DOCSLIB.ORG

Accelerating Research on ME/CFS

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Accelerating Research on ME/CFS Accelerating Research On ME/CFS Summary of the NIH meeting.... and reflections on how far we’ve come and still have to go Anthony L. Komaroff, MD Brigham and Women’s Hospital, Harvard Medical School April 5, 2019, National Institutes of Health No significant conflicts of interest Mid-1980’s: Where Were We? An illness characterized by only symptoms and no consistent objective abnormalities: • No consistent physical exam abnormalities • No diagnostic tests • No proven treatments • No information on prognosis • No evidence of underlying biological abnormalities Hence, a suspect illness 2019: Where Are We? 2019: Where Are We? Cases differ from healthy controls (and sometimes disease comparison controls): • Central and autonomic nervous system • Metabolism (particularly energy metabolism) • Immune phenotype and function • Microbiome (?) • Gene structure, gene expression and other epigenetic differences (?) 2019: The Questions Going Forward • What causes the symptoms of the illness? • What causes the abnormalities in various systems? • What links together these different abnormalities? And what triggers them? • Is there a hypothetical disease model that fits with the abnormalities reported? Agenda for this Talk • Summarize data presented at this conference, and in prior literature, regarding the various abnormalities that have been reported • Consider several alternative models that might explain much of the data Neurologic Changes Structural & functional brain imaging Autonomic abnormalities CNS Involvement in ME/CFS • Neuroendocrine dysfunction: Impairment of multiple limbic-hypothalamic-pituitary axes (involving cortisol, prolactin, & growth hormone) and serotonin (5-HT) system • Cognition: Impairments in information processing speed, memory and attention — not explained by concomitant psychiatric disorders • Autonomic dysfunction: Impaired sympathetic and parasympathetic function, 30-80% • MRI: Multiple anatomic and functional abnormalities • SPECT: Areas of reduced signal • PET: Immune cell activation (neuroinflammation) • EEG abnormalities: sharp/spike waves, distinctive spectral coherence pattern, impaired connectivity PET Evidence of Brain Inflammation Distinguishes ME/CFS from Healthy P<0.001 CFS: N=9 Controls: N=10. From: Nakatomi Y, et al. J Nucl Med 2014; 55:945–950 MR Spectroscopy of the Brain Suggests Neuroinflammation • 15 women with ME/CFS and 15 matched healthy controls • Abnormalities were found in multiple brain regions, particularly left anterior cingulate • Metabolite ratios in 7 regions correlated with fatigue • Increased ratio of choline/creatinine, and increased lactate, were prominent findings From: Mueller C, et al. Brain Imaging and Behavior 2019; doi.org/10.1007/x11682-018-0029-4 Lactate in Spinal Fluid in ME/CFS: In vivo Proton MR Spectroscopy 0.86 ±0.5 90 80 P<0.001 for each, compared to ME/CFS 70 60 50 0.29 0.25 40 ±0.3 ±0.2 30 20 10 0 ME/CFS Anxiety Healthy Mathew SJ, et al. NMR Biomed 2008 (DOI 10.1002/nbm.1315) Conclusions •The majority of adult and all pediatric studies show OI is strongly associated with ME/CFS •Upright posture consistently aggravates ME/CFS symptoms, even in the absence of HR and BP changes •CBF reductions are substantial •Primary causes of OI in ME/CFS need further elucidation (auto-antibodies? MCAS? Vascular compliance in EDS?) •Open treatment of OI is associated with improvement in fatigue and other symptoms. More practical clinical trials needed. Even in ME/CFS patients with a normal HR and BP response during TTT: abnormal decrease of cerebral blood flow Courtesy of Peter Rowe, NIH, April 2019 Metabolic Changes Impaired ATP production Hypometabolism Oxidative/Nitrosative Stress Early Lessons From Metabolomics Studies employing optimal techniques (e.g., mass spect) for identifying levels of hundreds of metabolites in patients with ME/CFS compared to matched healthy controls • Levels of most metabolites are lower, as occurs in hibernation1 • Abnormalities incriminate impairment of cellular energy (regulated by the availability of NADPH) 1 and oxidative phosphorylation2 • Possibly a defect in one critical enzyme, pyruvate dehydrogenase3 • Defects in pathways converting sugars, lipids and amino acids into energy 1-5 From: 1Naviaux RK, et al. PNAS 2016;113:E5472-80; 2Tomas C, et al. PLoS ONE 2017;12(10):e0186802. 3Fluge O, et al. JCI Insight 2016;1:e89376; 4Yamano E, et al. Sci Rep 2016;6:34990; 5Germain A, et al. Mol BioSyst 2017;13: 371-379. Mitochondrial Damage to nucleic acids ↑ Anaerobic dysfunction and lipid membranes metabolism: ↑ lactate ↑ Oxidative Stress ↑ COX-2 ↓ antioxidant levels (Zn, DHEA, glutathione, vit E, CoQ10) ↑ peroxide & superoxide ↑ isoprostane & oxidized LDL ↓ α-tochopherol ↑ NFκB ↑ Nitrosative Stress ↑ iNOS, NO, nitrate, peroxynitrite ↑ iNOS ↑ IgM against nitro-[amino acids] Courtesy of Maureen Hansen, NIH, April 2019 Putative Targets 18 Cross referencing with PharmGKB database 242 gene-drug interactions 92 FDA-approved drugs affecting 39 targetable gene products Treatable targets in 37 of the 50 gene modules 23 identified to have a significant association with symptoms Including Adaptive Immune System, B-cell receptors, TNFa 11 targetable gene products show significant change from HC in ME/CFS NCOA1, UBE21, TRAF1, FKBP5, AHR, FYN, IKBKG, CASP9, CA9, DDIT3, CTNNB1 Jeffrey et al. "Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules. Clinical Therapeutics. (in press) Based on the thirteen panels 43 CSF proteins were significantly different between the ME/CFS patients and matched controls with p-value <0.05. Generally increased levels of markers for neuroinflammation, cell damage and repair in ME/CFS patients. Both significant similarities and differences found when comparing ME/CFS and MS patients. Unpublished data Viral-Mitochondrial Connection • Mitochondrial architecture essential for innate immunity • Active (not latent) HHV-6 infection, at least in one cell line, fragments mitochondria • And inhibits ability of mitochondria to fuse • And reduces ATP production • Serum from ME/CFS fragments mitochondria, and removing serum resolves fragmentation Courtesy of Bhupesh Prusty, NIH, April 2019 Comparison of 20 CFS Cases and 20 Healthy Controls ) Zre ( N = Patients 20 (CCC) Controls 20 P = 1X 10-9 Impedance (Ohm) /Normalized to the Impedanceto baseline (Ohm) /Normalized Courtesy of Ronald W. Davis, NIH, April 2019 Immunologic Changes Lymphocyte phenotype and function Cytokines HLA Associations Highly simplified overview of the diverse stimuli and potential consequences of mast cell activation and secretion of cytokines, chemokines, and growth factors. Mukai K/Galli SJ. Immunological Reviews 2018; 282: 121–150 Immunological Abnormalities in ME/CFS • Increased levels of circulating immune complexes • Increased levels of immunoglobulin G • Decreased levels of certain IgG subsets • Increased numbers of CD8 + “cytotoxic” T cells bearing activation antigens (CD38 +, HLA-DR) • Poorly functioning natural killer (NK) cells • Increased blood levels of, and lymphocyte production of pro-inflammatory cytokines Cytokine Findings • Blood levels of many cytokines are significantly higher in ME/CFS patients than in healthy controls—in the first three years of illness, but not after1 • Levels of many cytokines in spinal fluid also distinguish patients from healthy controls2 • Levels of many circulating cytokines correlate positively with the severity of symptoms3 1Hornig M, et al. Science Advances 2015 (Feb 27);1:e1400121 2Hornig M, et al. Molecular Psychiatry (2016) 21, 261–269 3Montoya JG, et al. PNAS 2017;114:E7150-7158 Circulating Cytokines in ME/CFS Patients ❖ Innate (e.g. GM-CSF), adaptive (e.g. IFN--γ, IL-12), cross-talk (e.g. IL-17) immunity ❖ Th1 (e.g. IFN-γ), Th2 (e.g. IL-4, IL-5, IL-13), Th17 (e.g. IL-17) ❖ Leptin: perpetuation of inflammation, predominance in females, neuroinflammation ❖ TGF-β risk for non-Hodgkin’s lymphoma ❖ Of seventeen cytokines that correlated with severity, ten can be produced or induced by mast cells (Mukai K/Galli SJ. Immunological Reviews 2018; 282: 121–150) ❖ Mast cell: microglia interactions may influence neuroinflammation (Hendriksen et al, Neuroscience and Biobehavioral Reviews 2017 79:119-133) ❖ Could a central feature of ME/CFS be a dysregulated mast cell? CCL11, CXCL1, CXCL10, G-CSF, GM-CSF, IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, leukemia inhibitory factor (LIF), nerve growth factor, stem cell factor (SCF), and TGF-α. HLA Associations • Association with ME/CFS: • ↑ risk: DRB4*01:01 (OR 2.30) • ↓ risk: C*05:01 (OR 0.60), DRBR*01:03 (OR 0.6) • Association with severe ME/CFS • ↑ risk: Four HLA factors (OR 3-4.4) • ↓ risk: One HLA factor (OR 0.38) Courtesy of Jose G. Montoya, NIH, April 2019 ME/CFS CD4 and CD8 T cell subset differences grouped by age Unpublished data, Courtesy of Derya Unutmaz, NIH, April 2019 Courtesy of Mark Davis, NIH, April 2019 Epigenetic Studies Epigenetic Changes in ME/CFS Comparing ME/CFS to healthy controls: • The DNA methylome is different, particularly with regard to glucocorticoid sensitivity genes1 and in genes important in cellular metabolism2 • Expression of microRNAs is different, particularly in natural killer cells3 • Difference in transcription factor levels: increased levels of NFĸB4 • Increased HDAC expression, leading to decreased gene expression5 1 deVega WC, et al. PLoS One 2014;9:e104757 2 deVega WC, et al. BMC Med Genomics 2017;doi 10.1186/ s12920-017-0248-3 3 Petty RD, et al.
Load more

Recommended publications
  • Sickness Behavior and the Metabolic Demand of Immunity: Insight from a Live Bacterial Infection Model
    Sickness Behavior and the Metabolic Demand of Immunity: Insight from a Live Bacterial Infection Model. by Robert Michael Johnson A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama August 8, 2020 Keywords: Immunometabolism, Life-history Theory, Listeria monocytogenes Sickness Behavior, Trade-offs Copyright 2020 by Robert Michael Johnson Approved by Elizabeth Hiltbold Schwartz, Chair, Associate Professor of Biology Michael Greene, Associate Professor of Nutrition Robert Judd, Associate Professor of Pharmacology Kate Buckley, Assistant Professor of Biology Abstract Life-history theory states that animals have access to a finite amount of resources over their lifespan. These resources are allocated between growth, reproduction, and maintenance, and how these resources are allocated will affect the overall fitness of an organism. A fundamental assumption of this theory is that once a resource is utilized by a trait, it cannot be used by another trait. Thus, when the demand for resources for one trait increases, it will come at the cost of the other traits. The host’s immune system is responsible for survival from pathogenic invasions. Therefore, it is a critical part of maintenance. Studies have examined the trade-offs induced by an immune response. The current knowledge on trade-offs incurred during an immune response come from the use of pathogen-associated molecular patterns (PAMPs), non-pathogenic antigens such as sheep red blood cells (SRBCs), or keyhole limpet hemocyanin (KLH). These studies have observed trade-offs with metabolism and weight. Additionally, some of these studies have observed decreased activity, increased fatigue, loss of appetite, and fever.
    [Show full text]
  • NIH Public Access Author Manuscript Ann N Y Acad Sci
    NIH Public Access Author Manuscript Ann N Y Acad Sci. Author manuscript; available in PMC 2013 July 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Ann N Y Acad Sci. 2012 July ; 1261: 55–63. doi:10.1111/j.1749-6632.2012.06633.x. Glucocorticoid regulation of inflammation and its behavioral and metabolic correlates: from HPA axis to glucocorticoid receptor dysfunction Marni N. Silverman and Esther M. Sternberg National Institutes of Health National Institute of Mental Health Section on Neuroendocrine Immunology and Behavior Bethesda, MD 20892, USA Abstract Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress-related illnesses, such as depression, metabolic syndrome, cardiovascular disease or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress-related inflammatory illnesses and underscores the importance of prevention
    [Show full text]
  • Gut Dysbiosis in Severe Mental Illness and Chronic Fatigue: a Novel Trans-Diagnostic Construct? a Systematic Review and Meta-Analysis
    Molecular Psychiatry https://doi.org/10.1038/s41380-021-01032-1 REVIEW ARTICLE Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis 1,2 2 2 2 Jenelle Marcelle Safadi ● Alice M. G. Quinton ● Belinda R. Lennox ● Philip W. J. Burnet ● Amedeo Minichino 2 Received: 12 October 2020 / Revised: 18 December 2020 / Accepted: 13 January 2021 © The Author(s) 2021. This article is published with open access Abstract Reduced gut-microbial diversity (“gut dysbiosis”) has been associated with an anhedonic/amotivational syndrome (“sickness behavior”) that manifests across severe mental disorders and represent the key clinical feature of chronic fatigue. In this systematic review and meta-analysis, we investigated differences in proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue vs. controls and the association of these biomarkers with sickness behavior across diagnostic categories. Following PRISMA guidelines, we searched from inception to April 2020 for all the studies investigating proxy biomarkers of gut dysbiosis in patients with severe mental illness and chronic fatigue. Data were 1234567890();,: 1234567890();,: independently extracted by multiple observers, and a random-mixed model was used for the analysis. Heterogeneity was assessed with the I2 index. Thirty-three studies were included in the systematic review; nineteen in the meta-analysis (N = 2758 patients and N = 1847 healthy controls). When compared to controls, patients
    [Show full text]
  • Role of Brain Transmigrating Neutrophils in Depression-Like Behavior During Systemic Infection
    Molecular Psychiatry (2014) 19, 599–606 & 2014 Macmillan Publishers Limited All rights reserved 1359-4184/14 www.nature.com/mp ORIGINAL ARTICLE Role of brain transmigrating neutrophils in depression-like behavior during systemic infection A Aguliar-Valles1,3, J Kim1, S Jung1, B Woodside2 and GN Luheshi1 Peripheral inflammation induces transmigration of interleukin (IL)-1b-expressing neutrophils to the brain. We investigated the possibility that this presents a new route of immune-to-brain communication by assessing their role in sickness behaviors relevant for mood disorders. Mice treated with lipopolysaccharide (LPS) developed despair-like behavior, and administration of an anti- polymorphonuclear antibody abolished LPS-induced despair-like and asocial behaviors, which correlated with the levels of IL-1b expression in the brain. These behavioral changes were directly mediated by the energy-regulating hormone, leptin. Increasing the concentration of endogenous leptin during obesity exacerbated, whereas its neutralization using a specific antiserum attenuated sickness behaviors and importantly the neutrophil transmigrating process. Our results indicate a role for peripheral neutrophils in conveying inflammatory signals to the brain, which appears to be dependent on the energy status of the organism. This constitutes a novel mechanism of immune-to-brain communication relevant to mood disorders. Molecular Psychiatry (2014) 19, 599–606; doi:10.1038/mp.2013.137; published online 15 October 2013 Keywords: depression; IL-1b; infection; inflammation; leptin; neutrophil; obesity; sickness behavior INTRODUCTION to-brain communication through these routes depends on the Chronic inflammation and the associated display of brain-regulated transient increase in circulating cytokine levels that is usually sickness behaviors have been implicated in the etiology of a associated with acute responses.
    [Show full text]
  • Gut Brain Axis
    e Stressed GUT [axis] e Depressed BIN Clinical Education Michael Ash BSc DO ND Dip ION The Stressed Gut: The Depressed Brain: The Immune Link and the Gut Brain Axis ©Michael Ash BSc (Hons) DO, ND, Dip ION July 2008 The human immune system, its response to triggers and its subsequent local and systemic impact on human function is an expanding area of research. The mucosal immune tissues represent the largest immune interface with the external world, which includes environment, food, bacteria and emotion. As conditions as diverse as cardiovascular disease, inflammatory bowel disease and mental health are increasingly understood to be impacted upon by inflammation (cytokines), interest in the management of immune responsiveness is growing. The innate immune system whilst incapable of developing a memory and traditionally regarded as the unsophisticated arm is now understood to determine adaptive immune activity. The gastrointestinal tract represents the greatest area of interaction between the two components of immune function and natural therapeutics have a legitimate and effective role to play in this area for the management of human health. There have been increasing amounts of data published in last few years confirming and exploring the role of the immune system in the pathophysiology of depression and allied symptoms.1 Whilst it is now well understood, if not yet universally recognised, that one of the downstream consequences of depression is an altered capacity and function of the affected individuals humoral and cellular immune systems.2 Contemporary psychoneuroimmunology opinion has turned this concept upside down creating a paradigm shift; exploring the evolving model that depressive disorders can now be characterised as a set of symptoms driven by hyperactivation of the innate immune systems inflammatory responses.3 Increased inflammation in depressed people.
    [Show full text]
  • Sickness & Behavior in Me/Cfs (Chronic Fatigue Syndrome)
    From the Department of Physiology & Pharmacology Karolinska Institutet, Stockholm, Sweden SICKNESS & BEHAVIOR IN ME/CFS (CHRONIC FATIGUE SYNDROME) Martin Jonsjö Stockholm 2019 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Printed by Eprint AB 2019 © Martin Jonsjö, 2019 ISBN 978-91-7831-547-5 Sickness & behavior in ME/CFS (Chronic Fatigue Syndrome) THESIS FOR DOCTORAL DEGREE (Ph.D.) By Martin Jonsjö Principal Supervisor: Opponent: Associate professor Gunnar L Olsson Professor Neil Harrison Karolinska Institutet Cardiff University Department of Physiology & Pharmacology Department of Neuroscience Division of Anesthesiology and intensive care Division of Psychoimmunology Co-supervisors: Examination Board: Associate professor Rikard Wicksell Professor Fredrik Piehl Karolinska Institutet Karolinska Institutet Department of Clinical Neuroscience Department of Clinical Neuroscience Division of Psychology Division of Neuro Dr Linda Holmström Professor Katja Boersma Karolinska Institutet Örebro University Department of Women's and Children's Health Department of Law, Psychology and Social Work Division of Pediatric Neurology Center for Health and Medical Psychology Associate professor Anna Andreasson Associate professor Jonas Ramnerö Karolinska Institutet Stockholm University Department of Medicine, Solna Department of Psychology Division of Clinical Medicine Division of Social Sciences ABSTRACT Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic debilitating condition characterized by physical and mental fatigue with a heightened sensitivity to exertion. To date, the causes are unknown. However, recently the condition has been implicated as a chronic sickness behavior state. That is, the adaptive changes in brain and behavior commonly following acute infection (experiences of malaise, fatigue, brain fog and so forth) seem to have become chronic and thus maladaptive, since no infectious agent is present.
    [Show full text]
  • Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
    Psychoneuroendocrinology 113 (2020) 104578 Contents lists available at ScienceDirect Psychoneuroendocrinology journal homepage: www.elsevier.com/locate/psyneuen The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome) - associations with symptoms T Martin A Jonsjöa,b,f,*, Gunnar L Olssona,b, Rikard K Wicksellc, Kjell Alvingd, Linda Holmströma,e, Anna Andreassonf,g a Behavior Medicine, Karolinska University Hospital, Stockholm, Sweden b Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden c Dept. of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden d Dept. of Women's and Children's Health, Uppsala University, Uppsala, Sweden e Dept. of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden f Stress Research Institute, Stockholm University, Stockholm, Sweden g Dept. of Medicine Solna, Karolinska Institutet, Stockholm, Sweden ARTICLE INFO ABSTRACT Keywords: Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a Myalgic encephalomyelitis range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. Chronic fatigue syndrome The aim of this study was to explore the association between inflammatory markers previously shown to be ME/CFS related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cog- Cytokines nitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on Symptoms these associations. Methods: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF- α).
    [Show full text]
  • Sickness Behavior in Feverish Children Is Independent of the Severity of Fever
    RESEARCH ARTICLE Sickness behavior in feverish children is independent of the severity of fever. An observational, multicenter study FrancËois Corrard1,2*, Christian Copin1, Alain Wollner1, Annie Elbez1,3, VeÂronique Derkx1, SteÂphane Bechet1, Corinne Levy1, Michel Boucherat1, Robert Cohen1,2,3 1 Association Clinique et TheÂrapeutique Infantile du Val-de-Marne. Saint-Maur-des-FosseÂs. France, 2 Association FrancËaise de PeÂdiatrie Ambulatoire, ChambeÂry, France, 3 Department of Microbiology, CHI a1111111111 CreÂteil, CreÂteil, France a1111111111 a1111111111 * [email protected] (FC) a1111111111 a1111111111 Abstract Background. Objectives OPEN ACCESS Behavioral changes in a febrile child are usually considered to stem from the fever. We stud- Citation: Corrard F, Copin C, Wollner A, Elbez A, ied sickness behavior (SB) in terms of its clinical components and its relation to fever. Derkx V, Bechet S, et al. (2017) Sickness behavior in feverish children is independent of the severity of fever. An observational, multicenter study. PLoS Methods ONE 12(3): e0171670. doi:10.1371/journal. This observational, multicenter study included children aged 6 months to 3 years who were pone.0171670 either febrile (fever 12 hours, 39ÊC and 38ÊC at inclusion) or non-febrile and well. The Editor: Jacobus P. van Wouwe, TNO, child had to have been awake for the 2 hours preceding the consultation and cared for by NETHERLANDS the parent who brought him/her to the doctor. SB was evaluated according to 6 parameters Received: March 16, 2016 over this 2-hour period: time spent playing, distance covered, time spent seeking comfort, Accepted: January 24, 2017 time spent whining or crying, time spent in a state of irritation or of anger, most distorted Published: March 9, 2017 facial expression.
    [Show full text]
  • The Concept of Sickness Behavior: a Brief Chronological Account of Four Key Discoveries R.W
    Veterinary Immunology and Immunopathology 87 (2002) 443–450 The concept of sickness behavior: a brief chronological account of four key discoveries R.W. Johnson* Laboratory of Integrative Biology, 390 Animal Science Laboratory, Department of Animal Sciences, University of Illinois, 1207 West Gregory Drive, Urbana, IL 61801, USA Abstract Neurons do not have receptors to detect bacteria or viruses, yet the presence of these microorganisms can cause a sickness behavior syndrome that includes, e.g., fever, anorexia, and lethargy. Because the immune system has receptors capable of detecting these non-cognitive stimuli, how the immune system transmits a message to the brain has been studied to understand why behavior is altered in sick animals. The focus has been on several cytokines secreted by leukocytes; these include interleukin (IL)-1b, IL-6, and tumor necrosis factor-a (TNF-a). These cytokines are secreted by activated mononuclear phagocytic cells, and numerous studies show that both peripheral and central injection of IL-1b, IL-6, and TNF-a induce sickness behavior. Moreover, these cytokines and their receptors are present in the brain and inhibiting the secretion of cytokines or blocking their receptors in the brain blocks or abrogate the behavioral responses induced by inflammatory stimuli. Because the sickness behavior syndrome modulates the immune system and enhances recovery, the interplay between the immune system and central nervous system is an essential part of the overall host defense against pathogenic microorganisms. The purpose of this brief paper is to provide a chronological description of four critical advances that have led to the current understanding of how the immune system communicates with the brain to induce sickness behavior.
    [Show full text]
  • Note on Health Management System Ravi Kiran* Associate Professor, Department of Health, India
    Health Econ Outcome Res Open Access 2021, Vol.7, Issue 5, e110. Editorial Note on Health Management System Ravi Kiran* Associate Professor, Department of Health, India Corresponding Author* about the accessibility of outside treatment and backing that misdirect the health the executives framework into not conveying advanced self- Ravi Kiran medicines. This outcomes in the fake treatment concealment of clinical Associate Professor, Department of Health, manifestations. India E-mail: [email protected] Since Hippocrates, it has been perceived that the body makes them mend powers. Current developmental medication recognizes them with physiologically based self-medicines that give the body prophylactic, Copyright: © 2021 Ravi Kiran . This is an open-access article distributed mending, or remedial capacities against wounds, contaminations and under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the physiological disturbance Models includes: original author and source are credited. • Immune responses • Fever Received 18 May 2021; Accepted 22 May 2021; Published 29 May 2021 • Sickness behavior • Nausea Introduction • Morning sickness The Health Management system (HMS) is a developmental medication • Diarrhea regulative cycle proposed by Nicholas Humphrey in which actuarial evaluation of wellness and monetary sort money saving advantage • Hypoferremia investigation decides the body's guideline of its physiology and health. This consolidation of money saving advantage computations into body • Depression guideline gives a science grounded way to deal with mind–body marvels, • Pain for example, fake treatments that are generally not logical by low level, non-economic, and absolutely criticism based homeostatic or allostatic These advanced self-medicines sent by the body are capable by speculations.
    [Show full text]
  • (TNF) Is Required for Spatial Learning and Memory in Male Mice Under Physiological, but Not Immune-Challenged Conditions
    cells Article Tumor Necrosis Factor (TNF) Is Required for Spatial Learning and Memory in Male Mice under Physiological, but Not Immune-Challenged Conditions Leda Mygind 1,2, Marianne Skov-Skov Bergh 3, Vivien Tejsi 1,2, Ramanan Vaitheeswaran 1,2, Kate L. Lambertsen 1,2,4 , Bente Finsen 1,2,*,† and Athanasios Metaxas 1,2,5,*,† 1 Institute of Molecular Medicine, Department of Neurobiology, University of Southern Denmark, J.B. Winsløws Vej 25, DK-5000 Odense C, Denmark; [email protected] (L.M.); [email protected] (V.T.); [email protected] (R.V.); [email protected] (K.L.L.) 2 BRIDGE—Brain Research Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, DK-5000 Odense C, Denmark 3 Department of Forensic Sciences, Division of Laboratory Medicine, Oslo University Hospital, Loviseberggata, 60456 Oslo, Norway; [email protected] 4 Department of Neurology, Odense University Hospital, J.B. Winsløws Vej 4, DK-5000 Odense C, Denmark 5 School of Science, Department of Life Sciences, European University Cyprus, 6 Diogenis Str., Nicosia 1516, Cyprus * Correspondence: bfi[email protected] (B.F.); [email protected] (A.M.) † These authors contributed equally to work. Abstract: Increasing evidence demonstrates that inflammatory cytokines—such as tumor necrosis Citation: Mygind, L.; Bergh, M.S.-S.; factor (TNF)—are produced at low levels in the brain under physiological conditions and may be Tejsi, V.; Vaitheeswaran, R.; crucial for synaptic plasticity, neurogenesis, learning and memory. Here, we examined the effects of Lambertsen, K.L.; Finsen, B.; Metaxas, developmental TNF deletion on spatial learning and memory using 11–13-month-old TNF knockout A.
    [Show full text]
  • Interleukin-1 As a Mediator of Fatigue in Disease: a Narrative Review Megan E
    Roerink et al. Journal of Neuroinflammation (2017) 14:16 DOI 10.1186/s12974-017-0796-7 REVIEW Open Access Interleukin-1 as a mediator of fatigue in disease: a narrative review Megan E. Roerink1*, Marieke E. van der Schaaf2, Charles A. Dinarello1,3, Hans Knoop2,4 and Jos W. M. van der Meer1 Abstract Fatigue is commonly reported in a variety of illnesses, and it has major impact on quality of life. Previously, it was thought that fatigue originates in the skeletal muscles, leading to cessation of activity. However, more recently, it has become clear that the brain is the central regulator of fatigue perception. It has been suggested that pro- inflammatory cytokines, especially interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β), play a prominent role in the development of central fatigue, and several studies have been performed to elucidate the connection between inflammation and these central processes. In this narrative review, mechanisms of action of IL-1 are described, with special attention to its effect on the central nervous system. In addition, we present a summary of studies that (i) investigated the relationship between circulating IL-1α and IL-1β and fatigue severity and/or (ii) evaluated the effect of inhibiting IL-1 on fatigue. We aim to improve the understanding of fatigue in both inflammatory and non-inflammatory illnesses, which could help develop strategies to treat fatigue more effectively. Reviewing the studies that have been performed, it appears that there is a limited value of measuring circulating IL-1. However, inhibiting IL-1 has a positive effect on severe fatigue in most studies that have been conducted.
    [Show full text]