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Cytokine
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'''Cytokines''' are any class of immunoregulatory [[:Category:Proteins|proteins]] secreted by cells, especially [[Immune cells|immune system cells]].<ref>{{Cite web | url = https://www.merriam-webster.com/dictionary/cytokine#medicalDictionary | title = Definition of CYTOKINE | last = Merriam-Webster Medical Dictionary|first = | date = | website = Merrian-Webster Dictionary|language=en| archive-url = | archive-date = |url-status = | access-date=2018-10-06}}</ref> Cytokines are small proteins important in cell signaling that modulate the [[immune system]]. There are many different cytokines. They function as messenger molecules passing information around the body. They resemble [[hormone]]s in this way, but they are usually communicating in response to something external and lead to inflammatory or immune responses. ==Types of cytokines== *[[Chemokine]]s *[[Interferon]]s *[[Interleukin]]s *[[Lymphokine]]s *[[TNF-alpha |Tumor necrosis factor]] ==Cellular immune response== [[IFN-γ]], [[TNF-alpha|TNFα]] ==Antibody response== [[TGF-beta|TGF-β]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interleukin 13|IL-13]] ==Role in human disease== ===Chronic Fatigue Syndrome=== There is increasing evidence that cytokine expression is altered in CFS (ME). [[Mady Hornig]] et al (2015) indicates that there is a generally increased response in the first 3 years of illness.<ref name="Hornig, 2015" /> In 2017, a [[Jose Montoya|Montoya]], et al, study showed that "seventeen cytokines had a statistically significant upward linear trend that correlated with [[ME/CFS]] severity"..."thirteen of these are proinflammatory, likely contributing to many of the symptoms experienced by patients."<ref name=":11" /> Two large 2015 studies found a general pattern of down regulation in long term patients (Hornig, et al and Landi, et al). <ref name="Landi2015" /> It is worth noting that these differences can average each other out when data from newly diagnosed and long term patients are analysed together. More accurate data may necessitate patient groups being stratified by disease duration. In a 2017 study by Hornig, Lipkin et al, 51 Cytokines of cerebrospinal fluid were measured where they found Atypical and Classical cases of [[ME/CFS]]. There are differing immune signatures within the [[central nervous system]]. "Typically, symptoms of ME/CFS begin suddenly following a flu-like infection, but a subset of cases classified by the investigators as “atypical” follows a different disease course, either from triggers preceding symptoms by months or years, or accompanied by the later development of additional serious illnesses."<ref>{{Cite journal | last = Lipkin | first = W.I. | author-link = Ian Lipkin | last2 = Peterson | first2 = D.L. | author-link2 = Daniel Peterson | last3 = Ukaigwe | first3 = J. E. | author-link3 = J Ukaigwe | last4 = Che | first4 = X. | author-link4 = X Che | last5 = Eddy | first5 = M.L. | author-link5 = Meredith Eddy | last6 = Gottschalk | first6 = C.G. |last7 = Hornig | first7 = M. | date = Apr 2017 | title = Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations |url =https://www.nature.com/articles/tp201744|journal=Translational Psychiatry|language=en|volume=7|issue=4| pages = e1080|doi=10.1038/tp.2017.44|issn=2158-3188|quote=|via=}}</ref> When reading cytokine studies it is important to remember that with so many cytokines it is common to find some pattern and results can change quickly within individuals. In a small sample, if just a couple of people were fighting a cold then this could change the overall results. ===Fibromyalgia=== [[Fibromyalgia]]: Cytokines [[IL-1beta]], [[Interleukin 6|IL-6]] and [[TNF-alpha]] are involved with central and peripheral neuropathic pain which is experienced by [[Fibromyalgia]] patients.<ref>{{Cite journal | last = Staud | first = Roland | authorlink = Roland Staud | date = Mar 2004 | title = Fibromyalgia pain: do we know the source? | url = https://www.ncbi.nlm.nih.gov/pubmed/14770104/|journal=Current Opinion in Rheumatology|volume=16|issue=2 | pages = 157–163|issn=1040-8711|pmid=14770104|quote=|via=|doi=|pmc=|access-date=}}</ref> Profiles are distinguishing [[Systemic lupus erythematosus|Lupus]] and [[Rheumatoid arthritis|Rheumatoid Arthritis]] from Fibromyalgia.<ref>[https://www.ncbi.nlm.nih.gov/pubmed/25377646 Cytokine and chemokine profiles in fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus: a potentially useful tool in differential diagnosis. PubMed.gov NCBI-NLM]</ref> === Table of Cytokines === {| class="wikitable" !Cytokine !Description !Increased in ME/CFS !Decreased in ME/CFS |- |[[Interferon]]s |Interferons are antiviral agents that modulate the immune system. They stimulate [[Natural killer cell|Natural killer cells]] and [[Macrophage|macrophages]] to elicit antiviral and anti-tumor responses. | | |- |[[IFN-α]] |(''Interferon alpha'') A type I interferon produced by [[Leucocyte|Leucocytes.]] Major contributor to innate immunity against viral infection. |Increased<ref>{{Cite journal | last = Lever | first = A.M.L. | last2 = Lewis | first2 = D.M. | last3 = Bannister | first3 = B.A. | last4 = Fry | first4 = M. | last5 = Berry | first5 = N. | date = 1988-07-09 | title = INTERFERON PRODUCTION IN POSTVIRAL FATIGUE SYNDROME | url = https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(88)90029-3/abstract|journal=The Lancet|language=English|volume=332|issue=8602 | pages = 101|doi=10.1016/S0140-6736(88)90029-3|issn=0140-6736}}</ref><ref>{{Cite journal | last = Vojdani|first = A. | last2 = Ghoneum | first2 = M. | last3 = Choppa | first3 = P.C. | last4 = Magtoto | first4 = L. | last5 = Lapp | first5 = C.W. | date = 1997 | title = Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein Kinase RNA | url = https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.1997.tb00019.x|journal=Journal of Internal Medicine|language=en|volume=242|issue=6 | pages = 465–478|doi=10.1111/j.1365-2796.1997.tb00019.x|issn=1365-2796}}</ref> | |- |[[IFN-β]] |(''Interferon beta'') A type I interferon produced in [[Fibroblast|fibroblasts]] by [[RNAseL]]. It is used to reduce relapses in relapsing-remitting [[multiple sclerosis]]. Major contributor to innate immunity against viral infection. | | |- |[[Interferon kappa|IFN-κ]] |(''Interferon kappa'') A type I interferon | | |- |[[IFN-γ]] |(''Interferon gamma'') The only Type II interferon in humans, it is produced by [[T cell]]s and [[Natural killer cell|natural killer cell]]s. Critical to both innate and adaptive immunity. Promotes macrophage activation. |Increased<ref name=":5">{{Cite journal | last = Brenu|first = Ekua W. | last2 = van Driel | first2 = Mieke L. | last3 = Staines | first3 = Don R. | last4 = Ashton | first4 = Kevin J. | last5 = Ramos | first5 = Sandra B. | last6 = Keane | first6 = James | last7 = Klimas | first7 = Nancy G. | last8 = Marshall-Gradisnik | first8 = Sonya M. | date = 2011-05-28 | title = Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis |url =https://doi.org/10.1186/1479-5876-9-81|journal=Journal of Translational Medicine|volume=9|issue=1 | pages = 81|doi=10.1186/1479-5876-9-81|issn=1479-5876|pmc = 3120691|pmid=21619669}}</ref><ref name=":6">{{Cite journal | last = Brenu|first = Ekua W. | last2 = van Driel | first2 = Mieke L. | last3 = Staines | first3 = Donald R. | last4 = Ashton | first4 = Kevin J. | last5 = Hardcastle | first5 = Sharni L. | last6 = Keane | first6 = James | last7 = Tajouri | first7 = Lotti | last8 = Peterson | first8 = Daniel | last9 = Ramos | first9 = Sandra B. | date = 2012-05-09 | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis |url =https://doi.org/10.1186/1479-5876-10-88|journal=Journal of Translational Medicine|language=en|volume=10|issue=1 | pages = 88|doi=10.1186/1479-5876-10-88|issn=1479-5876|pmc = 3464733|pmid=22571715}}</ref><ref name=":7">{{Cite journal | last = Garcia | first = Melissa N. | last2 = Hause | first2 = Anne M. | last3 = Walker | first3 = Christopher M. | last4 = Orange | first4 = Jordan S. | last5 = Hasbun | first5 = Rodrigo | last6 = Murray | first6 = Kristy O. | date = 2014-07-25 | title = Evaluation of Prolonged Fatigue Post–West Nile Virus Infection and Association of Fatigue with Elevated Antiviral and Proinflammatory Cytokines |url =https://www.liebertpub.com/doi/abs/10.1089/vim.2014.0035|journal=Viral Immunology|volume=27|issue=7 | pages = 327–333|doi=10.1089/vim.2014.0035|issn=0882-8245|pmc = 4150370|pmid=25062274}}</ref><ref name=":16">{{Cite journal | last = Khaiboullina | first = Svetlana F. | last2 = DeMeirleir | first2 = Kenny L. | last3 = Rawat | first3 = Shanti | last4 = Berk | first4 = Grady S. | last5 = Gaynor-Berk | first5 = Rory S. | last6 = Mijatovic | first6 = Tatjana | last7 = Blatt | first7 = Natalia | last8 = Rizvanov | first8 = Albert A. | last9 = Young | first9 = Sheila G. | date = 2015-03-01 | title = Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis |url =http://www.sciencedirect.com/science/article/pii/S1043466614006024|journal=Cytokine|language=en|volume=72|issue=1 | pages = 1–8|doi=10.1016/j.cyto.2014.11.019|issn=1043-4666}}</ref> Increased in severe illness<ref name=":8">{{Cite journal | last = Hardcastle | first = Sharni Lee | last2 = Brenu | first2 = Ekua Weba | last3 = Johnston | first3 = Samantha | last4 = Nguyen | first4 = Thao | last5 = Huth | first5 = Teilah | last6 = Ramos | first6 = Sandra | last7 = Staines | first7 = Donald | last8 = Marshall-Gradisnik | first8 = Sonya | date = 2015-09-05 | title = Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615236/|journal=International Journal of Medical Sciences|volume=12|issue=10 | pages = 764–772|doi=10.7150/ijms.12399|issn=1449-1907|pmc=4615236|pmid=26516304}}</ref> Increased with illness severity<ref name=":11">{{Cite journal | last = Montoya | first = Jose G. | last2 = Holmes | first2 = Tyson H. | last3 = Anderson | first3 = Jill N. | last4 = Maecker | first4 = Holden T. | last5 = Rosenberg-Hasson | first5 = Yael | last6 = Valencia | first6 = Ian J. | last7 = Chu | first7 = Lily | last8 = Younger | first8 = Jarred W. | last9 = Tato | first9 = Cristina M. | date = 2017-08-22 | title = Cytokine signature associated with disease severity in chronic fatigue syndrome patients |url =https://pubmed.ncbi.nlm.nih.gov/28760971/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=114|issue=34| pages = E7150–E7158|doi=10.1073/pnas.1710519114|issn=1091-6490|pmc=5576836|pmid=28760971}}</ref> Increased in early illness<ref name="Hornig, 2015" /> |Decreased<ref name=":17">{{Cite journal | last = Neu|first = Daniel | last2 = Mairesse | first2 = Olivier | last3 = Montana | first3 = Xavier | last4 = Gilson | first4 = Medhi | last5 = Corazza | first5 = Francis | last6 = Lefevre | first6 = Nicolas | last7 = Linkowski | first7 = Paul | last8 = Le Bon | first8 = Olivier | last9 = Verbanck | first9 = Paul | date = 2014-09-01 | title = Dimensions of pure chronic fatigue: psychophysical, cognitive and biological correlates in the chronic fatigue syndrome | url =https://doi.org/10.1007/s00421-014-2910-1|journal=European Journal of Applied Physiology|language=en|volume=114|issue=9 | pages = 1841–1851|doi=10.1007/s00421-014-2910-1|issn=1439-6327}}</ref> Decreased IFN-γ/IL-10 ratio<ref name=":3">{{Cite journal | last = ter Wolbeek|first = Maike | last2 = van Doornen | first2 = Lorenz J.P. | last3 = Kavelaars | first3 = Annemieke | last4 = van de Putte | first4 = Elise M. | last5 = Schedlowski | first5 = Manfred | last6 = Heijnen | first6 = Cobi J. | date = 2007-11-01 | title = Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents |url =http://www.sciencedirect.com/science/article/pii/S0889159107000906|journal=Brain, Behavior, and Immunity|language=en|volume=21|issue=8 | pages = 1063–1074|doi=10.1016/j.bbi.2007.04.007|issn=0889-1591}}</ref> Decreased secretion from MAIT cells<ref name=":18">{{Cite journal | last = Karhan | first = Ece | last2 = Gunter | first2 = Courtney L. | last3 = Ravanmehr | first3 = Vida | last4 = Horne | first4 = Meghan | last5 = Kozhaya | first5 = Lina | last6 = Renzullo | first6 = Stephanie | last7 = Placek | first7 = Lindsey | last8 = George | first8 = Joshy | last9 = Robinson | first9 = Peter N. | date = 2019-12-26 | title = Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | url = https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1|journal=bioRxiv|language=en | pages = 2019.12.23.887505|doi=10.1101/2019.12.23.887505}}</ref> |- |[[Interferon lambda|IFN-λ]] |(''Interferon lambda'') Type III interferon. Immunity response against early stages of viral infection. | | |- |'''[[Interleukin|Interleukins]]''' |'''Promote the growth of immune system cells and help regulate the immune system''' | | |- |[[Interleukin 1|IL-1]] |(''Interleukin 1 subgroups: IL-1β, IL-1α'') Regulates immune and inflammatory response, and activates antigen presenting cells Acts as a major mediator in central fatigue pathways<ref>{{Cite journal | last = Yadlapati|first = Sujani | last2 = Efthimiou | first2 = Petros | date = 2016 | title=Impact of IL-1 inhibition on fatigue associated with autoinflammatory syndromes |url =https://pubmed.ncbi.nlm.nih.gov/26140469/|journal=Modern Rheumatology|volume=26|issue=1 | pages = 3–8|doi=10.3109/14397595.2015.1069459|issn=1439-7609|pmid=26140469}}</ref> Elevation of IL-1 in the brain contributes “[[sickness behavior]]".<ref>{{Cite journal | last = Roerink|first = Megan E. | last2 = van der Schaaf | first2 = Marieke E. | last3 = Dinarello | first3 = Charles A. | last4 = Knoop | first4 = Hans | last5 = van der Meer | first5 = Jos W.M. | date = 2017-01-21 | title = Interleukin-1 as a mediator of fatigue in disease: a narrative review | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251329/|journal=Journal of Neuroinflammation|volume=14|doi=10.1186/s12974-017-0796-7|issn=1742-2094|pmc=5251329|pmid=28109186}}</ref> IL-1β is a pro-inflammatory cytokine with metabolic and immuno-inflammatory functions.<ref name=":8" /> |Increased [[Interleukin 1 alpha|IL-1α]]<ref>{{Cite journal | last = Linde | first = A. | last2 = Andersson | first2 = B. | last3 = Svenson | first3 = S.B. | last4 = Ahrne | first4 = H. | last5 = Carlsson | first5 = M. | last6 = Forsberg | first6 = P. | last7 = Hugo | first7 = H. | last8 = Karstorp | first8 = A. | last9 = Lenkei | first9 = R. | date = Jun 1992 | title = Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome | url =https://pubmed.ncbi.nlm.nih.gov/1316417/|journal=The Journal of Infectious Diseases|volume=165|issue=6 | pages = 994–1000|doi=10.1093/infdis/165.6.994|issn=0022-1899|pmid=1316417}}</ref><ref name=":1">{{Cite journal | last = Patarca | first = R. | last2 = Klimas | first2 = N.G. | last3 = Lugtendorf | first3 = S. | last4 = Antoni | first4 = M. | last5 = Fletcher | first5 = M.A. | date = Jan 1994 | title = Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression | url =https://pubmed.ncbi.nlm.nih.gov/8148443/|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1 | pages = S147–153|doi=10.1093/clinids/18.supplement_1.s147|issn=1058-4838|pmid=8148443}}</ref><ref name=":4">{{Cite journal | last = Fletcher | first = Mary Ann | last2 = Zeng | first2 = Xiao Rong | last3 = Barnes | first3 = Zachary | last4 = Levis | first4 = Silvina | last5 = Klimas | first5 = Nancy G. | date = 2009-11-12 | title = Plasma cytokines in women with chronic fatigue syndrome | url =https://doi.org/10.1186/1479-5876-7-96|journal=Journal of Translational Medicine|language=en|volume=7|issue=1 | pages = 96|doi=10.1186/1479-5876-7-96|issn=1479-5876|pmc = 2779802|pmid=19909538}}</ref><ref name=":19">{{Cite journal | last = Maes | first = Michael | last2 = Twisk | first2 = Frank N.M. | last3 = Kubera | first3 = Marta | last4 = Ringel | first4 = Karl | date = 2012-02-01 | title = Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin | url =http://www.sciencedirect.com/science/article/pii/S0165032711005301|journal=Journal of Affective Disorders|language=en|volume=136|issue=3 | pages = 933–939|doi=10.1016/j.jad.2011.09.004|issn=0165-0327}}</ref> Increased IL-1α in females<ref name=":20">{{Cite journal | last = Smylie | first = Anne Liese | last2 = Broderick | first2 = Gordon | last3 = Fernandes | first3 = Henrique | last4 = Razdan | first4 = Shirin | last5 = Barnes | first5 = Zachary | last6 = Collado | first6 = Fanny | last7 = Sol | first7 = Connie | last8 = Fletcher | first8 = Mary Ann | last9 = Klimas | first9 = Nancy | date = 2013-06-25 | title = A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome | url =https://doi.org/10.1186/1471-2172-14-29|journal=BMC Immunology|language=en|volume=14|issue=1 | pages = 29|doi=10.1186/1471-2172-14-29|issn=1471-2172|pmc = 3698072|pmid=23800166}}</ref> Increased IL-1β<ref name=":4" /><ref name=":21">{{Cite journal | last = Scully|first = Paul | last2 = McKernan | first2 = Declan P | last3 = Keohane | first3 = John | last4 = Groeger | first4 = David | last5 = Shanahan | first5 = Fergus | last6 = Dinan | first6 = Timothy G | last7 = Quigley | first7 = Eamonn MM | date = Oct 2010 | title = Plasma Cytokine Profiles in Females With Irritable Bowel Syndrome and Extra-Intestinal Co-Morbidity | url = https://journals.lww.com/ajg/Abstract/2010/10000/Plasma_Cytokine_Profiles_in_Females_With_Irritable.20.aspx|journal=American Journal of Gastroenterology|language=en-US|volume=105|issue=10 | pages = 2235–2243|doi=10.1038/ajg.2010.159|issn=0002-9270}}</ref><ref name=":19" /><ref name=":22">{{Cite journal | last = Lattie | first = Emily G. | last2 = Antoni | first2 = Michael H. | last3 = Fletcher | first3 = Mary Ann | last4 = Penedo | first4 = Frank | last5 = Czaja | first5 = Sara | last6 = Lopez | first6 = Corina | last7 = Perdomo | first7 = Dolores | last8 = Sala | first8 = Andreina | last9 = Nair | first9 = Sankaran | date = 2012-08-01 | title = Stress management skills, neuroimmune processes and fatigue levels in persons with chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S088915911200061X|journal=Brain, Behavior, and Immunity|language=en|volume=26|issue=6 | pages = 849–858|doi=10.1016/j.bbi.2012.02.008|issn=0889-1591}}</ref><ref name=":17" /> Increased IL-1β, proportional to poor sleep quality<ref name=":10">{{Cite journal | last = Milrad | first = Sara F. | last2 = Hall | first2 = Daniel L. | last3 = Jutagir | first3 = Devika R. | last4 = Lattie | first4 = Emily G. | last5 = Ironson | first5 = Gail H. | last6 = Wohlgemuth | first6 = William | last7 = Nunez | first7 = Maria Vera | last8 = Garcia | first8 = Lina | last9 = Czaja | first9 = Sara J. | date = 2017-02-15 | title = Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women | url =https://pubmed.ncbi.nlm.nih.gov/28038892/|journal=Journal of Neuroimmunology|volume=303 | pages = 43–50|doi=10.1016/j.jneuroim.2016.12.008|issn=1872-8421|pmc=5258835|pmid=28038892}}</ref> Increased IL-1α in early illness<ref name=":13">{{Cite journal | last = Russell|first = Lindsey | last2 = Broderick | first2 = Gordon | last3 = Taylor | first3 = Renee | last4 = Fernandes | first4 = Henrique | last5 = Harvey | first5 = Jeanna | last6 = Barnes | first6 = Zachary | last7 = Smylie | first7 = AnneLiese | last8 = Collado | first8 = Fanny | last9 = Balbin | first9 = Elizabeth G. | date = 2016-03-10 | title = Illness progression in chronic fatigue syndrome: a shifting immune baseline | url =https://doi.org/10.1186/s12865-016-0142-3|journal=BMC Immunology|language=en|volume=17|issue=1 | pages = 3|doi=10.1186/s12865-016-0142-3|issn=1471-2172|pmc = 4785654|pmid=26965484}}</ref><ref name="Hornig, 2015" /> Increased IL-1RA in early illness<ref name="Hornig, 2015" /> Increased in those with 5-HT autoimmune activity<ref name=":14">{{Cite journal | last = Maes | first = Michael | last2 = Ringel | first2 = Karl | last3 = Kubera | first3 = Marta | last4 = Anderson | first4 = George | last5 = Morris | first5 = Gerwyn | last6 = Galecki | first6 = Piotr | last7 = Geffard | first7 = Michel | date = 2013-09-05 | title = In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation | url =http://www.sciencedirect.com/science/article/pii/S0165032713002541|journal=Journal of Affective Disorders|language=en|volume=150|issue=2 | pages = 223–230|doi=10.1016/j.jad.2013.03.029|issn=0165-0327}}</ref> |Decreased IL-1β in severe illness<ref name=":8" /> Decreased IL-1β<ref name=":9">{{Cite journal | last = Hornig|first = M. | last2 = Gottschalk | first2 = G. | last3 = Peterson | first3 = D.L. | last4 = Knox | first4 = K.K. | last5 = Schultz | first5 = A.F. |last6 = Eddy | first6 = M.L. | last7 = Che | first7 = X. | last8 = Lipkin | first8 = W.I. | date = Feb 2016 | title = Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome | url =https://www.nature.com/articles/mp201529/|journal=Molecular Psychiatry|language=en|volume=21|issue=2 | pages = 261–269|doi=10.1038/mp.2015.29|issn=1476-5578}}</ref> Decreased IL-1α and IL-1RA in later illness<ref name="Hornig, 2015" /> Decreased in later illness<ref name=":13" /> |- |[[Interleukin 2|IL-2]] |(''Interleukin 2'') Stimulates [[T cell|T-Cell]] growth, regulates immune system, controls cellular proliferation and differentiation |Increased<ref>{{Cite journal | last = Cheney|first = P.R. | last2 = Dorman | first2 = S.E. | last3 = Bell | first3 = D.S. | date = 1989-02-15 | title = Interleukin-2 and the chronic fatigue syndrome | url =https://pubmed.ncbi.nlm.nih.gov/2783643/|journal=Annals of Internal Medicine|volume=110|issue=4 | pages = 321|doi=10.7326/0003-4819-110-4-321_1|issn=0003-4819|pmid=2783643}}</ref><ref name=":6" /><ref name=":0">{{Cite journal | last = Milrad | first = Sara F. | last2 = Hall | first2 = Daniel L. | last3 = Jutagir | first3 = Devika R. | last4 = Lattie | first4 = Emily G. | last5 = Czaja | first5 = Sara J. | last6 = Perdomo | first6 = Dolores M. | last7 = Fletcher | first7 = Mary Ann | last8 = Klimas | first8 = Nancy | last9 = Antoni | first9 = Michael H. | date = 2018-09-01 | title = Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model | url = http://www.sciencedirect.com/science/article/pii/S0167876017301629|journal=International Journal of Psychophysiology|series=The Psychophysiology of Stress and Adaptation: Models, Pathways, and Implications|language=en|volume=131 | pages = 124–130|doi=10.1016/j.ijpsycho.2017.09.009|issn=0167-8760}}</ref><ref name=":16" /><ref name=":7" /> Increased in males<ref name=":20" /> |Depressed response post-exercise (increased in controls)<ref name=":12">{{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 | pages = 2779|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref> |- |[[Interleukin 3|IL-3]] |(''Interleukin 3'') Regulates blood-cell production | | |- |[[Interleukin 4|IL-4]] |(''Interleukin 4'') Induces naive [[Helper T cell|helper T cells]] to develop into [[Th2]] cells. Regulates immune system |Increased in early illness<ref name="Hornig, 2015" /> Increased<ref name=":1" /><ref name=":4" /><ref name=":16" /> Increased with illness severity<ref name=":11" /> |Decreased in females<ref name=":20" /> |- |[[Interleukin 5|IL-5]] |(''Interleukin 5'') Regulates [[Eosinophil|eosinophils]] in the bone marrow during inflammation |Increased<ref name=":4" /> Increased with illness severity<ref name=":11" /> |Decreased<ref name=":9" /><ref name=":16" /> |- |[[Interleukin 6|IL-6]] |(''Interleukin 6'') Regulates immune system, cellular proliferation and differentiation, and [[autoantibody]] production An important inflammatory cytokine and [[Hypothalamic-pituitary-adrenal axis|HPA axis]] modulator. IL-6 also plays a role in other CFS symptoms including [[hyperalgesia]], [[fatigue]], [[Sleep dysfunction|sleep impairment]], and [[depression]]. It has been reported that IL-6 induces excessive daytime sleepiness or disturbed [[Unrefreshing sleep|non-refreshing sleep]] in patients with CFS, and that increased levels are associated with a decrease in sleep quality.<ref name=":23">{{Cite journal | last = Yang|first = Tiansong | last2 = Yang | first2 = Yan | last3 = Wang | first3 = Delong | last4 = Li | first4 = Chaoran | last5 = Qu | first5 = Yuanyuan | last6 = Guo | first6 = Jing | last7 = Shi | first7 = Tianyu | last8 = Bo | first8 = Wang | last9 = Sun | first9 = Zhongren | date = 2019-06-28 | title = The clinical value of cytokines in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599310/|journal=Journal of Translational Medicine|volume=17|doi=10.1186/s12967-019-1948-6|issn=1479-5876|pmc=6599310|pmid=31253154}}</ref> IL-6 also directly increases glucose metabolism in human skeletal muscle<ref>{{Cite journal | last = Glund | first = Stephan | last2 = Deshmukh | first2 = Atul | last3 = Long | first3 = Yun Chau | last4 = Moller | first4 = Theodore | last5 = Koistinen | first5 = Heikki A. | last6 = Caidahl | first6 = Kenneth | last7 = Zierath | first7 = Juleen R. | last8 = Krook | first8 = Anna | date = 2007-06-01 | title = Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle | url =https://diabetes.diabetesjournals.org/content/56/6/1630|journal=Diabetes|language=en|volume=56|issue=6 | pages = 1630–1637|doi=10.2337/db06-1733|issn=0012-1797|pmid=17363741}}</ref> |Increased<ref name=":4" /><ref name=":0" /><ref name=":22" /><ref name=":16" /><ref name=":24">{{Cite web | url = https://www.hindawi.com/journals/mi/2018/3972104/ | title = Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome | last = Lynn | first = Megan | last2 = Maclachlan | first2 = Laura | date = 2018-06-10 | website = Mediators of Inflammation|language=en|access-date=2020-11-21 | last3 = Finkelmeyer | first3 = Andreas | last4 = Clark | first4 = James | last5 = Locke | first5 = James | last6 = Todryk | first6 = Stephen | last7 = Ng | first7 = Wan-Fai | last8 = Newton | first8 = Julia L. | last9 = Watson | first9 = Stuart}}</ref><ref name=":7" /> Increased [[Soluable Interleukin Receptor 6R|sIL-6R]]<ref name=":1"/> Increased, proportional to poor sleep quality<ref name=":10" /><ref>{{Cite journal | last = Nas | first = K. | last2 = Cevik | first2 = R. | last3 = Batum | first3 = S. | last4 = Sarac | first4 = A.J. | last5 = Acar | first5 = S. | last6 = Kalkanli | first6 = S. | date = 2011 | title = Immunologic and psychosocial status in chronic fatigue syndrome | url =https://pubmed.ncbi.nlm.nih.gov/21585130/|journal=Bratislavske Lekarske Listy|volume=112|issue=4 | pages = 208–212|issn=0006-9248|pmid=21585130}}</ref> Increased LIF with illness severity<ref name=":11" /> Increased in early illness<ref name="Hornig, 2015" /> Increased in later illness<ref name=":13" /> |Decreased<ref name=":3" /><ref name=":9" /><ref name=":17" /> Decreased in moderate illness<ref name=":8" /> Decreased LIF<ref name=":9" /> Decreased in early illness<ref name=":13" /> Decreased in later illness<ref name="Hornig, 2015" /> Depressed response post-exercise (increased in controls)<ref name=":25">{{Cite journal | last = Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses |url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2796.2009.02079.x|journal=Journal of Internal Medicine|language=en|volume=266|issue=2 | pages = 196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796}}</ref> Depressed response to LIF post-exercise (increased in controls)<ref name=":12" /> |- |[[Interleukin 7|IL-7]] |(''Interleukin 7'') Regulates [[adaptive immune system]], and tumor cell apoptosis |Increased with illness severity<ref name=":11" /><ref name=":8" /> |Decreased in later illness<ref name="Landi2015" /> |- |[[Interleukin 8|IL-8]] |(''Interleukin 8 or CXCL8 C-X-C motif chemokine ligand 8'') Regulates inflammatory response by orchestrating the migration of primarily [[Neutrophil|neutrophils]] to the site of infection. IL-8 has also been shown to be involved in cell proliferation, and tissue remodeling<ref>{{Cite book | last = El Ayadi|first = Amina | last2 = Herndon | first2 = David N. | last3 = Finnerty | first3 = Celeste C. | date = 2018-01-01|editor-last = Herndon|editor-first = David N. | title = 21 - Biomarkers in Burn Patient Care | url =http://www.sciencedirect.com/science/article/pii/B9780323476614000216|language=en| publisher = Elsevier | pages = 232–235.e2|isbn=978-0-323-47661-4}}</ref> |Increased<ref name=":26">{{Cite journal | last = Broderick|first = Gordon | last2 = Katz | first2 = Ben Z. | last3 = Fernandes | first3 = Henrique | last4 = Fletcher | first4 = Mary Ann | last5 = Klimas | first5 = Nancy | last6 = Smith | first6 = Frederick A. | last7 = O'Gorman | first7 = Maurice RG | last8 = Vernon | first8 = Suzanne D. | last9 = Taylor | first9 = Renee | date = 2012-09-13 | title = Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue | url =https://doi.org/10.1186/1479-5876-10-191|journal=Journal of Translational Medicine|language=en|volume=10|issue=1 | pages = 191|doi=10.1186/1479-5876-10-191|issn=1479-5876|pmc = 3480896|pmid=22973830}}</ref><ref>{{Cite journal | last = Sorenson | first = Matthew | last2 = Jason | first2 = Leonard | last3 = Lerch | first3 = Athena | last4 = Porter | first4 = Nicole | last5 = Peterson | first5 = Jonna | last6 = Mathews | first6 = Herbert | date = 2012-03-02 | title = The Production of Interleukin-8 is Increased in Plasma and Peripheral Blood Mononuclear Cells of Patients with Fatigue | url =https://m.scirp.org/papers/abstract/17756|journal=Neuroscience and Medicine|language=en|volume=3|issue=1 | pages = 720–726|doi=10.4236/nm.2012.31007}}</ref> Increased in severe illness<ref name=":8" /><ref name=":17" /> Increased in sudden onset illness<ref name=":2">{{Cite journal | last = Natelson | first = Benjamin H. | last2 = Weaver | first2 = Shelley A. | last3 = Tseng | first3 = Chin-Lin | last4 = Ottenweller | first4 = John E. | date = 2005-01-01 | title = Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome | url =https://cvi.asm.org/content/12/1/52|journal=Clinical and Diagnostic Laboratory Immunology|language=en|volume=12|issue=1 | pages = 52–55|doi=10.1128/CDLI.12.1.52-55.2005|issn=1071-412X|pmid=15642984}}</ref> Increased in early illness<ref name=":13" /> Increased in later illness<ref name="Hornig, 2015" /> |Decreased<ref name=":4" /><ref name=":9" /> Decreased post-exercise<ref name=":12" /> Decreased in later illness<ref name=":13" /> Decreased in early illness<ref name="Hornig, 2015" /> |- |[[Interleukin 9|IL-9]] |(''Interleukin 9'') Promotes [[mast cell]] growth, stimulates cell proliferation and cytotoxicity, and is involved in apoptosis | |Decreased<ref name=":16" /> |- |[[Interleukin 10|IL-10]] |(''Interleukin 10'') Regulates anti-inflammatory response and immune response to [[Pathogen|pathogens]] |Increased<ref name=":5" /><ref>{{Cite journal | last = Nakamura | first = Toru | last2 = Schwander | first2 = Stephan K. | last3 = Donnelly | first3 = Robert | last4 = Ortega | first4 = Felix | last5 = Togo | first5 = Fumiharu | last6 = Broderick | first6 = Gordon | last7 = Yamamoto | first7 = Yoshiharu | last8 = Cherniack | first8 = Neil S. | last9 = Rapoport | first9 = David | date = 2010-04-01 | title = Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia | url = https://cvi.asm.org/content/17/4/582|journal=Clinical and Vaccine Immunology|language=en|volume=17|issue=4 | pages = 582–587|doi=10.1128/CVI.00379-09|issn=1556-6811|pmid=20181767}}</ref><ref name=":17" /><ref name=":16" /><ref>{{Cite journal | last = Russell|first = Alice | last2 = Hepgul | first2 = Nilay | last3 = Nikkheslat | first3 = Naghmeh | last4 = Borsini | first4 = Alessandra | last5 = Zajkowska | first5 = Zuzanna | last6 = Moll | first6 = Natalie | last7 = Forton | first7 = Daniel | last8 = Agarwal | first8 = Kosh | last9 = Chalder | first9 = Trudie | date = Feb 2019 | title = Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/|journal=Psychoneuroendocrinology|volume=100 | pages = 276–285|doi=10.1016/j.psyneuen.2018.11.032|issn=0306-4530|pmc=6350004|pmid=30567628}}</ref> Increased in abnormal spinal fluid patients<ref name=":2" /> Increased at baseline (measurement 1)<ref name=":6" /> Increased IL-10 and decreased IFN-γ/IL-10 ratio<ref name=":3" /> |Decreased<ref>{{Cite journal | last = Borish|first = Larry | last2 = Schmaling | first2 = Karen | last3 = DiClementi | first3 = Jeannie D. | last4 = Streib | first4 = Joanne | last5 = Negri | first5 = Julie | last6 = Jones | first6 = James F. | date = 1998-08-01 | title = Chronic fatigue syndrome: Identification of distinct subgroups on the basis of allergy and psychologic variables |url =http://www.sciencedirect.com/science/article/pii/S0091674998700909|journal=Journal of Allergy and Clinical Immunology|language=en|volume=102|issue=2 | pages = 222–230|doi=10.1016/S0091-6749(98)70090-9|issn=0091-6749}}</ref><ref name=":9" /><ref>{{Cite web | url = https://www.hindawi.com/journals/mi/2015/929720/ | title = Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis | last = Peterson | first = D. | last2 = Brenu | first2 = E.W. | date = 2015-03-05 | website = Mediators of Inflammation|language=en|access-date=2020-11-19 | last3 = Gottschalk | first3 = G. | last4 = Ramos | first4 = S. | last5 = Nguyen | first5 = T. | last6 = Staines | first6 = D. | last7 = Marshall-Gradisnik | first7 = S.}}</ref> Decreased at 6 months (measurement 2)<ref name=":6" /> |- |[[Interleukin 11|IL-11]] |(''Interleukin 11'') Regulates [[inflammation]], and function of B-cells and T-cells. IL-11 inhibits tissue inflammation<ref>{{Cite journal | last = Cook|first = Stuart A. | last2 = Schafer | first2 = Sebastian | date = 2020-01-27 | title = Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation | url =https://www.annualreviews.org/doi/10.1146/annurev-med-041818-011649|journal=Annual Review of Medicine|language=en|volume=71|issue=1 | pages = 263–276|doi=10.1146/annurev-med-041818-011649|issn=0066-4219}}</ref> |Increased in early illness<ref name="Hornig, 2015" /> |Decreased in later illness<ref name="Hornig, 2015" /> |- |[[Interleukin 12|IL-12]] |(''Interleukin 12'') Regulates Th1 response, as well as activated T-cells, [[Natural killer cell|NK cells]], and [[Cytotoxic T cell|CTLs]]. IL-12 is a critical link between the innate and adaptive immunity<ref>{{Cite book | last = Rus | first = Violeta | last2 = Via | first2 = Charles S. | date = 2007-01-01|editor-last = Tsokos|editor-first = George C.|editor2-last = Gordon|editor2-first = Caroline|editor3-last = Smolen|editor3-first = Josef S. | title = Chapter 12 - Cytokines in Systemic Lupus Erythematosus |url =http://www.sciencedirect.com/science/article/pii/B9780323044349500178|language=en|location=Philadelphia| publisher = Mosby | pages = 109–120|isbn=978-0-323-04434-9}}</ref> |Increased<ref name=":4" /> Increased IL-12p70 with illness severity<ref name=":11" /> Increased IL-12p70<ref name=":7" /> Increased IL-12p75<ref name=":16" /> Increased IL-12p40 in early illness<ref name="Hornig, 2015" /> |Decreased IL-12B<ref name=":9" /> Decreased in later illness<ref name="Hornig, 2015" /> Depressed response to IL-12p40 post-exercise (increased in controls)<ref name=":12" /> Decreased IL-12p40<ref name=":24" /> |- |[[Interleukin 13|IL-13]] |(''Interleukin 13'') Regulates immune response ([[B cell|B-cells]] and [[Monocyte|monocytes]]). Involved in Th2 inflammation.<ref>{{Cite journal | last = Marone | first = Giancarlo | last2 = Granata | first2 = Francescopaolo | last3 = Pucino | first3 = Valentina | last4 = Pecoraro | first4 = Antonio | last5 = Heffler | first5 = Enrico | last6 = Loffredo | first6 = Stefania | last7 = Scadding | first7 = Guy W. | last8 = Varricchi | first8 = Gilda | date = 2019 | title=The Intriguing Role of Interleukin 13 in the Pathophysiology of Asthma | url = https://www.frontiersin.org/articles/10.3389/fphar.2019.01387/full|journal=Frontiers in Pharmacology|language=English|volume=10|doi=10.3389/fphar.2019.01387|issn=1663-9812}}</ref> |Increased<ref name=":16" /> Increased in early illness<ref name="Hornig, 2015" /> Increased with illness severity<ref name=":11" /> |Decreased<ref name=":4" /> |- |[[Interleukin 15|IL-15]] |(''Interleukin 15'') Stimulates activity of cytotoxic CD8+ T-cells and NK cells, and increases anti-tumor activities<ref>{{Cite journal | last = Carrero|first = Rosa M. Santana | last2 = Beceren-Braun | first2 = Figen | last3 = Rivas | first3 = Sarai C. | last4 = Hegde | first4 = Shweta M. | last5 = Gangadharan | first5 = Achintyan | last6 = Plote | first6 = Devin | last7 = Pham | first7 = Gabriel | last8 = Anthony | first8 = Scott M. | last9 = Schluns | first9 = Kimberly S. | date = 2019-01-08 | title = IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses |url =https://www.pnas.org/content/116/2/599|journal=Proceedings of the National Academy of Sciences|language=en|volume=116|issue=2 | pages = 599–608|doi=10.1073/pnas.1814642116|issn=0027-8424|pmid=30587590}}</ref> | |Decreased<ref name=":4" /> |- |[[Interleukin 16|IL-16]] |''(Interleukin 16)'' Modulates T-cell activation | |Decreased in later illness<ref name="Landi2015" /> |- |[[Interleukin 17|IL-17]] |(''Interleukin 17'') IL-17A and IL-17F regulate immune and inflammatory response in local tissue infection |Increased IL-17F with illness severity<ref name=":11" /> Increased IL-17A in early illness<ref name="Hornig, 2015" /> |Decreased<ref name=":6" /> Decreased IL-17F<ref name=":9" /><ref name=":16" /> Decreased IL-17A in later illness<ref name="Hornig, 2015" /> Depressed response to IL-17F post-exercise (increased in controls)<ref name=":12" /> Decreased secretion from CCR6+ Th17 cells and MAIT cells<ref name=":18" /> |- |[[Interleukin 23|IL-23]] |''(Interleukin 23)'' Regulates inflammatory autoimmune responses |Increased in males<ref name=":20" /> |Decreased<ref name=":26" /> Decreased IL-23p40<ref name=":24" /> |- |[[Tumor necrosis factor|'''Tumor Necrosis Factor''']] |'''Regulate inflammatory and immune responses''' | | |- |[[TNF-alpha|TNF-α]] |(''Tumor Necrosis Factor alpha'') Regulates acute and chronic inflammation<ref>{{Cite web | url = https://www.hindawi.com/journals/tswj/2013/875363/ | title = The Role of TNF-α and TNF Superfamily Members in the Pathogenesis of Calcific Aortic Valvular Disease | last = Galeone | first = Antonella | last2 = Paparella | first2 = Domenico | date = 2013-11-06 | website = The Scientific World Journal|language=en|access-date=2020-11-20 | last3 = Colucci | first3 = Silvia | last4 = Grano | first4 = Maria | last5 = Brunetti | first5 = Giacomina}}</ref> |Increased<ref name=":5" /><ref name=":0" /><ref name=":21" /><ref name=":19" /><ref name=":17" /><ref name=":24" /><ref name=":6" /><ref>{{Cite journal | last = Hilgers | first = A. | last2 = Frank | first2 = J. | date = 1994 | title = [Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes] | url = https://pubmed.ncbi.nlm.nih.gov/7856214/|journal=Wiener Medizinische Wochenschrift (1946)|volume=144|issue=16 | pages = 399–406|issn=0043-5341|pmid=7856214}}</ref> Increased post-exercise<ref name=":27">{{Cite journal | last = White | first = P.D. | last2 = Nye | first2 = K. E. | last3 = Pinching | first3 = A.J. | last4 = Yap | first4 = T.M. | last5 = Power | first5 = N. | last6 = Vleck | first6 = V. | last7 = Bentley | first7 = D.J. | last8 = Thomas | first8 = J.M. | last9 = Buckland | first9 = M. | date = 2004-01-01 | title = Immunological Changes After Both Exercise and Activity in Chronic Fatigue Syndrome | url =https://doi.org/10.1300/J092v12n02_06|journal=Journal of Chronic Fatigue Syndrome|volume=12|issue=2 | pages = 51–66|doi=10.1300/J092v12n02_06|issn=1057-3321}}</ref> Increased TNF-α and sTNFR1<ref name=":1" /> Increased, proportional to poor sleep quality<ref name=":10" /> Increased in early illness<ref name="Hornig, 2015" /> Increased in those with 5-HT autoimmune activity<ref name=":14" /> |Decreased<ref name=":3" /> Decreased in later illness<ref name="Hornig, 2015" /> Depressed response post-exercise (increased in controls)<ref name=":12" /><ref name=":25" /> |- |[[Lymphotoxin-alpha|LT-α]] |(''Lymphotoxin alpha - formerly TNF-β tumor necrosis factor-beta'') Regulates [[Innate immune system|innate immune]] response |Increased<ref name=":1" /><ref name=":4" /> |Decreased<ref name=":3" /><ref name=":9" /> Decreased post-exercise<ref name=":12" /> |- |FasL |(''Fas ligand or CD95L or CD178'') Regulates immune response and apoptosis |Increased in early illness<ref name="Hornig, 2015" /> |Decreased in later illness<ref name="Hornig, 2015" /> |- |[[TNF superfamily member 10|TNFSF10]] |(''TNF superfamily member 10 or TRAIL'') Regulates apoptosis in transformed cells and mostly functional in immune cells<ref>{{Cite journal | last = Tayyeb|first = Asima | last2 = Shah | first2 = Zafar Abbas | date = 2019-07-02 | title = Insilico investigation of TNFSF10 signaling cascade in ovarian serous cystadenocarcinoma | url = https://www.heighpubs.org/hjcsr/acst-aid1005.php|journal=Archives of Cancer Science and Therapy|language=en|volume=3|issue=1 | pages = 025–034|doi=10.29328/journal.acst.1001005}}</ref> |Increased in early illness<ref name="Hornig, 2015" /> |Decreased in later illness<ref name="Hornig, 2015" /> |- |[[CD40 ligand|CD40L]] |(''CD40 ligand or CD154'') Regulates immune response |Increased in later illness<ref name="Hornig, 2015" /> |Decreased in early illness<ref name="Hornig, 2015" /> Decreased<ref>{{Cite journal | last = White | first = Andrea T. | last2 = Light | first2 = Alan R. | last3 = Hughen | first3 = Ronald W. | last4 = Bateman | first4 = Lucinda | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | date = 2010 | title=Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1469-8986.2010.00978.x|journal=Psychophysiology|language=en|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1469-8986|pmc = 4378647|pmid=20230500}}</ref> |- |'''[[Chemokine|Chemokines]]''' |'''Direct cell migration, adhesion and activation''' | | |- |[[CCL2]] |(''C-C motif chemokine ligand 2'') Regulates inflammatory response |Increased in early illness<ref name="Hornig, 2015" /> |Decreased in later illness<ref name="Hornig, 2015" /> No change post-exercise, yet change in controls<ref name=":12" /> |- |[[CCL4]] |(''C-C motif chemokine ligand 4 or MIP-1β'') Regulates inflammatory response | |Decreased post-exercise<ref name=":12" /> |- |[[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] |''(C-C motif chemokine ligand 5 or RANTES: Regulated on activation, normal T cell expressed and secreted'') Regulates inflammatory response |Increased in moderate illness<ref name=":8" /> | |- |[[CCL11]] |(''C-C motif chemokine ligand 11)'' Regulates inflammatory response |Increased<ref name=":9" /> Increased with illness severity<ref name=":11" /> | |- |[[CCL24]] |(''C-C motif chemokine ligand 24 or eotaxin-2)'' |Increased in later illness<ref name="Landi2015" /> | |- |[[CXCL1]] |(''C-X-C motif chemokine ligand 1'') Regulates immune response via neutrophils<ref>{{Cite journal | last = Sawant | first = Kirti V. | last2 = Poluri | first2 = Krishna Mohan | last3 = Dutta | first3 = Amit K. | last4 = Sepuru | first4 = Krishna Mohan | last5 = Troshkina | first5 = Anna | last6 = Garofalo | first6 = Roberto P. | last7 = Rajarathnam | first7 = Krishna | date = 2016-09-14 | title = Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions |url =https://www.nature.com/articles/srep33123|journal=Scientific Reports|language=en|volume=6|issue=1 | pages = 33123|doi=10.1038/srep33123|issn=2045-2322}}</ref> |Increased with illness severity<ref name=":11" /> | |- |[[CX3CL1]] |(''C-X3-C motif chemokine ligand 1 or fractalkine'') | |Decreased in later illness<ref name="Landi2015" /> |- |[[CXCL9]] |(''C-X-C motif chemokine ligand 9'') | |Decreased in later illness<ref name="Landi2015" /> |- |[[IP-10|CXCL10]] |(''C-X-C motif chemokine ligand 10 or IP-10'') Regulates immune response via T cells, eosinophils, monocytes and NK cells<ref>{{Cite journal | last = Vazirinejad | first = Reza | last2 = Ahmadi | first2 = Zahra | last3 = Arababadi | first3 = Mohammad Kazemi | last4 = Hassanshahi | first4 = Gholamhossein | last5 = Kennedy | first5 = Derek | date = 2014 | title=The Biological Functions, Structure and Sources of CXCL10 and Its Outstanding Part in the Pathophysiology of Multiple Sclerosis |url =https://www.karger.com/Article/FullText/357780|journal=Neuroimmunomodulation|language=en|volume=21|issue=6 | pages = 322–330|doi=10.1159/000357780|issn=1021-7401|pmid=24642726}}</ref> |Increased<ref name=":9" /><ref name=":7" /> Increased with illness severity<ref name=":11" /> Increased post-exercise<ref name=":12" /> |Decreased<ref name=":24" /> |- |'''Colony Stimulating Factors''' |'''Promote cell proliferation and differentiation''' | | |- |[[Colony stimulating factor 1|CSF1]] |''(Colony stimulating factor 1 or M-CSF macrophage colony-stimulating factor)'' Regulates innate immunity and inflammatory response. Controls cellular proliferation and differentiation of monocytes and [[Macrophage|macrophages]]<ref>{{Cite web | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=CSF1 | title = CSF1 Gene - GeneCards {{!}} CSF1 Protein {{!}} CSF1 Antibody | website = genecards.org|access-date=2020-11-20}}</ref> | |Decreased<ref name=":9" /> |- |[[Colony stimulating factor 2|CSF2]] |''(Colony stimulating factor 2 or GM-CSF granulocyte-macrophage colony-stimulating factor)'' Controls cellular proliferation and differentiation of [[Granulocyte|granulocytes]] and macrophages<ref>{{Cite web | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=CSF2 | title = CSF2 Gene - GeneCards {{!}} CSF2 Protein {{!}} CSF2 Antibody | website = genecards.org|access-date=2020-11-20}}</ref> |Increased<ref name=":7" /> Increased with illness severity<ref name=":11" /> |Decreased<ref name=":9" /> |- |[[Colony stimulating factor 3|CSF3]] |''(Colony stimulating factor 3 or G-CSF granulocyte colony-stimulating factor)'' Controls cellular proliferation and differentiation of granulocytes<ref>{{Cite web | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=CSF3 | title = CSF3 Gene - GeneCards {{!}} CSF3 Protein {{!}} CSF3 Antibody | website = genecards.org|access-date=2020-11-20}}</ref> |Increased with illness severity<ref name=":11" /> |Decreased<ref name=":9" /> |- |[[KITLG]] |''(KIT ligand or SCF stem cell factor or MCGF mast cell growth factor or SLF steel factor)'' Regulates cell survival and proliferation |Increased with illness severity<ref name=":11" /> Increased in early illness<ref name="Hornig, 2015" /> |Decreased<ref name=":9" /> Decreased in later illness<ref name="Hornig, 2015" /> |- |'''Transforming Growth Factors''' |'''Regulation of immune cells''' | | |- |[[TGF-α]] |''(Transforming growth factor alpha)'' Regulates cellular proliferation and differentiation |Increased with illness severity<ref name=":11" /> | |- |[[Transforming growth factor beta|TGF‐β]] |''(Transforming growth factor beta)'' Regulates cellular proliferation and differentiation, and inflammatory processes |Increased<ref name=":11" /><ref>{{Cite journal | last = Chao|first = Chun C. | last2 = Janoff | first2 = Edward N. | last3 = Hu | first3 = Shuxian | last4 = Thomas | first4 = Kelly | last5 = Gallagher | first5 = Michael | last6 = Tsang | first6 = Monica | last7 = Peterson | first7 = Phillip K. | date = 1991-07-01 | title = Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/1043466691904972|journal=Cytokine|language=en|volume=3|issue=4 | pages = 292–298|doi=10.1016/1043-4666(91)90497-2|issn=1043-4666}}</ref><ref>{{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 = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222|journal=Clinical and Diagnostic Laboratory Immunology|language=en|volume=1|issue=2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref> Increased TGF-β1<ref name=":27" /><ref>{{Cite journal | last = Kennedy|first = G. | last2 = Spence | first2 = V. | last3 = Underwood | first3 = C. | last4 = Belch | first4 = J.J.F. | date = 2004-08-01 | title = Increased neutrophil apoptosis in chronic fatigue syndrome | url =https://jcp.bmj.com/content/57/8/891|journal=Journal of Clinical Pathology|language=en|volume=57|issue=8 | pages = 891–893|doi=10.1136/jcp.2003.015511|issn=0021-9746|pmid=15280416}}</ref> Increased at rest, but not post-exercise<ref>{{Cite journal | last = Clark|first = L.V. | last2 = Buckland | first2 = M. | last3 = Murphy | first3 = G. | last4 = Taylor | first4 = N. | last5 = Vleck | first5 = V. | last6 = Mein | first6 = C. | last7 = Wozniak | first7 = E. | last8 = Smuk | first8 = M. | last9 = White | first9 = P.D. | date = 2017 | title=Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: case–control study | url = https://onlinelibrary.wiley.com/doi/abs/10.1111/cei.13023|journal=Clinical & Experimental Immunology|language=en|volume=190|issue=3 | pages = 360–371|doi=10.1111/cei.13023|issn=1365-2249|pmc = 5680051|pmid=28779554}}</ref> | |- |[[Activin]] |Part of the TGF-β protein superfamily. Involved in the control of inflammation and muscle mass<ref name=":15">{{Cite journal | last = Lidbury|first = Brett A. | last2 = Kita | first2 = Badia | last3 = Lewis | first3 = Donald P. | last4 = Hayward | first4 = Susan | last5 = Ludlow | first5 = Helen | last6 = Hedger | first6 = Mark P. | last7 = de Kretser | first7 = David M. | date = 2017-03-16 | title = Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study | url = https://doi.org/10.1186/s12967-017-1161-4|journal=Journal of Translational Medicine|volume=15|issue=1 | pages = 60|doi=10.1186/s12967-017-1161-4|issn=1479-5876|pmc = 5353946|pmid=28302133}}</ref> |Increased Activin B<ref>{{Cite journal | last = Richardson | first = Alice M. | last2 = Lewis | first2 = Don P. | last3 = Kita | first3 = Badia | last4 = Ludlow | first4 = Helen | last5 = Groome | first5 = Nigel P. | last6 = Hedger | first6 = Mark P. | last7 = de Kretser | first7 = David M. | last8 = Lidbury | first8 = Brett A. | date = 2018-04-12 | title = Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection | url =https://doi.org/10.1186/s12967-018-1473-z|journal=Journal of Translational Medicine|volume=16|issue=1 | pages = 97|doi=10.1186/s12967-018-1473-z|issn=1479-5876|pmc = 5898049|pmid=29650052}}</ref><ref name=":15" /> |Decreased Activin B<ref>{{Cite journal | last = Lidbury|first = Brett A. | last2 = Kita | first2 = Badia | last3 = Richardson | first3 = Alice M. | last4 = Lewis | first4 = Donald P. | last5 = Privitera | first5 = Edwina | last6 = Hayward | first6 = Susan | last7 = de Kretser | first7 = David | last8 = Hedger | first8 = Mark | date = 2019-07-19 | title = Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity | url = https://pubmed.ncbi.nlm.nih.gov/31331036/|journal=Diagnostics (Basel, Switzerland)|volume=9|issue=3|doi=10.3390/diagnostics9030079|issn=2075-4418|pmc=6787626|pmid=31331036}}</ref> |- |[[Growth differentiation factor 15|GDF15]] |''(Growth differentiation factor 15)'' Part of the TGF-β protein superfamily. Highly elevated GDF15 has been linked to [[Mitochondrial disorder|mitochondrial disorders]] and skeletal [[Muscle fatigability|muscle fatigue]]<ref name=":28">{{Cite journal | last = Melvin | first = A. | last2 = Lacerda | first2 = E. | last3 = Dockrell | first3 = H.M. | last4 = O'Rahilly | first4 = S. | last5 = Nacul | first5 = L. | date = 2019-12-04 | title = Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome | url =https://doi.org/10.1186/s12967-019-02153-6|journal=Journal of Translational Medicine|volume=17|issue=1 | pages = 409|doi=10.1186/s12967-019-02153-6|issn=1479-5876|pmc = 6892232|pmid=31801546}}</ref> |Increased<ref name=":28" /> | |- |'''Adipokines''' | | | |- |[[Leptin]] |Dual role, acting as both a [[hormone]] and cytokine. Critical in [[Metabolic features of chronic fatigue syndrome|metabolic function]]. Helps regulate innate and adaptive immune response<ref>{{Cite journal | last = La Cava | first = Antonio | date = Oct 2017 | title = Leptin in inflammation and autoimmunity | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453851/|journal=Cytokine|volume=98 | pages = 51–58|doi=10.1016/j.cyto.2016.10.011|issn=1043-4666|pmc=5453851|pmid=27916613}}</ref> |Increased<ref name="Hornig, 2015" /> Increased with illness severity<ref name=":11" /><ref>{{Cite journal | last = Stringer | first = Elizabeth Ann | last2 = Baker | first2 = Katharine Susanne | last3 = Carroll | first3 = Ian R. | last4 = Montoya | first4 = Jose G. | last5 = Chu | first5 = Lily | last6 = Maecker | first6 = Holden T. | last7 = Younger | first7 = Jarred W. | date = 2013-04-09 | title = Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology | url = https://doi.org/10.1186/1479-5876-11-93|journal=Journal of Translational Medicine|language=en|volume=11|issue=1 | pages = 93|doi=10.1186/1479-5876-11-93|issn=1479-5876|pmc = 3637529|pmid=23570606}}</ref> | |- |[[Resistin]] |''(Also known as ADSF adipose tissue-specific secretory factor or XCP1 C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein)'' | |Decreased<ref name=":11" /> |- |'''Neurotrophins''' | | | |- |[[Nerve growth factor|NGF]] |''(Nerve growth factor)'' Regulates neuronal cell function and immune cell activity<ref>{{Cite journal | last = Minnone | first = Gaetana | last2 = De Benedetti | first2 = Fabrizio | last3 = Bracci-Laudiero | first3 = Luisa | date = 2017-05-11 | title = NGF and Its Receptors in the Regulation of Inflammatory Response | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454940/|journal=International Journal of Molecular Sciences|volume=18|issue=5|doi=10.3390/ijms18051028|issn=1422-0067|pmc=5454940|pmid=28492466}}</ref> |Increased with illness severity<ref name=":11" /><ref>{{Cite journal | date = 2020-03-01 | title = The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms |url =https://www.sciencedirect.com/science/article/pii/S0306453019313198|journal=Psychoneuroendocrinology|language=en|volume=113 | pages = 104578|doi=10.1016/j.psyneuen.2019.104578|issn=0306-4530}}</ref> | |- |'''Other Growth Factors''' | | | |- |[[Platelet derived growth factor subunit B|PDGFB]] |''(Platelet derived growth factor subunit B)'' Regulates cellular proliferation and differentiation, and embryonic development<ref>{{Cite web | url = https://medlineplus.gov/genetics/gene/pdgfb/ | title = PDGFB gene: MedlinePlus Genetics | website = medlineplus.gov|language=en|access-date=2020-11-20}}</ref> |Increased in later illness<ref name="Hornig, 2015" /> |Decreased PDGF-BB<ref name=":9" /> Decreased in early illness<ref name="Hornig, 2015" /> |- |[[FGF2]] |''(Fibroblast growth factor 2 or bFGF basic fibroblast growth factor or FGF-β)'' Regulates cellular proliferation and differentiation | |Decreased<ref name=":9" /> |- |[[Vascular endothelial growth factor|VEGFA]] |''(Vascular endothelial growth factor A)'' Regulates cellular proliferation and differentiation of vascular endothelial cells<ref>{{Cite web | url = https://www.genecards.org/cgi-bin/carddisp.pl?gene=VEGFA | title = VEGFA Gene - GeneCards {{!}} VEGFA Protein {{!}} VEGFA Antibody | website = genecards.org|access-date=2020-11-20}}</ref> | |Decreased<ref name=":9" /> Decreased in later illness<ref name="Landi2015" /> |} == Cytokines and Chemokines == Chemokines are cytokines that induce chemotaxis. Chemotaxis is the orchestrated movement of cells towards a specific location flagged by a chemical messenger. Unlike cytokines, chemokines have just one major role: to direct leukocytes toward pathogens, or to areas of injured/diseased tissue. *[http://www.wisegeek.org/what-is-the-difference-between-a-cytokine-and-a-chemokine.htm What is the Difference Between a Cytokine and a Chemokine?] (WiseGEEK) ==Notable studies== *2010, A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome<ref>{{Cite journal | last = Broderick|first = Gordon | authorlink = Gordon Broderick | last2 = Fuite | first2 = Jim | authorlink2 = Jim Fuite | last3 = Kreitz | first3 = Andrea | author-link3 = Andrea Kreitz | last4 = Vernon | first4 = Suzanne D | author-link4 = Suzanne Vernon | last5 = Klimas | first5 = Nancy | author-link5 = Nancy Klimas | last6 = Fletcher | first6 = Mary Ann | author-link6 = Mary Ann Fletcher | date = Oct 2010 | title = A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome | url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/|journal=[[Brain, behavior, and immunity]]|volume=24|issue=7 | pages = 1209–1217|doi=10.1016/j.bbi.2010.04.012|issn=0889-1591|pmc=2939140|pmid=20447453|quote=|via=}}</ref> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/ (Full text)] *2015, [http://advances.sciencemag.org/content/1/1/e1400121 Distinct plasma immune signatures in ME/CFS are present early in the course of illness]<ref name="Hornig, 2015" /> *2015, Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology<ref name="stanfordleptin">{{Cite journal | last1 = Stringer | first1 = EA | last2 = Baker | first2 = KS | last3 = Carrol | first3 = IR | last4 = Montoya | first4 = JG | author-link4 = Jose Montoya | last5 =Chu | first5 = L | author-link5 = Lily Chu | last6 = Maeker | first6 = HT | last7 =Younger | first7 = JW | author-link8 = Jarred Younger| title = Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: Evidence of inflammatory pathology | journal = J Transl Med.| date = Apr 9, 2013 | pmid = 23570606 | pmc = 3637529 | doi = 10.1186/1479-5876-11-93| url = http://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 }}</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-11-93 (Full text)] *2015, [http://www.sciencedirect.com/science/article/pii/S088915911400614X Plasma cytokine expression in adolescent chronic fatigue syndrome]<ref name="Wyller, 2016" /> *2016, [http://www.sciencedirect.com/science/article/pii/S1043466615301071 Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome]<ref name="Landi2015">{{Cite journal | last = Landi|first = Abdolamir | authorlink = Amir Landi | last2 = Broadhurst | first2 = David | authorlink2 = | last3 = Vernon | first3 = Suzanne D. | author-link3 = Suzanne Vernon | last4 = Tyrrell | first4 = D. Lorne J. | author-link4 = | last5 = Houghton | first5 = Michael | author-link5 = Michael Houghton | date = Feb 2016 | title = Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome | url =https://linkinghub.elsevier.com/retrieve/pii/S1043466615301071|journal=Cytokine|language=en|volume=78|issue= | pages = 27–36|doi=10.1016/j.cyto.2015.11.018|quote=|via=}}</ref> *2017, Cytokine signature associated with disease severity in chronic fatigue syndrome patients<ref name=":11" /> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576836/ (Full text)] *2017, Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment<ref>Megan E. Roerink, Hans Knoop, Ewald M. Bronkhorst, Henk A. Mouthaan, Luuk J.A.C. Hawinkels, Leo A. B. Joosten and [[Jos van der Meer|Jos W. M. van der Meer]], Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment, Journal of Translational Medicine, 2017 Vol 15:267 https://doi.org/10.1186/s12967-017-1371-9</ref> - [https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-017-1371-9 (Full text)] *2019, The clinical value of cytokines in chronic fatigue syndrome<ref name=":23" /> - [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599310/ (Full text)] == Learn More == * [https://www.genenames.org/ HGNC - Official nomenclature for cytokines, chemokines, and growth factors] ==See also== *[[Diagnostic biomarker]] == References == <references> <ref name="Hornig, 2015">{{Citation | last1 = Hornig | first1 = M | author-link1 = Mady Hornig | last2 = Montoya | first2 = JG | authorlink2 = Jose Montoya | last3 = Klimas | first3 = NG | author-link3 = Nancy Klimas | last4 = Levine | first4 = SM | author-link4 = Susan Levine | last5 =Felsenstein | first5 = D | author-link5 = Donna Felsenstein | last6 = Bateman | first6 = L | author-link6 = Lucinda Bateman | last7 =Peterson | first7 = DL | author-link8 = Daniel Peterson | last8 = Gottschalk | first8 = CG | author-link8 = Gunnar Gottschalk | last9 =Schultz | first9 = AF | author-link9 = Andrew Schultz | last10 = Che | first10 = X | author-link10 = Xiaoyu Che | last11 = Eddy | first11 = ML | author-link11 = Meredith Eddy | last12 = Komaroff | first12 = AL | author-link12 = Anthony Komaroff | last13 = Lipkin | first13 = WI | author-link13 = Ian Lipkin | title = Distinct plasma immune signatures in ME/CFS are present early in the course of illness | journal = Science Advances | volume = 1 | issue = 1 | page = | date = 2015 | pmid = | doi = 10.1126/sciadv.1400121 | url = http://advances.sciencemag.org/content/1/1/e1400121.full }}</ref> <ref name="Wyller, 2016">{{Citation | last1 = Wyller | first1 = Vegard Bruun | author-link1 = Vegard Wyller | last2 = Sørensend | first2 = Øystein | authorlink2 = Øystein Sørensend | last3 = Sulheima | first3 = Dag | author-link3 = Dag Sulheima | last4 = Fagermoen | first4 = Even | author-link4 = Even Fagermoen | last5 =Ueland | first5 = Thor | author-link5 = Thor Ueland | last6 = Mollnes | first6 = Tom Eirik| author-link6 = Tom Mollnes | title = Plasma cytokine expression in adolescent chronic fatigue syndrome | journal = Brain, Behavior, and Immunity | volume = 46 | issue = | page = 80–86 | date = 2015 | pmid = | doi = 10.1016/j.bbi.2014.12.025 }}</ref> </references> [[Category:Body systems]] [[Category:Immunology]]
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