<div class="t m0 x2 h7 y1f9 ff1 fs2 fc0 sc0 ls10 ws27c">pared to controls (Lange et al. <span class="fc1 ws36">1999</span><span class="ws27d">). 3 Tesla magnetic-</span></div>

<div class="t m0 x2 h7 y1fa ff1 fs2 fc0 sc0 ls10 ws1ac">resonance imaging (3 T MRI) scans have revealed signifi-cant</div>

<div class="t m0 x2 h7 y1fb ff1 fs2 fc0 sc0 ls5 wse">neuroanatomical changes, including reduced whitematter</div>

<div class="t m0 x2 h7 y1fc ff1 fs2 fc0 sc0 ls10 ws27e">volume (Puri et al. <span class="fc1 ws36">2011</span><span class="ws27f">). A 1.5 T MRI, on the otherhand</span></div>

<div class="t m0 x2 h7 y1fd ff1 fs2 fc0 sc0 ls10 wsf9">, showed no abnormalities suggesting brain atrophy orwhite</div>

<div class="t m0 x2 h7 y1fe ff1 fs2 fc0 sc0 ls10 ws280">matter lesions in patients with ME/CFS (Perrin et al.2010</div>

<div class="t m0 x2 h7 y1ff ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws271">). Greco et al. (</span>1997<span class="fc0 ws74">) found no specific white matterabnormalities</span></div>

<div class="t m0 x2 h7 y200 ff1 fs2 fc0 sc0 ls10 ws281">in ME/CFS. On SPECT imaging, ME/CFSshares</div>

<div class="t m0 x2 h7 y201 ff1 fs2 fc0 sc0 lsb7 ws282">some similarities with AIDS Dementia Complex:</div>

<div class="t m0 x2 h7 y202 ff1 fs2 fc0 sc0 ls10 ws283">acute changes in radionuclide uptake in the younger popu-lationmaybecausedbyinflammatoryprocessesatthecellular</div>

<div class="t m0 x2 h7 y204 ff1 fs2 fc0 sc0 ls10 ws285">or micro-vascular level (Schwartz et al. <span class="fc1 ws36">1994</span><span class="ws1bc">). Thefindings</span></div>

<div class="t m0 x2 h7 y205 ff1 fs2 fc0 sc0 ls10 ws37">in ME/CFS are consistent with the hypothesis thatthis</div>

<div class="t m0 x2 h7 y206 ff1 fs2 fc0 sc0 ls10 ws26">disease results from a viral infection of neurons, glia orMetab</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span><span class="ws13b">540 529</span></div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws286">vasculature (Schwartz et al. <span class="fc1 ws36">1994<span class="fc0 ws287">). Thus, viral infection canprovoke</span></span></div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 ws288">neurological dysfunction by interfering with intra-cellular</div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws17d">mechanisms or membrane transport systems or cere-bral</div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws1b">hypoperfusion due to vasculitis. All in all, these brainstudies</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws201">could indicate metabolic dysfunctions, neuroinflam-mation</div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls10 ws1cc">or maybe neuroprogression in patients with ME/CFS.Given</div>

<div class="t m0 x4 h7 y53 ff1 fs2 fc0 sc0 lsbd ws289">the different findings on activated immuno-inflammatory</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls10 ws28a">pathways in ME/CFS, it comes as no surprisetherefore</div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 ws139">that autonomic (Newton et al. <span class="fc1 ws36">2007</span><span class="ws28b">; Winkler et al.2004</span></div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws28c">) and endocrine abnormalities (Van Den Eede et al. <span class="fc1 ws36">2007</span>;</span></div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws1bf">Demitrack et al. <span class="fc1 ws36">1991<span class="fc0 ws28d">; Demitrack and Crofford <span class="fc1 ws36">1998</span><span class="lsc8 ws28e">)accom-pany</span></span></span></div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws1c">ME/CFS. Recently we have reviewed the autonomicdysfunctions</div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10 ws28f">and orthostatic abnormalities in ME/CFS (Maesand</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls10 ws21c">Twisk<span class="fc1 ws36">2009</span><span class="ws1d">). Autonomic symptoms are associated withcardiovascular</span></div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls10 ws290">abnormalities and may be explained by acti-vated</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls33 ws83">immuno-inflammatory, intracellular and O&NS path-</div>

<div class="t m0 x0 h8 y5d ff1 fs2 fc0 sc0 ls10 ws291">ways, including increased TNFα<span class="ws212">, NO-related mechanismsand</span></div>

<div class="t m0 x0 h8 y5e ff1 fs2 fc0 sc0 lsc9 ws292">NF-κB<span class="lsbe ws293"> (Maes et al. <span class="fc1 ls5d ws149">2011</span><span class="ls67 ws294">; Maes and Twisk <span class="fc1 ls5d ws149">2009</span><span class="ls7f">).Hypothalamic-pituitary-adrenal</span></span></span></div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws295">(HPA) axis hypofunction hasbeen</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc0 sc0 ls10 ws87">established in part of individuals with ME/CFS (Scott etal.</div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 lsbf ws296"><span class="fc1 ls1e ws98">1998</span><span class="lsc0 ws297">). This entails decreased production of cortisol,</span></div>

<div class="t m0 x0 h7 y115 ff1 fs2 fc0 sc0 ls10 ws298">blunted diurnal variation of cortisol, and blunted responsesto</div>

<div class="t m0 x0 h7 y116 ff1 fs2 fc0 sc0 ls10 ws1cb">a variety of provocation tests, including psychological andphysical</div>

<div class="t m0 x0 h7 y117 ff1 fs2 fc0 sc0 ls10 ws299">stressors (under review). Also these alterations inHPA-axis</div>

<div class="t m0 x0 h7 y118 ff1 fs2 fc0 sc0 lsc1 ws29a">function may be explained by immuno-inflammatory</div>

<div class="t m0 x0 h7 y119 ff1 fs2 fc0 sc0 ls10 ws29b">and O&NS effects, including increased NOproduction</div>

<div class="t m0 x0 h7 y11a ff1 fs2 fc0 sc0 ls10 ws1d0">attenuating HPA-axis functions (under review).Mechanistic</div>

<div class="t m0 x0 h4 yca ff2 fs2 fc0 sc0 ls10 ws28b">explanations for the onset of ME/CFSsymptoms</div>

<div class="t m0 x0 h4 ycb ff2 fs2 fc0 sc0 ls10 ws3a">including post exertional malaiseThis</div>

<div class="t m0 x0 h7 ycd ff1 fs2 fc0 sc0 ls10 ws23f">section will propose an immuno-inflammatory explana-tion</div>

<div class="t m0 x0 h7 yce ff1 fs2 fc0 sc0 ls10 ws23e">for the hallmark symptoms of the disease, includingfatigue</div>

<div class="t m0 x0 h7 ycf ff1 fs2 fc0 sc0 ls10 ws29c">, malaise, neurocognitive symptoms and a range ofabnormal</div>

<div class="t m0 x0 h7 yd0 ff1 fs2 fc0 sc0 ls10 ws1d0">responses to exertion that may be delayed by 24 oreven</div>

<div class="t m0 x0 h7 yd1 ff1 fs2 fc0 sc0 ls10 ws29d">48 h, which is often labeled as post exertional malaise</div>

<div class="t m0 x0 h7 yd2 ff1 fs2 fc0 sc0 ls10 ws29e">(VanNess et al. <span class="fc1 ws36">2010</span><span class="ws279">; Van Oosterwijck et al. <span class="fc1 ws36">2010</span><span class="lsca ws29f">;Carrutherset</span></span></div>

<div class="t m0 x0 h7 yd3 ff1 fs2 fc0 sc0 ls10 ws2a0">al.<span class="fc1 ws36">2011<span class="fc0 ws2a1">). The term refers to abnormal responses to even atrivial</span></span></div>

<div class="t m0 x0 h7 yd4 ff1 fs2 fc0 sc0 ls10 ws2a2">increase in normal levels of physical or neurocognitiveactivity.</div>

<div class="t m0 x0 h7 yd5 ff1 fs2 fc0 sc0 ls10 ws247">Post activity relapse may therefore be a better term.This</div>

<div class="t m0 x0 h7 yd6 ff1 fs2 fc0 sc0 ls10 ws1d2">phenomenon is often reported by ME patients to besimilar</div>

<div class="t m0 x0 h7 yd7 ff1 fs2 fc0 sc0 ls10 ws247">to the acute phase of influenza, with symptoms indi-cating</div>

<div class="t m0 x0 h7 yd8 ff1 fs2 fc0 sc0 ls10 ws17b">infection/inflammation, e.g. sore throat, lymph tender-ness</div>

<div class="t m0 x0 h7 yd9 ff1 fs2 fc0 sc0 ls10 ws134">or swelling, malaise, hyperalgesia and brain fog (Twiskand</div>

<div class="t m0 x0 h7 yda ff1 fs2 fc0 sc0 ls10 ws2a3">Maes<span class="fc1 ws36">2009</span><span class="ws2a4">). Insignificant increases in physical activity orminor</span></div>

<div class="t m0 x0 h7 ydb ff1 fs2 fc0 sc0 ls10 ws178">cognitive tasks may exacerbate immune dysfunction,</div>

<div class="t m0 x0 h7 ydc ff1 fs2 fc0 sc0 ls10 ws2a5">inflammation and O&NS thereby producing further signs ofthe</div>

<div class="t m0 x0 h7 ydd ff1 fs2 fc0 sc0 ls3a ws2a6">disease (Twisk and Maes <span class="fc1 ls1e ws98">2009</span><span class="ls71 ws2a7">). The effect may bedelayed</span></div>

<div class="t m0 x0 h7 yde ff1 fs2 fc0 sc0 ls10 ws191">, but is predictable and accumulative, varying in dura-tion</div>

<div class="t m0 x0 h7 ydf ff1 fs2 fc0 sc0 ls10 ws2a8">dependant on disease severity and accumulative activitylevels</div>

<div class="t m0 x0 h7 ye0 ff1 fs2 fc0 sc0 ls10 ws277">(VanNess et al. <span class="fc1 ws36">2010</span><span class="wsae">; Van Oosterwijck et al. <span class="fc1 ws36">2010</span>;</span></div>

<div class="t m0 x0 h7 ye1 ff1 fs2 fc0 sc0 ls10 ws24b">Carruthers et al. <span class="fc1 ws36">2011</span>).In</div>

<div class="t m0 x5 h7 ye2 ff1 fs2 fc0 sc0 ls10 ws2a9">ME/CFS there are significant correlations between typ-ical</div>

<div class="t m0 x2 h7 ye3 ff1 fs2 fc0 sc0 ls10 ws2aa">symptoms, such as fatigue, malaise, a subjective feeling ofinfection</div>

<div class="t m0 x2 h7 ye4 ff1 fs2 fc0 sc0 ls10 ws10b">,sleep disorders, autonomic symptoms and postexer-tional</div>

<div class="t m0 x2 h7 ye5 ff1 fs2 fc0 sc0 ls10 ws2ab">malaise and activated O&NS (see above) and immuno-inflammatory</div>

<div class="t m0 x2 h7 ye6 ff1 fs2 fc0 sc0 ls10 ws19">pathways, including increased neopterin andTNFαconcentrations</div>

<div class="t m0 x2 h8 ye7 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws2ac"> (Maes et al. <span class="fc1 ws36">2012a<span class="fc0 ws2ac">). This indicates thatthese</span></span></span></div>

<div class="t m0 x2 h7 y207 ff1 fs2 fc0 sc0 ls10 ws2ad">characteristic symptoms of ME/CFS are in part mediatedthrough</div>

<div class="t m0 x2 h7 y208 ff1 fs2 fc0 sc0 ls10 ws248">effects of immuno-inflammatory and O&NS path-</div>

<div class="t m0 x2 h7 y209 ff1 fs2 fc0 sc0 ls10 ws113">ways. We have previously reviewed that PICs, e.g. IL-1 andTNFα</div>

<div class="t m0 x2 h8 y20a ff1 fs2 fc0 sc0 ls73 ws18b"><span class="ls1e ws2ae">, and Th1-like cytokines, such as IFNγ<span class="lsc3 ws2af">, activatedO</span></span></div>

<div class="t m0 x2 h7 y20b ff1 fs2 fc0 sc0 ls10 ws2b0">&NS pathways and lowered antioxidant levels, includingcoenzyme</div>

<div class="t m0 x2 h7 y20c ff1 fs2 fc0 sc0 ls10 ws29d">Q10 and zinc, may elicit the characteristic symp-toms</div>

<div class="t m0 x2 h7 y20d ff1 fs2 fc0 sc0 ls10 ws2aa">of ME/CFS, such as fatigue, malaise, and neurocognitiveand</div>

<div class="t m0 x2 h7 y20e ff1 fs2 fc0 sc0 ls10 ws2ab">autonomic symptoms (Maes and Twisk <span class="fc1 ws36 v0">2010<span class="fc0 lscb ws2b1">;Maesetal.2012b</span></span></div>

<div class="t m0 x2 h7 y20f ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ls54 ws113">; Anderson et al. </span>2012<span class="fc0 ws1d0">). For example, PICs are heavilyimplicated</span></div>

<div class="t m0 x2 h7 y210 ff1 fs2 fc0 sc0 ls10 ws2b2">in the cause of fatigue in multiple sclerosis (MS)</div>

<div class="t m0 x2 h7 y211 ff1 fs2 fc0 sc0 ls10 ws1bf">(Heesen et al. <span class="fc1 ws36">2006<span class="fc0 ws77">). Fatigue is also one of the most disablingsymptoms</span></span></div>

<div class="t m0 x2 h7 y212 ff1 fs2 fc0 sc0 ls10 ws2b3">in MS, with up to two thirds of patients describingfatigue</div>

<div class="t m0 x2 h8 y213 ff1 fs2 fc0 sc0 ls10 ws2b4">as their main complaint (Schwid et al. <span class="fc1 ws36">2002</span><span class="ws2b5">). TNFα<span class="ff5 ws36"><span class="ff1 lsc4 ws2b6">,asa</span></span></span></div>

<div class="t m0 x2 h7 y214 ff1 fs2 fc0 sc0 ls10 ws2b7">principal proinflammatory mediator, is associated with MS-</div>

<div class="t m0 x2 h7 y215 ff1 fs2 fc0 sc0 ls10 ws252">related fatigue. This is in support of a pathogenic role of theMS-related</div>

<div class="t m0 x2 h7 y216 ff1 fs2 fc0 sc0 ls10 ws114">inflammatory process in the development of fa-tigue</div>

<div class="t m0 x2 h7 y217 ff1 fs2 fc0 sc0 ls10 ws2b8">(Flachenecker et al. <span class="fc1 ws36">2004<span class="fc0 ws295">). Also, the production of Th1cytokines</span></span></div>

<div class="t m0 x2 h8 y218 ff1 fs2 fc0 sc0 ls10 ws2b9">, e.g. IFNγ<span class="lscc ws2ba">,inMSpatientsisassociatedwiththeextent</span></div>

<div class="t m0 x2 h7 y219 ff1 fs2 fc0 sc0 ls10 ws95">of fatigue (Pokryszko-Dragan et al. <span class="fc1 ws36">2012</span><span class="ws2ac">). Other stud-ies</span></div>

<div class="t m0 x2 h8 y21a ff1 fs2 fc0 sc0 ls10 wse2">have reported that TNFα<span class="lscd ws2bb">,IL-1βand<span class="ff5 lsc5"><span class="ff1 ls10 ws298"> IL-6 could be in-volved</span></span></span></div>

<div class="t m0 x2 h7 y21b ff1 fs2 fc0 sc0 ls10 ws119">in the pathophysiology of mental fatigue through theirability</div>

<div class="t m0 x2 h7 y21c ff1 fs2 fc0 sc0 ls10 ws2bc">to attenuate the astroglial clearance of extracellularglutamate</div>

<div class="t m0 x2 h7 y21d ff1 fs2 fc0 sc0 ls10 ws90">(Rönnbäck and Elisabeth Hansson <span class="fc1 ws36">2004</span><span class="ws32">). An ad-</span></div>

<div class="t m0 x2 h7 y21e ff1 fs2 fc0 sc0 ls10 ws1c3">verse effect caused by specific PICs, such as IL-1, on learningand</div>

<div class="t m0 x2 h7 y21f ff1 fs2 fc0 sc0 ls10 ws2bd">memory capacities, has been observed in several experi-mental</div>

<div class="t m0 x2 h7 y220 ff1 fs2 fc0 sc0 ls10 ws7e">systems. IL-6 facilitates lipopolysaccharide-induceddisruption</div>

<div class="t m0 x2 h7 y221 ff1 fs2 fc0 sc0 ls10 ws102">in working memory and expression of other PICs</div>

<div class="t m0 x2 h8 y222 ff1 fs2 fc0 sc0 ls10 ws10d">(Sparkman et al. <span class="fc1 ws36">2006</span><span class="ws2be">). TFNαand<span class="ls50 ws2a6"> IL-1βregulate<span class="lsb3 ws2bf"> sleeparchitecture</span></span></span></div>

<div class="t m0 x2 h7 y223 ff1 fs2 fc0 sc0 ls10 ws2c0">together with IL-6 (Krueger and Majade <span class="fc1 ws36">1987<span class="fc0">;</span></span></div>

<div class="t m0 x2 h7 y224 ff1 fs2 fc0 sc0 ls10 ws29e">Cavadini et al. <span class="fc1 ws36">2007<span class="fc0 ws2c1">; Obal and Krueger <span class="fc1 ws36">2003<span class="fc0 ws87">) and can lead tosleep</span></span></span></span></div>

<div class="t m0 x2 h7 y225 ff1 fs2 fc0 sc0 ls17 ws2c2">wake reversal and even complete loss of circadiancontrol</div>

<div class="t m0 x2 h7 y226 ff1 fs2 fc0 sc0 ls10 ws2c3">(Obal and Krueger <span class="fc1 ws36">2003</span>).As</div>

<div class="t m0 x5 h7 y227 ff1 fs2 fc0 sc0 ls10 ws17a">explained above, bacterial translocation through bind-ingtotheTLR4complexinducesNF-κBandimmuno-inflammatory</div>

<div class="t m0 x2 h7 y229 ff1 fs2 fc0 sc0 ls10 ws17f">and O&NS pathways and thus may cause be-havioral</div>

<div class="t m0 x2 h7 y22a ff1 fs2 fc0 sc0 ls10 ws2c6">and neuro-immune changes, including autoimmuneresponses</div>

<div class="t m0 x2 h7 y22b ff1 fs2 fc0 sc0 ls10 ws1cd">directed against gangliosides (Maes et al. <span class="fc1 ws36">2012c<span class="fc0">).Raised</span></span></div>

<div class="t m0 x2 h8 y22c ff1 fs2 fc0 sc0 ls10 ws2c7">levels of IFNγ<span class="ws2c8">, IL-1, IL-2 and TNFαactivate<span class="wsed"> thetryptophan-degrading</span></span></div>

<div class="t m0 x2 h7 y22d ff1 fs2 fc0 sc0 ls10 ws287">enzyme, indoleamine 2,3-dioxygenase</div>

<div class="t m0 x2 h7 y22e ff1 fs2 fc0 sc0 ls10 wsc3">(IDO), which causes alterations in the tryptophan catabolite</div>

<div class="t m0 x2 h7 y22f ff1 fs2 fc0 sc0 ls10 ws246">(TRYCAT) pathway (Anderson et al. <span class="fc1 ws36">2012<span class="fc0 ws167">). Increased IDOactivation</span></span></div>

<div class="t m0 x2 h7 y230 ff1 fs2 fc0 sc0 ls10 ws298">lowers plasma tryptophan and enhances the pro-duction</div>

<div class="t m0 x2 h7 y231 ff1 fs2 fc0 sc0 ls10 ws2c9">of neurotoxic catabolites, e.g. quinolinic acid, a strongagonist</div>

<div class="t m0 x2 h7 y232 ff1 fs2 fc0 sc0 ls10 wsbd">of the glutamatergic N-methyl-D-aspartate (NMDA)</div>

<div class="t m0 x2 h7 y233 ff1 fs2 fc0 sc0 ls88 ws2c2">receptor. Decreased tryptophan levels may cause physio-</div>

<div class="t m0 x2 h7 y234 ff1 fs2 fc0 sc0 ls10 ws2ca">somatic symptoms, such as fatigue, autonomic symptoms,</div>

<div class="t m0 x2 h7 y235 ff1 fs2 fc0 sc0 ls77 ws23d">hyperalgesia and somatic presentations (Anderson et al.530</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc1 sc0 ls10 ws36">2012<span class="fc0 ws1c">). Disorders in the TRYCAT pathway are detected inpost-viral</span></div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 ws9a">fatigue syndrome (Anderson et al. <span class="fc1 ws36">2012<span class="fc0">).In</span></span></div>

<div class="t m0 x4 h8 y4f ff1 fs2 fc0 sc0 ls10 ws2a3">the presence of increased levels of IL-1 and TFNα<span class="lsde ws2cb">,ATPconsumption</span></div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws2cc">is greatly accelerated, and levels of anaerobicglycolysis</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws119">and glucose consumption are increased (Berg et al.2003</div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws109">). The combined effects of these actions cause a greatermetabolic</span></div>

<div class="t m0 x0 h7 y53 ff1 fs2 fc0 sc0 ls10 ws28d">demand even in the resting state (Berg et al. <span class="fc1 ws36">2003</span>).TNFαincreases</div>

<div class="t m0 x0 h8 y54 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws246"> ROS production in the mitochondrial elec-tron</span></div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 ws2cd">transport chain. NO is known to inhibit mitochondrialrespiration</div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc0 sc0 ls10 ws2ce">, due to reversible binding to cytochrome C oxidasethus</div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws240">competing with oxygen and inhibiting energy production</div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws2cf">(Brown and Bal-Price <span class="fc1 ws36">2003</span><span class="ws1c3">). Moreover, NO can be convertedto</span></div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10 ws162">other reactive species, including peroxynitrite, NO2, N2O3,</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls10 ws278">and S-nitrosothiols, that may inhibit mitochondrial respirationand</div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 lsb3 ws2d0">activate mitochondrial permeability transition, whicheventually</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10 wsbf">may trigger neuronal apoptosis or necrosis (Brownand</div>

<div class="t m0 x0 h7 y5d ff1 fs2 fc0 sc0 ls10 ws298">Bal-Price<span class="fc1 ws36">2003</span><span class="ws2d1">). PICs can directly disrupt glucose ho-meostasis</span></div>

<div class="t m0 x0 h8 y5e ff1 fs2 fc0 sc0 ls10 ws2d2">and the availability of ATP. TNFα<span class="lsa ws2d3">,IL-1βand<span class="ff5 lsd1"><span class="ff1 ls10 ws2d4"> IFNγmay</span></span></span></div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws168">significantly inhibit insulin secretion by beta cells in thepancreas</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc0 sc0 ls10 ws283">(Kiely et al. <span class="fc1 ws36">2007</span><span class="wscd">). This increases cellular glucoseconsumption</span></div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 ls10 ws248">and lactate and glutamate levels (Kiely et al.2007</div>

<div class="t m0 x0 h7 y115 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws21c">). The resultant decrease in ATP may shift cellular me-tabolism</span></div>

<div class="t m0 x0 h7 y116 ff1 fs2 fc0 sc0 ls10 ws1ed">towards a catabolic state, showing how mitochon-drial</div>

<div class="t m0 x0 h7 y117 ff1 fs2 fc0 sc0 ls10 ws2d5">dysfunction can severely impair glucose metabolism.PICs</div>

<div class="t m0 x0 h7 y118 ff1 fs2 fc0 sc0 ls10 ws16e">in general lead to the upregulation of nicotinamideadenine</div>

<div class="t m0 x0 h7 y119 ff1 fs2 fc0 sc0 ls10 ws2ad">dinucleotide phosphate (NADP) oxidase and resultantincreased</div>

<div class="t m0 x0 h7 y11a ff1 fs2 fc0 sc0 ls10 ws235">production of ROS (Morgan et al. <span class="fc1 ws36">2007</span><span class="ws2d6">). Thisprocess</span></div>

<div class="t m0 x0 h7 y11b ff1 fs2 fc0 sc0 ls10 ws2d7">may generate superoxide anion dependent damageand</div>

<div class="t m0 x0 h7 y11c ff1 fs2 fc0 sc0 ls10 wsad">formation of peroxinitrite which subsequently may con-</div>

<div class="t m0 x0 h7 y11d ff1 fs2 fc0 sc0 ls10 ws2d8">tribute to permanent damage to mitochondria (Mohankumaret</div>

<div class="t m0 x0 h7 y11e ff1 fs2 fc0 sc0 ls10 wsbe">al.<span class="fc1 ws36">1991</span><span class="lsdf ws124">; Shintani et al. </span><span class="fc1 ws36">1993</span><span class="ws2d2">; Linthorst et al. <span class="fc1 ws36">1995</span><span class="ws2d9">). IL-1 notonly</span></span></div>

<div class="t m0 x0 h7 y11f ff1 fs2 fc0 sc0 ls10 ws1dd">causes hypoglycemia, but also resets glucose homeosta-sis</div>

<div class="t m0 x0 h7 y120 ff1 fs2 fc0 sc0 ls10 ws2da">in the brain; both phenomena together favor an increaseduptake</div>

<div class="t m0 x0 h7 y121 ff1 fs2 fc0 sc0 ls10 ws1cc">of glucose by immune cells during inflammation (DelRey</div>

<div class="t m0 x0 h7 y122 ff1 fs2 fc0 sc0 ls10 ws139">etal.<span class="fc1 ws36">2006</span><span class="ws3a">). All in all, glucose usage can easily exceedsupply</span></div>

<div class="t m0 x0 h7 y123 ff1 fs2 fc0 sc0 ls10 ws2db">and the increased demand for ATP cannot be met sincemitochondrial</div>

<div class="t m0 x0 h8 y124 ff1 fs2 fc0 sc0 ls10 ws1cc">functions are compromised by TNFαand<span class="ff5 lsd2"><span class="ff1 ls10 ws2dc"> NO.Cytokines</span></span></div>

<div class="t m0 x0 h7 y125 ff1 fs2 fc0 sc0 ls10 ws298">can also lead to cerebral hypoperfusion via pro-</div>

<div class="t m0 x0 h8 y126 ff1 fs2 fc0 sc0 ls10 ws2dd">longed exposure to IL-1β<span class="ws2de">(Maher et al. <span class="fc1 ws36">2003<span class="fc0 ws2df">). The ensuinglack</span></span></span></div>

<div class="t m0 x0 h7 y127 ff1 fs2 fc0 sc0 ls10 wsbf">of glucose would potentially explain the brain fog that somany</div>

<div class="t m0 x0 h7 y128 ff1 fs2 fc0 sc0 ls10 ws11a">people with this illness complain of.TNFαreduces</div>

<div class="t m0 x4 h8 y129 ff1 fs2 fc0 sc0 ls10 ws36"><span class="ws2a2"> mitochondrial respiration via effects at thelevel</span></div>

<div class="t m0 x0 h7 y12a ff1 fs2 fc0 sc0 ls10 ws8a">of complex III of the electron transport chain and byROS</div>

<div class="t m0 x0 h7 y12b ff1 fs2 fc0 sc0 ls10 ws2e0">production (Samavati et al. <span class="fc1 ws36">2008</span><span class="ws2e1">; Gudz et al. <span class="fc1 ws36">1997</span>).The</span></div>

<div class="t m0 x0 h7 y1cc ff1 fs2 fc0 sc0 ls10 ws134">latter may induce opening of mitochondrial permeabil-ity</div>

<div class="t m0 x0 h7 y1cd ff1 fs2 fc0 sc0 ls10 ws2e2">transition pores, which may cause uncoupling of oxida-tive</div>

<div class="t m0 x0 h7 y1ce ff1 fs2 fc0 sc0 ls15 ws6f">phosphorylation (Chernyak<span class="fc1 ls18 ws7a">1997</span><span class="ls17 ws275">). The condition ofincreased</span></div>

<div class="t m0 x0 h7 y1cf ff1 fs2 fc0 sc0 lsd4 ws2e3">ATP consumption and mitochondrial damagemeans</div>

<div class="t m0 x0 h7 y1d0 ff1 fs2 fc0 sc0 ls10 ws2e4">that exceeding a threshold of physical and mentalexertion</div>

<div class="t m0 x0 h7 y1d1 ff1 fs2 fc0 sc0 ls10 ws2e5">will lead to all available ATP becoming exhaustedand</div>

<div class="t m0 x0 h7 y1d2 ff1 fs2 fc0 sc0 ls10 ws2e6">thus a crash may ensue. It takes damaged mitochondriatime</div>

<div class="t m0 x0 h7 y1d3 ff1 fs2 fc0 sc0 lsd5 ws2e7">to replenish said ATP, le<span class="lsd6 ws2e3">ading to a profound post-exertional</span></div>

<div class="t m0 x0 h8 y1d4 ff1 fs2 fc0 sc0 ls10 ws2e8">disability. Anything that increases TNFαactivityduring</div>

<div class="t m0 x2 h7 y1d5 ff1 fs2 fc0 sc0 ls10 ws10c">this <span class="ff6 lsd8">“</span><span class="ws36">recharge<span class="ff6 lsd9">”</span><span class="ws2e9">period, such as stress, will greatlydelay</span></span></div>

<div class="t m0 x2 h7 y1d6 ff1 fs2 fc0 sc0 ls10 ws1a9">recharge and possibly create longer term disability byfurther</div>

<div class="t m0 x2 h7 y1d7 ff1 fs2 fc0 sc0 ls10 wsf1">damaging the inner membrane. Chronically elevatedcytokines</div>

<div class="t m0 x2 h7 y1d8 ff1 fs2 fc0 sc0 ls10 ws11a">act on the brain and hypothalamus to create a newhomeostatis</div>

<div class="t m0 x2 h7 y1d9 ff1 fs2 fc0 sc0 ls10 ws11">of glucose metabolism, and the autonomic ner-vous</div>

<div class="t m0 x2 h7 y1da ff1 fs2 fc0 sc0 ls10 ws2ea">system controlling heart rate, respiratory rate, bloodpressure</div>

<div class="t m0 x2 h7 y1db ff1 fs2 fc0 sc0 ls10 ws2eb">, vascular tone, gastric peristalsis, etc. (Del Rey etal.</div>

<div class="t m0 x2 h7 y1dc ff1 fs2 fc0 sc0 ls10 ws2ec"><span class="fc1 ws36">2006</span><span class="ws2ed">). The autonomic symptoms observed in ME/CFScould</span></div>

<div class="t m0 x2 h7 y1dd ff1 fs2 fc0 sc0 ls10 ws5d">be obvious consequences of such a shift.Increased</div>

<div class="t m0 x5 h8 y1de ff1 fs2 fc0 sc0 ls10 ws253">TNFαand<span class="ws233"> O&NS, iNOS, low ATP and highTGFβ1</span></div>

<div class="t m0 x2 h8 y1df ff1 fs2 fc0 sc0 lsdf ws2ee"><span class="ls54 ws2b3"> levels deplete glutathione (Castagna et al. <span class="fc1 ls34 wsc6">1995</span><span class="lse0 ws2ef">;Phelpset</span></span></div>

<div class="t m0 x2 h7 y1e0 ff1 fs2 fc0 sc0 ls32 ws2f0">al.<span class="fc1 ls34 wsc6">1995<span class="fc0 ws199">). A depletion in glutathione levels is often accom-panied</span></span></div>

<div class="t m0 x2 h7 y1e1 ff1 fs2 fc0 sc0 ls28 ws2f1">by a partial blockade in the methylation cycle. More-</div>

<div class="t m0 x2 h7 y1e2 ff1 fs2 fc0 sc0 ls28 ws2f2">over, nitric and nitrous acid inhi<span class="ls54 ws2f3">bit methionine synthase (Layser1978</span></div>

<div class="t m0 x2 h7 y1e3 ff1 fs2 fc1 sc0 ls34 wsc6"><span class="fc0 ls31 ws2f4">; Danishpajooh et al. </span>2001<span class="fc0 ls32 ws2f5">; Kerkeni et al. </span>2006<span class="fc0 ls2a ws2f6">; Culley etal.</span></div>

<div class="t m0 x2 h7 y1e4 ff1 fs2 fc0 sc0 ls2a ws2f7"><span class="fc1 ls34 wsc6">2007</span><span class="ls2c ws2f8">). A number of studies mentioned earlier have demon-strated</span></div>

<div class="t m0 x2 h7 y1e5 ff1 fs2 fc0 sc0 ls4f ws2f9">reduced glutathione in people with ME/CFS. A recentstudy</div>

<div class="t m0 x2 h7 y236 ff1 fs2 fc0 sc0 ls10 ws237">confirmed these earlier findings and found that lowglutathione</div>

<div class="t m0 x2 h7 y237 ff1 fs2 fc0 sc0 ls31 ws2fa">levels and high lactate levels correlated with meas-urements</div>

<div class="t m0 x2 h7 y238 ff1 fs2 fc0 sc0 ls27 ws2ab">of physical health and disability (Shungu et al. <span class="fc1 ls34 wsc6">2012</span><span class="ls37">).Figure</span></div>

<div class="t m0 x5 h7 y239 ff1 fs2 fc0 sc0 lsda ws2fb"><span class="fc1 lsdb">2summarizes</span><span class="lsdc ws2fc"> how the different immuno-inflammatory</span></div>

<div class="t m0 x2 h7 y23a ff1 fs2 fc0 sc0 ls33 ws2fd">pathways may cause the typical symptoms ofME</div>

<div class="t m0 x2 h7 y23b ff1 fs2 fc0 sc0 ls29">/CFS.Mechanistic</div>

<div class="t m0 x2 h4 y1eb ff2 fs2 fc0 sc0 ls10 ws2fe">explanations for the chronic and relapsing<span class="ff9">–</span></div>

<div class="t m0 x2 h4 y1ec ff2 fs2 fc0 sc0 ls10 ws2ff">remitting nature of ME/CFSME</div>

<div class="t m0 x2 h7 y1ee ff1 fs2 fc0 sc0 ls10 ws277">/CFS is characterized by highly increased IgM-relatedautoimmune</div>

<div class="t m0 x2 h7 y1ef ff1 fs2 fc0 sc0 ls10 ws24e">response directed against disrupted lipid mem-brane</div>

<div class="t m0 x2 h7 y1f0 ff1 fs2 fc0 sc0 ls10 ws197">components, by-products of lipid peroxidation, an-chorage</div>

<div class="t m0 x2 h7 y1f1 ff1 fs2 fc0 sc0 lse1 ws300">molecules, and NO-modified amino-acids ascompared</div>

<div class="t m0 x2 h7 y1f2 ff1 fs2 fc0 sc0 ls10 ws61">with normal controls (Maes et al. <span class="fc1 ws36">2006b</span><span class="ws32">). Theseresults</span></div>

<div class="t m0 x2 h7 y1f3 ff1 fs2 fc0 sc0 lsdd ws301">show that self-epitopes, which are normally notdetected</div>

<div class="t m0 x2 h7 y1f4 ff1 fs2 fc0 sc0 ls10 ws28d">by the immune system, have become immunogenicfollowing</div>

<div class="t m0 x2 h7 y1f5 ff1 fs2 fc0 sc0 ls10 ws302">damage by O&NS (Maes et al. <span class="fc1 ws36">2006b</span><span class="ws2ac">). A distinc-tive</span></div>

<div class="t m0 x2 h7 y1f6 ff1 fs2 fc0 sc0 lse2 ws303">pattern of proteins modified by oxidative stress inpeople</div>

<div class="t m0 x2 h7 y1f7 ff1 fs2 fc0 sc0 ls10 ws2c7">with ME/CFS was also reported in a recent studyinvolving</div>

<div class="t m0 x2 h7 y1f8 ff1 fs2 fc0 sc0 ls10 ws3e">proteomic analysis (Schutzeretal.<span class="fc1 ws36">2011</span>).Such</div>

<div class="t m0 x5 h7 y1f9 ff1 fs2 fc0 sc0 ls10 ws304">antibodies directed against lipids have also beendetected</div>

<div class="t m0 x2 h7 y1fa ff1 fs2 fc0 sc0 ls51 ws79">in remitting-relapsing MS (Geffard et al. <span class="fc1 ls18 ws7a">2002</span><span class="ls10">;</span></div>

<div class="t m0 x2 h7 y1fb ff1 fs2 fc0 sc0 ls10 ws305">Boullerne et al. <span class="fc1 ws36">1996</span><span class="ws293">). However the latter study reportedthat</span></div>

<div class="t m0 x2 h7 y1fc ff1 fs2 fc0 sc0 ls10 ws306">there was no significant level of IgM against azelaicacid</div>

<div class="t m0 x2 h7 y1fd ff1 fs2 fc0 sc0 ls10 ws307">detected, whereas Maes et al. (<span class="fc1 ws36">2006b</span><span class="ws274">) found increasedIgM</span></div>

<div class="t m0 x2 h7 y1fe ff1 fs2 fc0 sc0 ls2 ws308">responses directed against azelaic acid in ME/CFSpatients.</div>

<div class="t m0 x2 h7 y1ff ff1 fs2 fc0 sc0 ls10 ws309">The circulating IgM antibody titers in MS appearto</div>

<div class="t m0 x2 h7 y200 ff1 fs2 fc0 sc0 ls10 ws30a">be related to the presence of inflammation, because theyincrease</div>

<div class="t m0 x2 h7 y201 ff1 fs2 fc0 sc0 ls6b ws158">during relapses and <span class="ls3 ws18">decrease during remissions</span></div>

<div class="t m0 x2 h7 y202 ff1 fs2 fc0 sc0 ls10 ws15e">(Bodet et al. <span class="fc1 ws36">2004</span><span class="ws30b">). This suggests that the level of immuneactivation</span></div>

<div class="t m0 x2 h7 y203 ff1 fs2 fc0 sc0 ls10 ws1b2">, O&NS and magnitude of autoimmunity may infact</div>

<div class="t m0 x2 h7 y204 ff1 fs2 fc0 sc0 ls10 ws28b">be greater in ME/CFS than in MS.Increased</div>

<div class="t m0 x5 h7 y205 ff1 fs2 fc0 sc0 ls10 ws2dc">levels of peroxinitrite and nitrosothiols and low-ered</div>

<div class="t m0 x2 h7 y206 ff1 fs2 fc0 sc0 ls10 ws30c">levels of reduced glutathione have been found in the CSFMetab</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span><span class="ws13b">540 531</span></div>

</div>

</div>

<div class="t m0 x0 h7 y23c ff1 fs2 fc0 sc0 ls10 ws28f">of patients with MS, suggesting a role for nitrosative stress inMS</div>

<div class="t m0 x0 h7 y23d ff1 fs2 fc0 sc0 ls10 ws25e">(Calabrese et al. <span class="fc1 ws36">2003<span class="fc0 ws30d">). This situation is also found in ME/</span></span></div>

<div class="t m0 x0 h7 y23e ff1 fs2 fc0 sc0 ls10 ws23e">CFS, as discussed earlier, and therefore following factorscould</div>

<div class="t m0 x0 h7 y23f ff1 fs2 fc0 sc0 ls10 wsbc">contribute to relapses in MS and ME/CFS. Innate pat-</div>

<div class="t m0 x0 h7 y240 ff1 fs2 fc0 sc0 ls10 ws30e">tern recognition receptors recognize O&NS damaged selfepitopes</div>

<div class="t m0 x0 h7 y241 ff1 fs2 fc0 sc0 ls10 wsbd">, and the various components of the innate immunesystem</div>

<div class="t m0 x0 h7 y242 ff1 fs2 fc0 sc0 ls10 ws30f">, including innate IgM antibodies, collaborate to medi-ate</div>

<div class="t m0 x0 h7 y243 ff1 fs2 fc0 sc0 ls10 ws23f">their removal (Weismann and Binder <span class="fc1 ws36">2012</span><span class="ws1a6">). In MS, IL-6and</span></div>

<div class="t m0 x0 h8 y244 ff1 fs2 fc0 sc0 ls10 ws2d4">TNFαlevels<span class="ws310"> are significantly increased during relapses ascompared</span></div>

<div class="t m0 x0 h7 y245 ff1 fs2 fc0 sc0 ls10 ws1a3">to remission (Hautecoeur et al. <span class="fc1 ws36">1997</span><span class="ws2ac">), as are IL-17and</span></div>

<div class="t m0 x0 h7 y246 ff1 fs2 fc0 sc0 ls10 ws290">IL-23 (Wang etal.<span class="fc1 ws36">2011</span><span class="wsc4">). Plasmacytoid dendritic cells,</span></div>

<div class="t m0 x0 h7 y247 ff1 fs2 fc0 sc0 lsc3 ws29b">which are elevated in the CNS during relapses, may beexplained</div>

<div class="t m0 x0 h7 y248 ff1 fs2 fc0 sc0 ls10 ws21c">by either virus infections or down regulatory pro-cesses</div>

<div class="t m0 x0 h7 y249 ff1 fs2 fc0 sc0 ls10 ws24c">(Longhini et al. <span class="fc1 ws36">2011</span><span class="ws216">). This dendritic subset is impor-tant</span></div>

<div class="t m0 x0 h7 y24a ff1 fs2 fc0 sc0 ls10 ws2d8">in stimulating or downregulating effector T cells in MS</div>

<div class="t m0 x0 h7 y24b ff1 fs2 fc0 sc0 ls10 ws6c">(Geffard et al. <span class="fc1 ws36">2002<span class="fc0 ls44 ws311">; Bayley-Bucktrout et al. </span>2008<span class="fc0 ws312">). By stim-ulating</span></span></div>

<div class="t m0 x0 h7 y24c ff1 fs2 fc0 sc0 ls10 ws1cc">the maturation of dendritic cells, and upregulating themembrane</div>

<div class="t m0 x0 h7 y24d ff1 fs2 fc0 sc0 ls10 ws295">expression of CD80, CD86, CD83, and HLA-DR</div>

<div class="t m0 x0 h7 y24e ff1 fs2 fc0 sc0 ls10 ws313">(Csillag et al. <span class="fc1 ws36">2010<span class="fc0 ws1e5">), O&NS induces maturation of dendriticcells</span></span></div>

<div class="t m0 x0 h8 y24f ff1 fs2 fc0 sc0 ls10 ws24c">(Kantengwa et al. <span class="fc1 ws36">2003</span><span class="ws27f">). Moreover, NF-κBisactivatedby</span></div>

<div class="t m0 x0 h7 y250 ff1 fs2 fc0 sc0 ls10 ws72">threshold levels of oxidative stress (Khalaf et al. <span class="fc1 ws36">2010</span>)</div>

<div class="t m0 x0 h7 y251 ff1 fs2 fc0 sc0 ls10 ws315">leading to the activation of autoreactive T cells. Thus chronicinflammation</div>

<div class="t m0 x0 h7 y252 ff1 fs2 fc0 sc0 ls10 ws9d">, due to the causes mentioned earlier, leads to acycle</div>

<div class="t m0 x0 h7 y253 ff1 fs2 fc0 sc0 ls10 ws1d">where there is increasing damage to neoepitopes, ulti-mately</div>

<div class="t m0 x0 h7 y254 ff1 fs2 fc0 sc0 ls10 ws30a">leading to a surge of PICs due to immune activationand</div>

<div class="t m0 x2 h7 y255 ff1 fs2 fc0 sc0 ls10 ws247">a cascade of further inflammatory damage and dysfunc-tion</div>

<div class="t m0 x2 h7 y256 ff1 fs2 fc0 sc0 ls10 ws316">of mitochondria, constituting a flare up of active diseaseor</div>

<div class="t m0 x2 h7 y257 ff1 fs2 fc0 sc0 ls10 ws10">relapse.We</div>

<div class="t m0 x5 h7 y258 ff1 fs2 fc0 sc0 ls10 ws317">tentatively propose that (partial) remission is inducedby</div>

<div class="t m0 x2 h7 y259 ff1 fs2 fc0 sc0 ls10 ws6c">the response of the CNS to immune activation. The CNSmodulates</div>

<div class="t m0 x2 h7 y25a ff1 fs2 fc0 sc0 ls15 ws1b0">immune responses through neuronal and hor-monal</div>

<div class="t m0 x2 h7 y25b ff1 fs2 fc0 sc0 ls10 ws318">effects. Thus, the sympathetic and parasympatheticsystem</div>

<div class="t m0 x2 h7 y25c ff1 fs2 fc0 sc0 lse3 ws75">and neuroendocrine axes attenuate immuneresponses</div>

<div class="t m0 x2 h7 y25d ff1 fs2 fc0 sc0 ls10 ws319">, whereas the peripheral nervous systems reinforcelocal</div>

<div class="t m0 x2 h7 y25e ff1 fs2 fc0 sc0 ls10 ws31a">immune responses (Sternberg <span class="fc1 ws36">2006</span><span class="wsbb">). In the first stage,</span></div>

<div class="t m0 x2 h7 y25f ff1 fs2 fc0 sc0 ls10 ws31b">the peripheral immune and nervous systems work togetherto</div>

<div class="t m0 x2 h7 y260 ff1 fs2 fc0 sc0 ls10 ws31c">activate local immune responses and to eliminate invad-ing</div>

<div class="t m0 x2 h7 y261 ff1 fs2 fc0 sc0 ls10 ws31d">pathogens. In a later stage, however, counter-regulatoryneuronal</div>

<div class="t m0 x2 h7 y262 ff1 fs2 fc0 sc0 ls10 ws31e">and neuroendocrine mechanisms are mounted thattend</div>

<div class="t m0 x2 h7 y263 ff1 fs2 fc0 sc0 ls10 ws31f">to terminate inflammation and thus restore host homeo-stasis</div>

<div class="t m0 x2 h7 y264 ff1 fs2 fc0 sc0 ls10 ws154">(Sternberg <span class="fc1 ws36">2006</span><span class="wsf1">). Activation of the vagus nerve indu-ces</span></div>

<div class="t m0 x2 h7 y265 ff1 fs2 fc0 sc0 ls10 ws1ac">the release of transmitters that facilitate Th2 responses</div>

<div class="t m0 x2 h7 y266 ff1 fs2 fc0 sc0 ls10 ws320">(Liang et al. <span class="fc1 ws36">2011</span><span class="ws321">). Activation of the vagus nerve decreasesthe</span></div>

<div class="t m0 x2 h8 y267 ff1 fs2 fc0 sc0 ls10 wsec">expression of M1 monocytes, which produce TNFα<span class="wsb8">, IL-6</span></div>

<div class="t m0 x2 h8 y268 ff1 fs2 fc0 sc0 ls10 ws78">, and IL-1β.<span class="ws322"> Together, this indicates that activation of thevagus</span></div>

<div class="t m0 x2 h7 y269 ff1 fs2 fc0 sc0 ls10 ws2dd">neural circuit produces an anti-inflammatory cellularmilieu</div>

<div class="t m0 x2 h7 y26a ff1 fs2 fc0 sc0 ls10 ws139">(Valdes-Ferrer et al. <span class="fc1 ws36">2010</span>).The</div>

<div class="t m0 x5 h7 y26b ff1 fs2 fc0 sc0 ls10 ws37">role of the peripheral nervous system in modulatingthe</div>

<div class="t m0 x2 h7 y26c ff1 fs2 fc0 sc0 ls10 ws323">initial effects of immune activation and tissue inflam-mation</div>

<div class="t m0 x2 h7 y26d ff1 fs2 fc0 sc0 ls10 ws2c">is complex and beyond the scope of this paper. TheNFNFNFNFInfectionsViral</div>

<div class="t m0 x8 h11 y271 ffa fs7 fc3 sc0 lse5 ws340">and bacterialinfectionsBacterialtranslocationHyperalgesia</div>

<div class="t m0 xa h13 y275 ffb fs9 fc3 sc0 lse8 ws341">, neuro-cognitive</div>

<div class="t m0 xb h14 y276 ffb fsa fc3 sc0 lsf6 ws342">ssFatigue</div>

<div class="t m0 xc h13 y277 ffb fs9 fc3 sc0 lsec ws343">(muscle)</div>

<div class="t m0 xc h13 y278 ffb fs9 fc3 sc0 lsf7 ws344">Disabling fatigueDisabling</div>

<div class="t m0 xc h13 y279 ffb fs9 fc3 sc0 lsf8 ws345">fatigue,</div>

<div class="t m0 xd h13 y27a ffb fs9 fc3 sc0 lse9 ws346">malaise, neuro-cognitive</div>

<div class="t m0 xe h13 y27b ffb fs9 fc3 sc0 lsea ws347">andautonomic</div>

<div class="t m0 xc h13 y27d ffb fs9 fc3 sc0 lse8 ws349">sleep disordersPhysio-somatic</div>

<div class="t m0 xf h14 y27e ffb fsa fc3 sc0 lseb ws34a">ssPhysio-somatic</div>

<div class="t m0 xf h13 y27f ffb fs9 fc3 sc0 lsec ws34b">ssDisabling</div>

<div class="t m0 xc h13 y280 ffb fs9 fc3 sc0 lsf7 ws344">fatiguePEMDisabling</div>

<div class="t m0 x11 h13 y282 ffb fs9 fc3 sc0 lsed ws348">fatigue, painExhaustion</div>

<div class="t m0 xc h13 y283 ffb fs9 fc3 sc0 lsec ws343">, PEMMental</div>

<div class="t m0 x11 h13 y284 ffb fs9 fc3 sc0 lsea ws34c">fatigue, neuro-cognitive</div>

<div class="t m0 xb h13 y285 ffb fs9 fc3 sc0 lsee ws34d">ssCOX-2iNOS</div>

<div class="t m0 x13 h13 y287 ffb fs9 fc3 sc0 lsf8 ws345">/ O&NSAutoimmunityPICsTryptophanTRYCATsMitochondriaATPGlutathioneLactateP53Brain</div>

<div class="t m0 x15 h13 y291 ffb fs9 fc3 sc0 lsf9 ws34e">andNeuro-immunedisordersNF-</div>

<div class="t m0 xe h15 y295 ffb fsb fc3 sc0 ls103 ws34f">/ CFSEpitopespreadingBystanderdamageMimicryFig.</div>

<div class="t m0 x0 h5 y29b ff2 fs4 fc0 sc0 ls10 ws32f">2 <span class="ff1 ws330">Immuno-inflammatory pathways causing the typical symptomsof</span></div>

<div class="t m0 x0 h5 y29c ff1 fs4 fc0 sc0 ls10 ws331">MyalgicEncephalomyelitis (ME) and chronic fatigue syndrome</div>

<div class="t m0 x0 hd y29d ff1 fs4 fc0 sc0 ls10 ws332">(CFS). Different pathogens activate nuclear factor <span class="ff5 ws44">κB</span><span class="ws333"> (NF-κB<span class="ws334">) andconsequently</span></span></div>

<div class="t m0 x0 h5 y29e ff1 fs4 fc0 sc0 ls10 ws335">cyclooxygenase 2 (COX-2), inducible nitric oxide syn-thase</div>

<div class="t m0 x0 h5 y29f ff1 fs4 fc0 sc0 ls10 ws335">(iNOS), oxidative and nitrosative stress (O&NS) pathways andpro-inflammatory</div>

<div class="t m0 x0 h5 y2a0 ff1 fs4 fc0 sc0 ls10 ws336">cytokines (PICs). Autoimmune responses may ensuethrough</div>

<div class="t m0 x0 h5 y2a1 ff1 fs4 fc0 sc0 ls10 ws337">different mechanisms, including bystander damage, mimicryand</div>

<div class="t m0 x2 h5 y2a2 ff1 fs4 fc0 sc0 ls10 ws338">epitope spreading, and O&NS damage to self-epitopes.PICsandO</div>

<div class="t m0 x2 h5 y2a3 ff1 fs4 fc0 sc0 ls10 ws339">&NS processes may activate the tryptophan catabolite (TRYCAT)</div>

<div class="t m0 x2 h5 y2a4 ff1 fs4 fc0 sc0 ls10 ws33a">pathway, cause mitochondrial dysfunctions including lowered ATPlevels</div>

<div class="t m0 x2 hd y2a5 ff1 fs4 fc0 sc0 ls10 ws33b">and brain dysfunctions. Upon activation of NF-κB<span class="ws33c">, tumor sup-pressor</span></div>

<div class="t m0 x2 h5 y2a6 ff1 fs4 fc0 sc0 ls10 ws33d">p53 may be downregulated. Translational research has shownthat</div>

<div class="t m0 x2 h5 y2a7 ff1 fs4 fc0 sc0 ls10 ws33e">these biological aberrations may cause the different symptoms (ss)</div>

<div class="t m0 x2 h5 y2a8 ff1 fs4 fc0 sc0 ls10 ws33f">of ME and CFS, including post-exertional malaise (PEM)</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">532 Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls105 ws350">antagonistic actions of the factors amplifying immuno-inflammatory</div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 lsc0 ws351">pathways and the CNS would potentiallyaccount</div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws352">for a relapsing-remitting pattern. The findings thatthe</div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws95">T cell pool of remitted MS patients is in a state of anergy</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws26e">(Fransson et al. <span class="fc1 ws36">2009</span><span class="ws353">) is of particular interest. Thus, activeMS</span></div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls8 ws354">is associated with activated Th1/Th17 responses asdiscussed</div>

<div class="t m0 x0 h7 y53 ff1 fs2 fc0 sc0 ls10 ws355">earlier, while it appears that people in remissionhave</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls106 ws1e3">their immune system biased towards Th2 or Tregphenotypes.</div>

<div class="t m0 x0 h7 y55 ff1 fs2 fc0 sc0 ls10 wsb">The immune abnormalities reported in peoplewith</div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc0 sc0 ls10 ws219">ME/CFS vary between Th1 and maybe Th17, Th2 andTh2</div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls10 ws1f">/Treg responses. This is the pattern one would expect ifthe</div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls10 ws356">relapsing-remitting nature of ME/CFS is produced bythe</div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10 wsd2">interactions described above. A Th17 profile is inducedby</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls17 ws357">prolonged elevation of IL-6 and IL-23, which are inthemselves</div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls10 ws358">the product of elevated O&NS pathways andchronic</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10 ws17a">inflammation. IL-6 inhibits forkhead box P3 (scur-fin</div>

<div class="t m0 x0 h7 y5d ff1 fs2 fc0 sc0 ls10 ws359">, Foxp3) by activating the transcription of Signal Trans-ducer</div>

<div class="t m0 x0 h7 y5e ff1 fs2 fc0 sc0 ls10 wsf8">and Activator of Transcription 3 (STAT-3) and henceattenuates</div>

<div class="t m0 x0 h7 y5f ff1 fs2 fc0 sc0 ls10 ws137">the functions of Treg cells (Samanta et al. <span class="fc1 ws36">2008</span>;</div>

<div class="t m0 x0 h7 y60 ff1 fs2 fc0 sc0 lsc2 ws35a">Korn et al. <span class="fc1 ls21 ws85">2009<span class="fc0 ws35b">). Also, IL-23 inhibits Foxp3 and thuspromotes</span></span></div>

<div class="t m0 x0 h7 y61 ff1 fs2 fc0 sc0 ls10 ws35c">Th17 differentiation (Zhuetal.<span class="fc1 ws36">2010</span><span class="ws12d">; Lal et al.2011</span></div>

<div class="t m0 x0 h7 y115 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws4">; Mus et al. </span>2010<span class="fc0">).Another</span></div>

<div class="t m0 x4 h7 y116 ff1 fs2 fc0 sc0 ls10 ws1b">plausible explanation for the chronic relapsingremitting</div>

<div class="t m0 x0 h7 y117 ff1 fs2 fc0 sc0 ls10 ws114">nature of the disease revolves around tumor sup-pressor</div>

<div class="t m0 x0 h7 y118 ff1 fs2 fc0 sc0 ls10 ws99">p53.P53 is activated by factors that cause DNAdamage</div>

<div class="t m0 x0 h7 y119 ff1 fs2 fc0 sc0 ls10 ws35d">, including free radicals. P53 arrests the cell cycle,</div>

<div class="t m0 x0 h7 y11a ff1 fs2 fc0 sc0 ls10 ws35e">activates DNA repair and initiates apoptosis. P53 is alsocrucial</div>

<div class="t m0 x0 h7 y11b ff1 fs2 fc0 sc0 ls19 ws6f">in matching increased mitochondrial function toincreases</div>

<div class="t m0 x0 h7 y11c ff1 fs2 fc0 sc0 ls10 ws35f">in demand for ATP (Niu et al. <span class="fc1 ws36">2005</span><span class="ws360">; Matoba etal.</span></div>

<div class="t m0 x0 h7 y11d ff1 fs2 fc0 sc0 ls10 ws361"><span class="fc1 ws36">2006</span><span class="ws23a">). P53 regulates energy metabolism by balancingglycolysis</span></div>

<div class="t m0 x0 h7 y11e ff1 fs2 fc0 sc0 ls10 wsfe">and oxidative phosphorylation. In conditions ofoxidative</div>

<div class="t m0 x0 h7 y11f ff1 fs2 fc0 sc0 ls10 ws362">stress, p53 activation results in decreased glycol-ysis.</div>

<div class="t m0 x0 h7 y120 ff1 fs2 fc0 sc0 ls10 ws29">In such an environment, p53 expression acts to upre-gulate</div>

<div class="t m0 x0 h7 y121 ff1 fs2 fc0 sc0 ls10 ws2b8">glutathione. The ultimate aim of both functions is thereduction</div>

<div class="t m0 x0 h7 y122 ff1 fs2 fc0 sc0 ls10 ws363">of oxidative stress. p53 also regulates mitochon-drial</div>

<div class="t m0 x0 h7 y123 ff1 fs2 fc0 sc0 ls10 ws364">oxygen production via the synthesis of cytochrome Coxidase.</div>

<div class="t m0 x0 h7 y124 ff1 fs2 fc0 sc0 ls10 ws27">In normal circumstances activation of p53 leads toan</div>

<div class="t m0 x0 h8 y125 ff1 fs2 fc0 sc0 ls10 ws24">upregulation of mitochondrial respiration. NF-κBandp53</div>

<div class="t m0 x0 h7 y126 ff1 fs2 fc0 sc0 ls10 ws366">have antagonistic strategies in the cell and thereforecannot</div>

<div class="t m0 x0 h7 y127 ff1 fs2 fc0 sc0 ls10 ws367">function simultaneously in the same cell (Ak andLevine</div>

<div class="t m0 x0 h7 y128 ff1 fs2 fc0 sc0 ls10 ws2af"><span class="fc1 ws36">2010</span><span class="ws368">). Thus, upon activation of one of these twotranscription</span></div>

<div class="t m0 x0 h7 y129 ff1 fs2 fc0 sc0 ls10 ws369">factors the other is downregulated. Moreover,</div>

<div class="t m0 x0 h7 y12a ff1 fs2 fc0 sc0 ls10 ws298">STAT-3 activation leads to the downregulation of p53 ex-pression</div>

<div class="t m0 x0 h7 y12b ff1 fs2 fc0 sc0 ls10 ws19f">(Niu et al. <span class="fc1 ws36">2005</span><span class="ws36a">), while the latter is required forFoxp3</span></div>

<div class="t m0 x0 h7 y1cc ff1 fs2 fc0 sc0 ls10 ws139">expression (Jung et al. <span class="fc1 ws36">2010</span>).Therefore</div>

<div class="t m0 x4 h7 y1cd ff1 fs2 fc0 sc0 ls10 ws36b">, it may be hypothesized that ME/CFS may beaccompanied</div>

<div class="t m0 x0 h7 y1ce ff1 fs2 fc0 sc0 ls10 ws36c">by lowered p53 expression. Lower transcrip-tion</div>

<div class="t m0 x0 h7 y1cf ff1 fs2 fc0 sc0 ls10 ws10">of p53 causes a shift from ATP production by oxidativephosphorylation</div>

<div class="t m0 x0 h7 y1d0 ff1 fs2 fc0 sc0 ls10c ws75">to glycolysis. This can lead to a severeenergy</div>

<div class="t m0 x0 h7 y1d1 ff1 fs2 fc0 sc0 ls10 ws202">deficit and high levels of lactate production (Xianget</div>

<div class="t m0 x0 h7 y1d2 ff1 fs2 fc0 sc0 ls88 ws36d">al.<span class="fc1 ls18 ws7a">2010</span><span class="ls107 ws193">; Holley and St Clair <span class="fc1 ls18 ws7a">2009</span><span class="ls1d ws36e">). Thus, increasedlevels</span></span></div>

<div class="t m0 x0 h8 y1d3 ff1 fs2 fc0 sc0 lsd4 ws350">of NF-κB<span class="ls108 ws20f"> as observed in ME/CFS may cause agradual</span></div>

<div class="t m0 x0 h7 y1d4 ff1 fs2 fc0 sc0 ls10 ws285">downregulation of p53 (Holley and St Clair <span class="fc1 ws36">2009</span>),</div>

<div class="t m0 x2 h7 y1d5 ff1 fs2 fc0 sc0 ls10 ws36f">which may lead to a gradual worsening of symptoms. In-</div>

<div class="t m0 x2 h7 y1d6 ff1 fs2 fc0 sc0 ls15 ws370">creasing levels of mitochondrial damage however act to</div>

<div class="t m0 x2 h7 y1d7 ff6 fs2 fc0 sc0 ls50">“<span class="ff1 ls3f ws84">switch on</span><span class="ls109">”<span class="ff1 ls15 ws2e3">the transcription of p53. This can have theeffects</span></span></div>

<div class="t m0 x2 h7 y2a9 ff1 fs2 fc0 sc0 ls10 ws371">of raising levels of Foxp3 and thus a reduction insymptoms.</div>

<div class="t m0 x2 h7 y2aa ff1 fs2 fc0 sc0 ls10 ws372">P53 activation can also induce cell-cycle arrestand</div>

<div class="t m0 x2 h7 y2ab ff1 fs2 fc0 sc0 ls60 ws193">allow mitochondrial hea<span class="ls16 ws86">ling. A drop in free radicalproduction</span></div>

<div class="t m0 x2 h7 y2ac ff1 fs2 fc0 sc0 ls10 ws373">acts to suspend the activation of p53. This allowsthe</div>

<div class="t m0 x2 h8 y2ad ff1 fs2 fc0 sc0 ls10 ws371">levels of NF-κB<span class="ws374"> and oxidative stress to downregulatep53</span></div>

<div class="t m0 x2 h7 y2ae ff1 fs2 fc0 sc0 ls10 ws363">and Foxp3, and remission is terminated. A number ofsuch</div>

<div class="t m0 x2 h7 y2af ff1 fs2 fc0 sc0 ls10 wsf9">cycles are possible with a worsening of active diseaseover</div>

<div class="t m0 x2 h7 y2b0 ff1 fs2 fc0 sc0 ls10 ws5d">time. The presence of raised anticardiolipin antibodiesin</div>

<div class="t m0 x2 h7 y2b1 ff1 fs2 fc0 sc0 ls10 ws375">up to 95 % of patients with ME/CFS (Klein and Berg1995</div>

<div class="t m0 x2 h7 y2b2 ff1 fs2 fc1 sc0 ls10 ws36"><span class="fc0 ws362">) is consistent with the presence of peroxidative mito-chondrial</span></div>

<div class="t m0 x2 h7 y2b3 ff1 fs2 fc0 sc0 ls10 ws8f">damage and loss of cytochrome C oxidase func-tion</div>

<div class="t m0 x2 h7 y2b4 ff1 fs2 fc0 sc0 ls10 ws7c">(Paradies et al. <span class="fc1 ws36">1998</span>).Future</div>

<div class="t m0 x2 h4 y2b5 ff2 fs2 fc0 sc0 ls10 ws376">researchFuture</div>

<div class="t m0 x2 h7 y91 ff1 fs2 fc0 sc0 ls10 ws377">research should further examine the different inflam-matory</div>

<div class="t m0 x2 h7 y2b6 ff1 fs2 fc0 sc0 ls10 ws223">and O&NS pathways, the transition to autoimmuneresponses</div>

<div class="t m0 x2 h7 y2b7 ff1 fs2 fc0 sc0 lsc2 ws35a">and damage to mitochondria, the intracellularsignaling</div>

<div class="t m0 x2 h7 y2b8 ff1 fs2 fc0 sc0 ls10 ws1c6">networks involved, neuro-inflammation and brainmetabolic</div>

<div class="t m0 x2 h7 y2b9 ff1 fs2 fc0 sc0 ls10 ws2d8">changes in relation to the new diagnostic criteria</div>

<div class="t m0 x2 h7 y2ba ff1 fs2 fc0 sc0 ls10 ws107">(Maes et al. <span class="fc1 ws36">2012a</span><span class="ws39 v0">). We suggest that future research shouldbe</span></div>

<div class="t m0 x2 h7 y2bb ff1 fs2 fc0 sc0 ls15 ws378">based on cohort selection using PET scans to detectactivated</div>

<div class="t m0 x2 h7 y2bc ff1 fs2 fc0 sc0 ls10 ws379">microglia (Gerhardetal.<span class="fc1 ws36">2006</span><span class="ws28d">). We would suggestobjective</span></div>

<div class="t m0 x2 h7 y2bd ff1 fs2 fc0 sc0 ls71 ws6f">testing for the existence of BBB permeabilityusing</div>

<div class="t m0 x2 h7 y2be ff1 fs2 fc0 sc0 ls10 ws37a">dynamic Gadolinium-DTPA MRI scanning (Larssonand</div>

<div class="t m0 x2 h7 y2bf ff1 fs2 fc0 sc0 ls10 wse4">Tofts<span class="fc1 ws36">1992</span><span class="ws37b">). The initial challenge would be to isolatepeople</span></div>

<div class="t m0 x2 h7 y2c0 ff1 fs2 fc0 sc0 ls10 ws37c">with ME from those with CFS and CF (Maes et al.2012a</div>

<div class="t m0 x2 h7 y2c1 ff1 fs2 fc1 sc0 ls1e ws98"><span class="fc0 ls10a ws370">) via the use of PET, SPECT scans, 3 T MRI orGadolinium-DTPA</span></div>

<div class="t m0 x5 h7 y2c3 ff1 fs2 fc0 sc0 ls10 ws23f">spectroscopy and proteomic approaches for detect-ing</div>

<div class="t m0 x2 h7 y2c4 ff1 fs2 fc0 sc0 ls10 ws37d">and characterizing nitrosatively and oxidatively modi-fied</div>

<div class="t m0 x2 h7 y2c5 ff1 fs2 fc0 sc0 ls10 ws1dd">lipids, proteins and DNA produce specific sensitive andreproducible</div>

<div class="t m0 x2 h7 y2c6 ff1 fs2 fc0 sc0 ls10 ws9a">results (Aulak et al. <span class="fc1 ws36">2001</span><span class="ws2ac">). Luminex assays forthe</span></div>

<div class="t m0 x2 h7 y2c7 ff1 fs2 fc0 sc0 ls10 ws37e">determination of cytokine levels in supernatants frommitogen</div>

<div class="t m0 x2 h7 y2c8 ff1 fs2 fc0 sc0 ls10 ws37f">stimulated cultured peripheral blood mononuclearcells</div>

<div class="t m0 x2 h7 y2c9 ff1 fs2 fc0 sc0 ls10 ws2d7">(PMBCs) are regarded as producing reliable and re-</div>

<div class="t m0 x2 h7 y2ca ff1 fs2 fc0 sc0 ls10 ws380">producible results while minimizing intra and inter labora-tory</div>

<div class="t m0 x2 h7 y2cb ff1 fs2 fc0 sc0 ls10 ws381">variation (Griffiths et al. <span class="fc1 ws36">2002</span><span class="ws382">; Fulton et al. <span class="fc1 ws36">1997</span><span class="ws383">; Fulyaet</span></span></div>

<div class="t m0 x2 h7 y2cc ff1 fs2 fc0 sc0 ls10 ws19f">al.<span class="fc1 ws36">2006</span><span class="ws12d">; de Jager et al. <span class="fc1 ws36">2009</span><span class="ws236">). Real time reverse tran-scriptase</span></span></div>

<div class="t m0 x2 h7 y2cd ff1 fs2 fc0 sc0 ls10 ws17b">PCR provides a sensitive and quantitative measureof</div>

<div class="t m0 x2 h7 y2ce ff1 fs2 fc0 sc0 ls10 ws70">cytokinemRNA levels in PBMCs. STAT gene expres-sion</div>

<div class="t m0 x2 h7 y2cf ff1 fs2 fc0 sc0 ls6b ws13">, p53 expression and Foxp3 transcription should bemeasured.Mitochondrial</div>

<div class="t m0 x5 h7 y2d1 ff1 fs2 fc0 sc0 ls8 ws354">dysfunction and ATP levels should beassessed</div>

<div class="t m0 x2 h7 y2d2 ff1 fs2 fc0 sc0 ls10 ws384">using a combination of nuclear magnetic resonancespectroscopy</div>

<div class="t m0 x2 h7 y2d3 ff1 fs2 fc0 sc0 ls10 ws2be">, (31)P magnetic-resonance spectroscopy andblood</div>

<div class="t m0 x2 h7 y2d4 ff1 fs2 fc0 sc0 ls10 ws113">tests measuring ATP synthesis in PMBCs (Dykens etal.</div>

<div class="t m0 x2 h7 y2d5 ff1 fs2 fc0 sc0 ls10 ws385"><span class="fc1 ws36">2008</span><span class="ws166">; Chaumeil et al. <span class="fc1 ws36">2009</span><span class="ws386">). Exercise stress testing hasthe</span></span></div>

<div class="t m0 x2 h7 y2d6 ff1 fs2 fc0 sc0 ls10 ws355">potential to do harm to people with ME/CFS and thusMetab</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">Brain Dis (2013) 28:523<span class="ff6 lsf">–</span><span class="ws13b">540 533</span></div>

</div>

</div>

<div class="t m0 x0 h7 y4d ff1 fs2 fc0 sc0 ls10 ws102">the non-ischemic repeat handgrip test should be consideredas</div>

<div class="t m0 x0 h7 y4e ff1 fs2 fc0 sc0 ls10 ws7c">a simple non-invasive test for mitochondrial dysfunction</div>

<div class="t m0 x0 h7 y4f ff1 fs2 fc0 sc0 ls10 ws387">(Meulemans et al. <span class="fc1 ws36">2007</span><span class="ws108">). The aerobic forearm test providesthe</span></div>

<div class="t m0 x0 h7 y50 ff1 fs2 fc0 sc0 ls10 ws66">basis of a simple measure of mitochondrial function andcould</div>

<div class="t m0 x0 h7 y51 ff1 fs2 fc0 sc0 ls10 ws388">be adapted to perform measurements over a 3 dayperiod</div>

<div class="t m0 x0 h7 y52 ff1 fs2 fc0 sc0 ls10 ws134">(Garrabou et al. <span class="fc1 ws36">2006</span>).Genetic</div>

<div class="t m0 x4 h7 y53 ff1 fs2 fc0 sc0 lsb5 ws389">polymorphisms in the DNA repair mecha-nisms</div>

<div class="t m0 x0 h7 y54 ff1 fs2 fc0 sc0 ls21 ws38a">and O&NS pathways, single nucleotide polymor-phisms</div>

<div class="t m0 x0 h8 y55 ff1 fs2 fc0 sc0 ls3a ws38b">(SNPs) in the NF-κB<span class="ls19 ws38c"> and p53 pathways mayfurther</span></div>

<div class="t m0 x0 h7 y56 ff1 fs2 fc0 sc0 ls10d ws38d">reveal genetic vulnerabilities to develop ME/</div>

<div class="t m0 x0 h7 y57 ff1 fs2 fc0 sc0 ls115 ws38e">CFS. Next generation sequencing offers a rapid andsensitive</div>

<div class="t m0 x0 h7 y58 ff1 fs2 fc0 sc0 ls1e ws38f">method for detecting the wide range of SNPsin</div>

<div class="t m0 x0 h7 y59 ff1 fs2 fc0 sc0 ls10e ws390">the human genome and offers promise for investigat-ing</div>

<div class="t m0 x0 h7 y5a ff1 fs2 fc0 sc0 ls10f ws391">SNPs in patients with ME and CFS now that sci-entific</div>

<div class="t m0 x0 h7 y5b ff1 fs2 fc0 sc0 ls1e ws184">diagnostic criteria have been established (Maes etal.</div>

<div class="t m0 x0 h7 y5c ff1 fs2 fc0 sc0 ls10f ws392"><span class="fc1 ls21 ws85">2012a</span><span class="ls116 ws393">;Goyaetal.2010<span class="ls7a ws14a">;Karchin2009<span class="ls5b">).ConclusionFigure</span></span></span></div>

<div class="t m0 x0 h7 y2d8 ff1 fs2 fc0 sc0 ls10 ws394"><span class="fc1 ls110">3shows</span><span class="ws30"> the neuro-immune pathways that may leadto</span></div>

<div class="t m0 x0 h7 y2d9 ff1 fs2 fc0 sc0 ls10 ws395">ME/CFS. A prolonged severe but non persistent infectionby</div>

<div class="t m0 x0 h7 y2da ff1 fs2 fc0 sc0 ls10 ws72">a number of potential pathogens may result in chronicactivation</div>

<div class="t m0 x0 h7 y2db ff1 fs2 fc0 sc0 ls10 ws113">of immune responses. The latter involve the acti-vation</div>

<div class="t m0 x0 h7 y2dc ff1 fs2 fc0 sc0 ls10 ws396">of immuno-inflammatory and O&NS pathways anddepletion</div>

<div class="t m0 x0 h7 y2dd ff1 fs2 fc0 sc0 ls10 ws397">of the body<span class="ff6 ws36">’</span><span class="ws113">s antioxidant defenses. Elevated PICsand</span></div>

<div class="t m0 x2 h7 y2de ff1 fs2 fc0 sc0 ls10 ws1dd">other inflammatory and O&NS compounds are detectedby</div>

<div class="t m0 x2 h7 y2df ff1 fs2 fc0 sc0 ls10 ws398">the vagus nerve and other bottom-up signals leading tothe</div>

<div class="t m0 x2 h7 y2e0 ff1 fs2 fc0 sc0 ls16 ws86">activation of microglia and neuro-inflammation. Thelatter</div>

<div class="t m0 x2 h7 y2e1 ff1 fs2 fc0 sc0 ls111 ws1ad">and O&NS pathways may persist once the initialinfection</div>

<div class="t m0 x2 h7 y2e2 ff1 fs2 fc0 sc0 ls10 ws28">has been cleared. Elevated and persistent O&NSlead</div>

<div class="t m0 x2 h7 y2e3 ff1 fs2 fc0 sc0 ls112 ws16f">to damage to lipids, proteins and DNA which thenbecome</div>

<div class="t m0 x2 h7 y2e4 ff1 fs2 fc0 sc0 ls10 ws399">recognized by the immune system as non self. Thisleads</div>

<div class="t m0 x2 h7 y2e5 ff1 fs2 fc0 sc0 ls10 ws39a">to the production of autoreactive T cells which causefurther</div>

<div class="t m0 x2 h7 y2e6 ff1 fs2 fc0 sc0 ls10 wsb1">damage. Descent into overt autoimmunity may beprecipitated</div>

<div class="t m0 x2 h7 y2e7 ff1 fs2 fc0 sc0 ls10 ws1a8">by further infections via molecular mimicry,</div>

<div class="t m0 x2 h7 y2e8 ff1 fs2 fc0 sc0 ls10 ws39b">bystander activation and epitope spreading. This ongoinginsidious</div>

<div class="t m0 x2 h7 y2e9 ff1 fs2 fc0 sc0 ls10 ws1cd">process increases the concentration of PICs via anumber</div>

<div class="t m0 x2 h8 y2ea ff1 fs2 fc0 sc0 ls10 ws39c">of mechanisms and activates NF-κB<span class="ws39d">, COX-2 andiNOS.</span></div>

<div class="t m0 x2 h7 y2eb ff1 fs2 fc0 sc0 ls10 ws39e">These processes may also involve enhanced STAT-3leading</div>

<div class="t m0 x2 h7 y2ec ff1 fs2 fc0 sc0 ls10 wsad">to the depletion of Foxp3 and chronic activation ofthe</div>

<div class="t m0 x2 h7 y2ed ff1 fs2 fc0 sc0 ls10 ws260">immune system. The combination of existing abnormal-ities</div>

<div class="t m0 x2 h7 y2ee ff1 fs2 fc0 sc0 ls10 ws39f">leads to mitochondrial damage and ATP deficit, auto-nomic</div>

<div class="t m0 x2 h7 y2ef ff1 fs2 fc0 sc0 ls113 ws1e2">dysregulation, and neuroendocrine and brainchanges</div>

<div class="t m0 x2 h7 y2f0 ff1 fs2 fc0 sc0 ls10 ws184">, including lowered cerebral blood flow and whitematter</div>

<div class="t m0 x2 h7 y2f1 ff1 fs2 fc0 sc0 ls5 ws308">volume, and maybe inflammatory lesions in thebrain.</div>

<div class="t m0 x2 h7 y2f2 ff1 fs2 fc0 sc0 ls10 ws3a0">Increased PICs, O&NS and mitochondrial damageand</div>

<div class="t m0 x2 h7 y2f3 ff1 fs2 fc0 sc0 ls10 ws2e5">ATP deficit are responsible for the hallmark symptomsof</div>

<div class="t m0 x2 h7 y2f4 ff1 fs2 fc0 sc0 ls10 ws27">the disease including post exertional malaise. The antag-onism</div>

<div class="t m0 x2 h7 y2f5 ff1 fs2 fc0 sc0 ls10 ws3a1">between peripheral immune activation, chronic in-flammation</div>

<div class="t m0 x2 h7 y2f6 ff1 fs2 fc0 sc0 ls10 ws168">and CNS responses is held to be responsible forthe</div>

<div class="t m0 x2 h7 y2f7 ff1 fs2 fc0 sc0 ls10 ws7c">relapsing-remitting pattern of the disease.Fig.</div>

<div class="t m0 x0 h5 y2f8 ff2 fs4 fc0 sc0 ls10 ws3a2">3 <span class="ff1 ws4c">The neuro-immunepathways</span></div>

<div class="t m0 x0 h5 y2f9 ff1 fs4 fc0 sc0 ls10 ws3a3">that are involved inthe</div>

<div class="t m0 x0 h5 y2fa ff1 fs4 fc0 sc0 ls10 ws3a4">pathophysiology of ME/</div>

<div class="t m0 x0 h5 y2fb ff1 fs4 fc0 sc0 ls10 ws3a5">CFS and may cause the typicalsymptoms</div>

<div class="t m0 x0 h5 y2fc ff1 fs4 fc0 sc0 ls10 ws3a6">of ME and CFS (seeConclusion</div>

<div class="t m0 x0 h5 y2fe ff1 fs4 fc0 sc0 ls10 ws3a9">explanation)</div>

<div class="t m0 x0 h5 yb3 ff1 fs4 fc0 sc0 ls10 ws4f">534 Metab Brain Dis (2013) 28:523<span class="ff6 lsf">–</span>540</div>

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</div>

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<p>
<em>(PDF) A neuro-immune model of Myalgic....</em> Available from: <a href="https://www.researchgate.net/publication/227710342_A_neuro-immune_model_of_Myalgic_EncephalomyelitisChronic_fatigue_syndrome">https://www.researchgate.net/publication/227710342_A_neuro-immune_model_of_Myalgic_EncephalomyelitisChronic_fatigue_syndrome</a> [accessed Aug 20 2018].</p>

Neuro-immune Model

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