# NEW RESEARCH: Cytokine Overproduction May Be Key to Chronic Fatigue Syndrome



## wanderingstar (Dec 1, 1999)

Here's some lastest info from Medscape & Reuters about CFS. Researchers, who were looking at another condition, have proposed that *"Cytokine Overproduction May Be Key to Chronic Fatigue Syndrome". * http://www.medscape.com/reuters/prof/2001/...025clin007.html It talks about an overactive immune system without an obvious target of infection, possibly being the key to understanding CFS. This may be indicated in terms of symptoms by those recurrent sore throats and fevers some (many??) CFS patients can get. I'm really interested and excited by this. Obviously the research has a long way to go (doesn't it always!), but .... it gives me new hope that this illness will be properly understood one day. Wow!


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## wanderingstar (Dec 1, 1999)

FYI: "Cytokines: Soluble proteins, secreted by cells of the immune system, that act as messengers to help regulate an immune response."From the Merck Manual http://www.merck.com/pubs/mmanual_home/sec16/167.htm


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## trbell (Nov 1, 2000)

interesting info. immune overproduction of one or another substance may be implicated in other functional somatic syndromes as well tom


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## Susan Purry (Nov 6, 2001)

Tom, could you tell us which other syndromes those are, and do you have any info/research on the topic? Thanks,


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## Susan Purry (Nov 6, 2001)

I'm so cross! The link I originally posted to the article at Medscape (by Reuters) no longer works. So I searched for the article on Medscape (by title of the document), found it, but cannot access it. And I can't find it at Reuters. Any ideas anyone?


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## eric (Jul 8, 1999)

susan, here is some info. J Neuroimmunol 2001 Oct 1;119(2):343-9 Related Articles, Books, LinkOut LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome patients is increased but supersensitive to inhibition by dexamethasone. Visser J, Graffelman W, Blauw B, Haspels I, Lentjes E, de Kloet ER, Nagelkerken L. Division of Immunological and Infectious Diseases, TNO Prevention and Health, P.O. Box 2215, 2301 CE, Leiden, The Netherlands. Several causes have been held responsible for the chronic fatigue syndrome (CFS), including an altered hypothalamus-pituitary-adrenal gland (HPA)-axis activity, viral infections and a reduced Th1 activity. Therefore, it was investigated whether the regulation of IL-10 is different in CFS. 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 patients and controls, IL-12 secretion was equally sensitive to suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive in CFS-patients. In controls, IL-10 and IL-12 secretion were inversely correlated with free serum cortisol (r=-0.492, p<0.02 and r=-0.434, p<0.05, respectively). In CFS, such an inverse correlation was found for IL-12 (r=-0.611, p<0.02) but not for IL-10 (r=-0.341, ns). These data are suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS. PMID: 11585638 [PubMed - indexed for MEDLINE] Med Hypotheses 2001 Aug;57(2):231-7 Related Articles, Books, LinkOut Chronic fatigue syndrome: neurological findings may be related to blood--brain barrier permeability. Bested AC, Saunders PR, Logan AC. Environmental Health Clinic, Sunnybrook and Women's College, Health Sciences Centre, Toronto, Canada. Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS). It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS. The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation. Copyright 2001 Harcourt Publishers Ltd. Publication Types: Review Review, Academic PMID: 11461179 [PubMed - indexed for MEDLINE] Appl Neuropsychol 2001;8(1):51-64 Related Articles, Books, LinkOut Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG. E. M. Papper Laboratory of Clinical Immunology, Center for Behavioral Medicine Research, Miami Veterans Administration Medical Center, University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101, USA. The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed chronic fatigue syndrome (CFS). 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. The initiation of the syndrome is frequently sudden and often follows an acute viral illness. Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (







impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses. PMID: 11388124 [PubMed - indexed for MEDLINE] Clin Diagn Lab Immunol 2001 May;8(3):658-62 Related Articles, Books, LinkOut Detection of immunologically significant factors for chronic fatigue syndrome using neural-network classifiers. Hanson SJ, Gause W, Natelson B. Department of Psychology, Rutgers University, Newark, New Jersey 07102, USA. jose###kreizler.rutgers.edu 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. In the past linear methods were unable to detect differences between CFS groups and non-CFS control groups in the nonveteran population. An examination of the cluster structure for 29 immunological factors revealed a complex, nonlinear decision surface. Multilayer neural networks showed an over 16% improvement in an n-fold resampling generalization test on unseen data. A sensitivity analysis of the network found differences between groups that are consistent with the hypothesis that CFS symptoms are a consequence of immune system dysregulation. Corresponding decreases in the CD19(+) B-cell compartment and the CD34(+) hematopoietic progenitor subpopulation were also detected by the neural network, consistent with the T-cell expansion. Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was interleukin-4 (IL-4). Seeing an increase in IL-4 suggests a shift to a type 2 cytokine pattern. Such a shift has been hypothesized, but until now convincing evidence to support that hypothesis has been lacking. PMID: 11329477 [PubMed - indexed for MEDLINE]


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## eric (Jul 8, 1999)

here you go Susan.







BETHESDA, MD (Reuters Health) Oct 25 - Overproduction of cytokines appears to be a cause of chronic fatigue syndrome (CFS), according to a panel of experts on the disease that convened here on Monday and Tuesday. "There are a number of paradigms in which either viral infections or cytokine administration cause changes which appear to trigger some of the manifestations of CFS," the panel said in its draft consensus statement, which was released Wednesday. "It seems plausible that the overproduction of some pro-inflammatory cytokines contributes to the fatigue." The panel was sponsored by the Centers for Disease Control and Prevention, the National Institutes of Health, and the Chronic Fatigue and Immune Dysfunction Syndrome Association of America. Dr. Roberto Patarca-Montero, co-director of the E. M. Papper Laboratory of Clinical Immunology at the University of Miami School of Medicine, told Reuters Health that a high cytokine level can be an excellent marker for an immunological problem such as CFS. However, the research community is still divided on which cytokines to measure and how to measure them, added Dr. Patarca-Montero, who is not a panel member. "Some people say the best one to measure is interleukin-6, while some say it's interleukin-1. As to the method, you can either make your own assay in the lab or purchase a commercially available kit, and not all kits are the same." What triggers cytokines to start sending messages that the body's immune system needs to get to work is another question still being looked at, said panel co-chair Dr. Dimitris A. Papanicolaou, assistant professor of endocrinology at Emory University in Atlanta. "We know that cytokines cause many CFS symptoms, but how do they get activated? We don't know." In one intriguing development, researchers at Emory University found that many hepatitis and melanoma patients who were given large doses of interferon-alpha to help cure their disease ended up developing symptoms similar to CFS, including fever, sore throat, and fatigue. That research could prove to be a model for testing possible cures for CFS, Dr. Papanicolaou said. Interleukin-6 is found mostly in the body's fat cells, he pointed out. Although most research on CFS to date has not focused on the number of obese patients in each study, future studies will look more closely at this particular factor, he said. Dr. Papanicolaou added that he is hopeful that more information about the causes of CFS will be available in 2 or 3 years, when a large epidemiological study of CFS patients will be finished. That study is being sponsored by the CDC. Copyright ï¿½ 2001 Reuters Ltd.


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## trbell (Nov 1, 2000)

susan, what I was referring to was a suspicion that overproduction of cytokins seems to be related to a long standing history of chronic stress which might be gender specific (acute stress seems to be related to ibs-d for females and chronic stress might be related to ibs-c for males). This might also be true for other conditions such as fibro and depression. It's pretty speculative but my physician (who is also GI boardedand knowledgeable about cfs) thinks it's worth pursuing. If you have any way of doing a search on psychinfo (your library might do this for you) it might be worthwhile as this info will be in psych and neuropsych databases but not yet in the medical databases.I'll try and keep yopu posted and you could even send an email query to Esther Sternberg at NIMH. 'Embodying psychological thriving' by Elissa Epel, et.al., Journal of Social Issues 54 (2) 301-322 is a good and fairly readable introduction to thse topics.tom


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## trbell (Nov 1, 2000)

this link eric posted on another thread explains the connection in fairly clear language. http://www.med.ucla.edu/ndp/Newsletters/Wi...teredStress.htm tom


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