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      A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

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          Abstract

          A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

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          The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system.

          The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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            A community-based study of chronic fatigue syndrome.

            Most previous estimates of the prevalence of chronic fatigue syndrome (CFS) have derived largely from treated populations, and have been biased by differential access to health care treatment linked with sex, ethnic identification, and socioeconomic status. To assess the point prevalence of CFS in an ethnically diverse random community sample. A sample of 28,673 adults in Chicago, Ill, was screened by telephone, and those with CFS-like symptoms were medically evaluated. MAIN OUTCOME MEASURES AND ANALYSES: Self-report questionnaires, psychiatric evaluations, and complete medical examinations with laboratory testing were used to diagnose patients with CFS. Univariate and multivariate statistical techniques were used to delineate the overall rate of CFS in this population, and its relative prevalence was subcategorized by sex, ethnic identification, age, and socioeconomic status. There was a 65.1% completion rate for the telephone interviews during the first phase of the study. Findings indicated that CFS occurs in about 0.42% (95% confidence interval, 0.29%-0.56%) of this random community-based sample. The highest levels of CFS were consistently found among women, minority groups, and persons with lower levels of education and occupational status. Chronic fatigue syndrome is a common chronic health condition, especially for women, occurring across ethnic groups. Earlier findings suggesting that CFS is a syndrome primarily affecting white, middle-class patients were not supported by our findings.
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              Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas.

              Chronic fatigue syndrome (CFS) is a debilitating illness with no known cause or effective therapy. Population-based epidemiologic data on CFS prevalence and incidence are critical to put CFS in a realistic context for public health officials and others responsible for allocating resources and for practicing physicians when examining and caring for patients. We conducted a random digit-dialing survey and clinical examination to estimate the prevalence of CFS in the general population of Wichita, Kan, and a 1-year follow-up telephone interview and clinical examination to estimate the incidence of CFS. The survey included 33 997 households representing 90 316 residents. This report focuses on 7162 respondents aged 18 to 69 years. Fatigued (n = 3528) and randomly selected nonfatigued (n = 3634) respondents completed telephone questionnaires concerning fatigue, other symptoms, and medical history. The clinical examination included the Diagnostic Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, laboratory testing, and a physical examination. The overall weighted point prevalence of CFS, adjusted for nonresponse, was 235 per 100,000 persons (95% confidence interval, 142-327 per 100,000 persons). The prevalence of CFS was higher among women, 373 per 100,000 persons (95% confidence interval, 210-536 per 100,000 persons), than among men, 83 per 100,000 persons (95% confidence interval, 15-150 per 100,000 persons). Among subjects nonfatigued and fatigued for less than 6 months, the 1-year incidence of CFS was 180 per 100,000 persons (95% confidence interval, 0-466 per 100,000 persons). Chronic fatigue syndrome constitutes a major public health problem. Longitudinal follow-up of this cohort will be used to further evaluate the natural history of this illness.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 January 2014
                : 9
                : 1
                : e84839
                Affiliations
                [1 ]Center for Psychological Studies, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
                [2 ]Graduate School for Computer and Information Sciences, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
                [3 ]Institute for Neuro-Immune Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
                [4 ]Department of Medicine, Faculty of Dentistry and Medicine, University of Alberta, Edmonton, Alberta, Canada
                [5 ]Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, United States of America
                [6 ]Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
                [7 ]College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
                [8 ]College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida, United States of America
                University of Tennessee, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TJAC DBM GB. Performed the experiments: TJAC PF MAR RMDR GB. Analyzed the data: TJAC PF DBM GB. Contributed reagents/materials/analysis tools: MAF NGK. Wrote the paper: TJAC DBM GB.

                Article
                PONE-D-13-35136
                10.1371/journal.pone.0084839
                3885655
                24416298
                00cbc1cc-5d83-4838-a822-722f4d01504f
                Copyright @ 2014

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 26 August 2013
                : 19 November 2013
                Page count
                Pages: 11
                Funding
                Funding came from the US Department of Defense Congressionally Directed Medical Research Program (CDMRP) awards ( http://cdmrp.army.mil/) GW093042 (Broderick - PI) and GW080152 (Klimas - PI) as well as the National Institutes of Health (NIH)( http://www.nih.gov/) R01 award RES0008852 (Klimas - PI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Endocrine System
                Endocrine Physiology
                Hormones
                Neuroendocrinology
                Immune Physiology
                Cytokines
                Computational Biology
                Regulatory Networks
                Signaling Networks
                Systems Biology
                Immunology
                Immune System
                Cytokines
                Systems Biology
                Theoretical Biology
                Mathematics
                Discrete Mathematics

                Uncategorized
                Uncategorized

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