6 Cytokine Abnormalities

From: <a href="https://www.ncbi.nlm.nih.gov/books/NBK6294/">Cytokines, Chemokines and Their Receptors - Madame Curie Bioscience Database - NCBI Bookshelf</a>

As introduced earlier, the immune system is essentially a network supersystem utilizing specialized languages for communication between cells. This chapter focused on only the powerful language of cytokine and chemokine signaling but others exist such as hormone, neurotransmitter, complement and allergic mediator production. At their discretion, immune cells can listen to or send these signals as required to reach cells in the immediate microenvironment or throughout the organism. Just as miscommunication can crash modern electronic networks, the information super-highway of the immune system is not without its vulnerabilities. The knockout models discussed above exemplify the dramatic consequences of man-made alterations to immune network communication. The permanent absence of a particular cytokine at a whole-body level, however, may mask more subtle defects in the role of the conventional signaling component. Similarly, natural defects in communication appear to drive the pathogenesis of autoimmunity. In cases such as this, however, headway is being made in understanding how the immune system communicates and many therapies are being developed that may reset dangerous crashes and return an organism to ‘online’ protective status. A new understanding of the language used by cells of immune system to achieve this protection is emerging and cytokines and chemokines will certainly be at the heart of our progress in communication.

From: <a href="https://www.omf.ngo/2017/09/09/molecular-underpinnings/">Molecular Underpinnings of ME/CFS Explored at the Open Medicine Foundation Symposium | Open Medicine Foundation</a>

Imunologist Dr. Montoya worked with on his big cytokine study, Davis talked about that study first. This long awaited study – six or seven years in the making, he said – found almost no differences in cytokine levels between ME/CFS patients and healthy controls but still suggested that many cytokines contributed to severity in ME/CFS.

The difference between the null finding with the controls and the dramatic association between cytokine levels and severity within the ME/CFS group was striking indeed. With no less than a third of the 51 cytokines associated with severity, the results were strong, indeed. Those strong findings made it all the more remarkable that the less severely ill and moderate cases of ME/CFS either had normal or lower than normal cytokine levels.

Something unusual is clearly going on with cytokines and ME/CFS – something Mark Davis hadn’t seen before. He suggested that the healthier patients might be able to tamp down a pro-inflammatory process that the sicker patients can’t rein in at all – leaving them exposed to the full force of the pro-inflammatory cytokines. Exhibiting his wry sense of humor, Davis opined that that idea “could be true, might be true and ended up with calling it a “definite maybe”.

Davis saved the best for last. Mark Davis has developed a method to track T cell clonal expansion in various diseases. T cells “go clonal”; i.e. start producing replicas of themselves in vast numbers when they meet up with an antigen – a protein nipped off a pathogen or toxin by an immune presenting cell – they don’t like. The T-cells produced during this process are like honing missile; they’re designed for one purpose and one purpose only – to search out and destroy anything that presents with that antigenic signature. High numbers of clonally produced T cells are a sure sign of significant immune activation.

Davis has found high rates of clonal expansion in several disease including Lyme disease, and several autoimmune diseases. When he turned to ME/CFS he found the same signature – T-cells that were popping off clonal cells like there was no tomorrow. Like Lyme disease the clonal expansion found in ME/CFS involved their cytotoxic or killer T-cells. ME/CFS patients’ killer T-cells were on the attack.

Either an autoimmune process or some sort of foreign antigen; i.e. an infection or toxin, had to be setting those T cells in ME/CFS on edge. Davis’ findings are preliminary; he’s finding a strong signal but needs to test more samples. If his findings hold up, the next step is attempting to identify what is tweaking the T cells in the ME/CFS patients. If Davis can find that out, he may have a shot at discovering what is triggering the disease.

Right now his bet is on an autoimmune process probably initiated by an infection. Everything he sees about the disease says autoimmunity to him right now.

There are several reasons to hope that Ron Davis gets his ME/CFS research center funded: his experience in managing large projects successfully, the remarkable growth of his team, the prominent scientific advisors he’s gathered, plus, of course, the nano-needle research and the hunt for the mysterious factor in the blood that appears to be whacking ME/CFS patients’ cells. Another very good reason is Mark Davis’ new findings; included in the research center proposal is a nice fat grant to extend Mark Davis’s work.

During the discussion period following Mark Davis’s talk, the other Davis – Ron Davis – who loves to ask probing questions, asked Mark Davis to tell him why the cytokines are not an “artifact” of this disease. Why aren’t cytokines just noise that’s distracting us from the real problems in ME/CFS, Davis asked.

The other Davis admitted that it wasn’t clear if the cytokines were correlations or if they were causal but argued that the data he has from 1000 healthy people suggests that something is really off in the immune systems of Chronic Fatigue Syndrome patients.

Naviaux has a way of turning things on their head sometimes. He seems to look at things from angles that others don’t think of. He also agreed that finding T-cells stimulated in ME/CFS suggests a problem is there, but noted that another big problem in ME/CFS could be things that aren’t being activated. Ron Davis earlier noted that the factor in the plasma that’s whacking ME/CFS patients cells might be something that’s missing.

Naviaux couldn’t stress enough how important it was to stress ME/CFS patients’ systems and see what happens. Only then could you identify what’s being produced and not being produced in this disease.

From: <a href="https://paradigmchange.me/me/abnormalities-cytokines/">ME and CFS Medical Abnormalities – Cytokines and Complement | Myalgic Encephalomyelitis</a>

Groven N, Fors EA, Iversen VC, White LR, Reitan SK. Association between cytokines and psychiatric symptoms in chronic fatigue syndrome and healthy controls. Nord J Psychiatry. 2018 Jul 31:1-5. PMID: 30063870

Twenty patients diagnosed with CFS/ME according to the Fukuda criteria and 20 age- and sex-matched healthy controls were enrolled in the study. Plasma was analysed by ELISA for levels of the cytokines TNF-α, IL-4, IL-6 and IL-10. Increased plasma levels of TNF-α in CFS/ME patients almost reached significance compared to healthy controls (p = .056).

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Lynn M, Maclachlan L, Finkelmeyer A, Clark J, Locke J, Todryk S, Ng WF, Newton JL, Watson S. Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome. Mediators Inflamm. 2018 Jun 10;2018:3972104. PMID: 29983634

This study aimed to compare the glucocorticoid receptor (GR) function between CFS, primary Sjögren’s syndrome (a disease group control), and sedentary healthy controls (HCs), and to investigate its relationship with clinical measures. CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs.

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Roerink ME, Knoop H, Bronkhorst EM, Mouthaan HA, Hawinkels LJAC, Joosten LAB, van der Meer JWM. Cytokine signatures in chronic fatigue syndrome patients: a Case Control Study and the effect of anakinra treatment. J Transl Med. 2017 Dec 29;15(1):267. PMID: 29284500

Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. This study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra.

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Wyller VB, Nguyen CB, Ludviksen JA, Mollnes TE. Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome. J Transl Med. 2017 Dec 4;15(1):245. PMID: 29202780

This study compared the plasma levels of the three TGF-β isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-β levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group. Plasma levels of all TGF-β isoforms were not altered in adolescent CFS. However, the TGF-β isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-β3 might partly mediate an association between plasma cortisol and B cell gene expression.

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Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, Chu L, Younger JW, Tato CM, Davis MM. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):E7150-E7158. PMID: 28760971

To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Of 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

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Hornig M, Gottschalk CG, Eddy ML, Che X, Ukaigwe JE, Peterson DL, Lipkin WI. Immune network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome with atypical and classical presentations. Transl Psychiatry. 2017 Apr 4;7(4):e1080. PMID: 28375204

Classically, ME/CFS cases present after a prodrome consistent with infection; however, some cases are atypical and have a different presentation and comorbidities that pose challenges for differential diagnosis. The researchers analyzed cerebrospinal fluid (CSF) from 32 cases with classical ME/CFS and 27 cases with atypical ME/CFS using a 51-plex cytokine assay. Atypical subjects differed in cytokine profiles from classical subjects.

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Russell L, Broderick G, Taylor R, Fernandes H, Harvey J, Barnes Z, Smylie A, Collado F, Balbin EG, Katz BZ, Klimas NG, Fletcher MA. Illness progression in chronic fatigue syndrome: a shifting immune baseline. BMC Immunol. 2016 Mar 10;17(1):3. PMID: 26965484

Preliminary results suggest that IL-1α, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS.

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Landi A, Broadhurst D, Vernon SD, Tyrrell DL, Houghton M. Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome. Cytokine. 2016 Feb;78:27-36. PMID: 26615570

The authors measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 ME/CFS patients and controls We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. In addition, they identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-γ (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients.

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Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients. Int J Med Sci. 2015 Sep 5;12(10):764-72. PMID: 26516304

IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients.

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Peterson D, Brenu EW, Gottschalk G, Ramos S, Nguyen T, Staines D, Marshall-Gradisnik S. Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. Mediators Inflamm. 2015;2015:929720. PMID:25834308

IL-10 was significantly reduced in CFS/ME patients in comparison to controls.

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Hornig M, Gottschalk G, Peterson DL, Knox KK, Schultz AF, Eddy ML, Che X, Lipkin WI. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. Mol Psychiatry. 2016 Feb;21(2):261-9. PMID: 25824300

Researchers found revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling, in a group of ME/CFS patients. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

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Khaiboullina SF, DeMeirleir KL, Rawat S, Berk GS, Gaynor-Berk RS, Mijatovic T, Blatt N, Rizvanov AA, Young SG, Lombardi VC. Cytokine expression provides clues to the pathophysiology of Gulf War illness d anmyalgic encephalomyelitis. Cytokine. 2015 Mar;72(1):1-8. PMID: 25514671

The authors identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters.

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Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, Yamamoto Y, Cherniack NS, Klapholz M, Rapoport D, Natelson BH. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013 Nov;20(11):1736-42. PMID: 24027260

The authors conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. They found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines.

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Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, Younger JW. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013 Apr 9;11:93. PMID: 23570606

Self-reported fatigue severity was significantly correlated with leptin levels in 60% of the participants with CFS and in 10% of healthy controls.  A machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

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Nakamura T, Schwander SK, Donnelly R, Ortega F, Togo F, Broderick G, Yamamoto Y, Cherniack NS, Rapoport D, Natelson BH. Cytokines across the night in chronic fatigue syndrome with and without fibromyalgia. Clin Vaccine Immunol. 2010 Apr;17(4):582-7. PMID: 20181767

The authors found evidence to support a role for an increase in interleukin-10, an anti-inflammatory cytokine. Although the changes were small, they may contribute to the common complaint in CFS patients of disrupted sleep.

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Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in Chronic Fatigue Syndrome. Brain Behav Immun. 2010 May 4. PMID: 20447453

CFS patients have specific immune responses related to the presence of inflammatory processes consistent with the presence of a latent viral infection.

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Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12;7:96. PMID: 19909538

CFS patients display a large number of abnormal cytokines, with increases in some (LTalpha, IL-1alpha, IL-1beta, IL-4, IL-5, IL-6 and IL-12) and decreases in others (IL-8, IL-13 and IL-15).  Some of these have the potential of serving as biomarkers for the disease.

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Geller RD, Giclas PC. Chronic fatigue syndrome and complement activation. BMJ Case Rep. 2009;2009. PMID: 21686614

This report describes a case of chronic fatigue syndrome (CFS) that followed a well-documented episode of acute Epstein-Barr virus (EBV) mononucleosis. After 2 years of chronic fatigue following the acute illness, measurements of complement split products were positive for complement activation and remained positive for 14 months, after which the patient then recovered from CFS.

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Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, Heim C. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008 Apr;70(3):298-305. PMID: 18378875

The study results suggest an altered diurnal cortisol rhythm and IL-6 concentrations in CFS cases.

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Metzger K, Frémont M, Roelant C, De Meirleir K. Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochem Biophys Res Commun. 2008 Nov 7;376(1):231-3. PMID: 18774769

T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells. The results suggest a role of Th17 cells in the pathogenesis of CFS.

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Vollmer-Conna U, Cameron B, Hadzi-Pavlovic D, Singletary K, Davenport T, Vernon S, Reeves WC, Hickie I, Wakefield D, Lloyd AR; Dubbo Infective Outcomes Study Group. Postinfective fatigue syndrome is not associated with altered cytokine production. Clin Infect Dis. 2007 Sep 15;45(6):732-5. PMID: 17712757

The authors concluded that ongoing production of cytokines does not play a role in postinfective fatigue syndrome.

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ter Wolbeek M, van Doornen LJ, Kavelaars A, van de Putte EM, Schedlowski M, Heijnen CJ. Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain Behav Immun. 2007 Nov;21(8):1063-74. PMID: 17544255

Although overlap in symptomatology between the general population and patients with CFS was observed, only CFS patients show a skewing of the cytokine balance towards an anti-inflammatory profile.

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Pall ML. Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle. Med Hypotheses. 2007;69(4):821-5. PMID: 17448611

The author discusses how NF-kappa-beta activity in CFS might be triggered.

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Carlo-Stella N, Badulli C, De Silvestri A, Bazzichi L, Martinetti M, Lorusso L, Bombardieri S, Salvaneschi L, Cuccia M. A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles. Clin Exp Rheumatol. 2006 Mar-Apr;24(2):179-82. PMID: 16762155

There is a highly significant increase of TNF -857 TT and CT genotypes among CFS patients with respect to controls and a significant decrease of IFN gamma low producers (A/A) among patients with respect to controls.

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Gaab J, Rohleder N, Heitz V, Engert V, Schad T, Schürmeyer TH, Ehlert U. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology. 2005 Feb;30(2):188-98. PMID: 15471616

Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. TNF-alpha and IL-6 were especially problematic.

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Tomoda A, Joudoi T, Rabab el-M, Matsumoto T, Park TH, Miike T. Cytokine production and modulation: comparison of patients with chronic fatigue syndrome and normal controls. Psychiatry Res. 2005 Mar 30;134(1):101-4. PMID: 15808295

CFS patients showed significantly lower mRNA levels and transforming growth factor-beta1 (TGF-beta1) production. Cytokine dysregulation affects CFS pathogenesis. TGF-beta1 may aid treatment because it affects CFS inflammatory characteristics.

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Sackner MA, Gummels EM, Adams JA. Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Med Hypotheses. 2004;63(1):118-23. PMID: 15193362

It is hypothesized that CFS has chronic inflammation at its basis.

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Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004 Feb;135(2):294-302. PMID: 14738459

The authors found evidence of a significant bias towards Th2- and Tc2-type immune responses in CFS compared to controls. In contrast, levels of IFN-gamma, IL-2 and IL-10-producing cells were similar in both study groups. There is an effector memory cell bias towards type 2 responsiveness in patients with CFS, as well as ongoing type 0 immune activation in unstimulated cultures of peripheral blood cells.

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Shephard RJ. Cytokine responses to physical activity, with particular reference to IL-6: sources, actions, and clinical implications. Crit Rev Immunol. 2002;22(3):165-82. PMID: 12498381

Prolonged endurance exercise induces a sequenced release of pro- and anti-inflammatory cytokines, and IL-6 plays a dominant role. Although many types of cells are capable of producing cytokines, the main source of the exercise-induced IL-6 production appears to be the exercising muscle.

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Arnold MC, Papanicolaou DA, O’Grady JA, Lotsikas A, Dale JK, Straus SE, Grafman J. Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome. Psychol Med. 2002 Aug;32(6):1075-89. PMID: 12214788

An IL-6 provocation exacerbated the CFS patients’ self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.

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Kerr JR, Barah F, Mattey DL, Laing I, Hopkins SJ, Hutchinson IV, Tyrrell DA. Circulating tumour necrosis factor-alpha and interferon-gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol. 2001 Dec;82(Pt 12):3011-9. PMID: 11714978

Patients with a parvovirus B19 infection had elevated IL-6, TNF-alpha, IL-1 beta, and IFN-gamma.

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Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. J Neuroimmunol. 2001 Oct 1;119(2):343-9. PMID: 11585638

In CFS patients, LPS-induced cytokine secretion in whole blood cultures showed a significant increase in IL-10 and a trend towards a decrease in IL-12 as compared with healthy controls. In general, the data are suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS.

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Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Appl Neuropsychol. 2001;8(1):51-64. PMID: 11388124

In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation.

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Hanson SJ, Gause W, Natelson B. Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers. Clin Diagn Lab Immunol. 2001 May;8(3):658-62. PMID: 11329477

Neural-network classifiers were used to detect immunological differences in groups of chronic fatigue syndrome (CFS) patients that heretofore had not shown significant differences from controls. Of all the cytokines evaluated, the only one to be in the final model was interleukin-4 (IL-4).

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Cannon JG, Angel JB, Ball RW, Abad LW, Fagioli L, Komaroff AL. Acute phase responses and cytokine secretion in chronic fatigue syndrome. J Clin Immunol. 1999 Nov;19(6):414-21. PMID: 10634215

CFS is associated with increased IL-6 secretion which is manifested by chronically elevated plasma alpha2-macroglobulin concentrations.

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Moss RB, Mercandetti A, Vojdani A. TNF-alpha and chronic fatigue syndrome. J Clin Immunol. 1999 Sep;19(5):314-6. PMID: 10535608

CFS patients have a significant increase serum TNF-alpha in patients with CFS (P<0.0001) compared to non-CFS controls.

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Gupta S, Aggarwal S, Starr A. 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. Int J Mol Med. 1999 Feb;3(2):209-13. PMID: 9917531

A significant increase in spontaneous, phytohemagglutinin- and lipopolysaccharide-induced IL-6 secretion by both lymphocytes and monocytes was observed in CFS patients during ‘natural fatigue’ as compared to during state. However, no such changes in IL-6 production were observed during fatigue experienced after exercise. These data suggest a role of IL-6 in natural symptomatology and perhaps in the pathogenesis of CFS. In addition, the data demonstrate that laboratory-induced fatigue (experimental fatigue) may not be a good model to study immunological changes in CFS; immunological parameters should be studied in a longitudinal manner during the natural course of the disease.

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Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, Peterson PK, Komaroff AL. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. J Clin Immunol. 1997 Mar;17(2):160-6. PMID: 9083892

TGF-beta levels were significantly higher in CFS patients compared to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue.

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Gupta S, Aggarwal S, See D, Starr A. Cytokine production by adherent and non-adherent mononuclear cells in chronic fatigue syndrome. J Psychiatr Res. 1997 Jan-Feb;31(1):149-56. PMID: 9201656

The levels of spontaneously (unstimulated) produced TNF-alpha by non-adherent lymphocytes and spontaneously produced IL-6 by both adherent monocytes and non-adherent lymphocytes were significantly increased in CFS patients. The abnormality of IL-6 was also observed at mRNA level. In contrast, spontaneously produced IL-10 by both adherent and non-adherent cells and by PHA-activated non-adherent cells were decreased.

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Peterson PK, Sirr SA, Grammith FC, Schenck CH, Pheley AM, Hu S, Chao CC. Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. Clin Diagn Lab Immunol. 1994 Mar;1(2):222-6. PMID: 7496949

At rest, serum transforming growth factor beta (TGF-beta) levels were elevated in CFS patients. Serum TGF-beta and cerebral blood flow abnormalities, detected by single-photon emission-computed tomographic scanning, were accentuated postexercise in the CFS group.

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Patarca R, Klimas NG, Lugtendorf S, Antoni M, Fletcher MA. Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression. Clin Infect Dis. 1994 Jan;18 Suppl 1:S147-53. PMID: 8148443

CFS patients had higher circulating levels of TNF-alpha and TNF-beta than controls.

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Chao CC, Janoff EN, Hu SX, Thomas K, Gallagher M, Tsang M, Peterson PK. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991 Jul;3(4):292-8. PMID: 1873478

Serum bioactive transforming growth factor beta (TGF-beta) levels were higher in patients with CFS. Lipopolysaccharide-stimulated release of interleukin 1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha was increased; enhanced IL-6 release to phytohemagglutinin was also observed.

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Cheney PR, Dorman SE, Bell DS. Interleukin-2 and the chronic fatigue syndrome. Ann Intern Med. 1989 Feb 15;110(4):321. PMID: 2783643