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=== Immune activation === <embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo> There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples. ==== Oxidative stress ==== <embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo> In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref> ==== Complement C4a ==== In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref> ==== Cytokines ==== The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below). {| class="wikitable" |<small>Study</small> |<small>Number of participants</small> |<small>Exercise challenge</small> |<small>Cytokines tested:</small> |<small>Results:</small> |- |<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref> |<small>10 ([[Holmes criteria]], all cases were post-infectious)</small> |<small>Walking 1 mile per hour for 30 min</small> |<small>[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]</small> |<small>Negative results</small> |- |<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref> |<small>12 ([[Australian criteria]])</small> |<small>30 min hand grip exercises</small> |<small>[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]</small> |<small>Negative results</small> |- |<small>La Manca et al. (1999)</small><ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref> |<small>20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included</small> |<small>An exhaustive treadmill exercise test</small> |<small>[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]</small> |<small>Negative results</small> |- |<small>Cannon et al. (1997)</small><ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref> |<small>8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”</small> |<small>Stepping up and down on a platform for 15 min</small> |<small>[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).</small> |<small>Negative results</small> |- |<small>Gupta et al. (1998)</small><ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref> |<small>5 (Holmes criteria)</small> |<small>30 min hand grip exercises</small> |<small>[[Interleukin 6|IL-6]]</small> |<small>Negative results</small> |- |<small>Cannon et al. (1999)</small><ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref> |<small>10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”</small> |<small>Stepping up and down on a platform for 15 min</small> |<small>[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]</small> |<small>Negative results</small> |- |<small>Jammes et al. (2009)</small><ref name="Jammes2009" /> |<small>9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small> |<small>Cycling test until maximal work load</small> |<small>[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]</small> |<small>Negative results</small> |- |<small>Robinson et al (2010)</small><ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref> |<small>6 (Fukuda criteria)</small> |<small>Incremental exercise test to exhaustion</small> |<small>[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]</small> |<small>Negative results</small> |- |<small>Andrea White et al. (2010)</small><ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref> |<small>19 (Fukuda criteria)</small> |<small>The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."</small> |<small>[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]</small> <small> </small> |<small>Positive results for a subgroup (11/19) of patients with high PEM</small> <small> </small> |- |<small>Andrew Lloyd et al. (2018)</small><ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref> |<small>24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"</small> |<small>Symptom limited exercise on an ergocycle.</small> |<small>Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small> <small> </small> <small>[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]</small> <small> </small> <small>Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]</small> <small> </small> <small>[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small> <small> </small> <small>[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]</small> <small> </small> <small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small> <small> </small> <small>Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]</small> |<small>Positive results: ME/CFS had a distinct cytokine profile post-exercise.</small> |} Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote>
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