Neuroimmunology: Difference between revisions

[[Epigenetic]] medicine encompasses a new branch of neuroimmunology that studies the brain and behavior, and has provided insights into the mechanisms underlying [[brain development]], [[evolution]], [[neuronal]] and network plasticity and homeostasis, [[senescence]], the [[etiology]] of diverse [[neurological diseases]] and neural regenerative processes. It is leading to the discovery of environmental stressors that dictate initiation of specific neurological disorders and specific disease [[biomarker]]s. The goal is to "promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of [[endogenous]] regional neural [[stem cells]]".<ref>{{cite journal |author1=Abdolmaleky H.M. |author2=Thiagalingam S. |author3=Wilcox M. | year = 2005 | title = Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope | url = | journal = American Journal of Pharmacogenomics | volume = 5 | issue = 3| pages = 149–160 | doi=10.2165/00129785-200505030-00002 | pmid=15952869|s2cid=16397510 }}</ref>

Several studies have shown that regulation of stem cell maintenance and the subsequent fate determinations are quite complex. The complexity of determining the fate of a stem cell can be best understood by knowing the "circuitry employed to orchestrate stem cell maintenance and progressive neural fate decisions".<ref>{{cite journal |author1=Diamandis P. |author2=Wildenhain J. |author3=Clarke I.D. |author4=Sacher A.G. |author5=Graham J. |author6=Bellows D.S. |author7=Ling E.K. |author8=Ward R.J. |author9=Jamieson L.G. | year = 2007 | title = Chemical genetics reveals a complex functional ground state of neural stem cells. Nat | url = | journal = Chem. Biol. | volume = 3 | issue = 5| pages = 268–273 | doi=10.1038/nchembio873|pmid=17417631 |display-authors=etal}}</ref> Neural fate decisions include the utilization of multiple neurotransmitter signal pathways along with the use of epigenetic regulators. The advancement of neuronal stem cell differentiation and glial fate decisions must be orchestrated timely to determine subtype specification and subsequent maturation processes including myelination.<ref>{{cite journal |author1=Shen S. |author2=Casaccia-Bonnefil P. | year = 2007 | title = Post-translational modifications of nucleosomal histones in oligodendrocyte lineage cells in development and disease | url = | journal = Journal of Molecular Neuroscience | volume = 35 | issue = 1| pages = 13–22 | doi=10.1007/s12031-007-9014-x| pmc=2323904 | pmid=17999198}}</ref>

Neurodevelopmental disorders result from impairments of growth and development of the brain and nervous system and lead to many disorders. Examples of these disorders include [[Asperger syndrome]], [[traumatic brain injury]], [[communication]], speech and language disorders, genetic disorders such as [[fragile-X syndrome]], [[Down syndrome]], [[epilepsy]], and [[fetal alcohol syndrome]]. Studies have shown that [[autism spectrum disorders]] (ASDs) may present due to basic disorders of epigenetic regulation.<ref>{{cite journal | author1 = Herbert M.R.|author1linkauthor1-link=Martha Herbert|author2=Russo J.P.|author3=Yang S.|author4=Roohi J.|author5=Blaxill M.|author6=Kahler S.G.|author7=Cremer L.|author8=Hatchwell E. | year = 2006 | title = Autism and environmental genomics | url = | journal = Neurotoxicology | volume = 27 | issue = 5| pages = 671–684 | doi=10.1016/j.neuro.2006.03.017|pmid=16644012|bibcode=2006NeuTx..27..671H }}</ref> Other neuroimmunological research has shown that deregulation of correlated epigenetic processes in ASDs can alter gene expression and brain function without causing classical genetic lesions which are more easily attributable to a cause and effect relationship.<ref>{{cite journal |author1=Badcock C. |author2=Crespi B. | year = 2006 | title = Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism | url = | journal = Journal of Evolutionary Biology | volume = 19 | issue = 4| pages = 1007–1032 | doi=10.1111/j.1420-9101.2006.01091.x | pmid=16780503|s2cid=14628770 }}</ref> These findings are some of the numerous recent discoveries in previously unknown areas of gene misexpression.

Increasing evidence suggests that neurodegenerative diseases are mediated by erroneous epigenetic mechanisms. Neurodegenerative diseases include [[Huntington's disease]] and [[Alzheimer's disease]]. Neuroimmunological research into these diseases has yielded evidence including the absence of simple Mendelian inheritance patterns, global transcriptional dysregulation, multiple types of pathogenic [[RNA alterations]], and many more.<ref>{{cite journal |author1=Greene L.A. |author2=Liu D.X. |author3=Troy C.M. |author4=Biswas S.C. | year = 2007 | title = Cell cycle molecules define a pathway required for neuron death in development and disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1772 | issue = 4| pages = 392–401 | doi=10.1016/j.bbadis.2006.12.003 | pmid=17229557 | pmc=1885990}}</ref> In one of the experiments, a treatment of Huntington’s disease with histone deacetylases (HDAC), an enzyme that removes acetyl groups from lysine, and DNA/RNA binding anthracylines that affect nucleosome positioning, showed positive effects on behavioral measures, neuroprotection, nuclesomenucleosome remodeling, and associated chromatin dynamics.<ref>{{cite journal |author1=Abel T. |author2=Zukin R.S. | year = 2008 | title = Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders | url = | journal = Current Opinion in Pharmacology | volume = 8 | issue = 1| pages = 57–64 | doi=10.1016/j.coph.2007.12.002| pmc=2405764 | pmid=18206423}}</ref> Another new finding on neurodegenerative diseases involves the overexpression of HDAC6 suppresses the neurodegenerative phenotype associated with Alzheimer’s disease pathology in associated animal models.<ref>{{cite journal |author1=Pandey U.B. |author2=Nie Z. |author3=Batlevi Y. |author4=McCray B.A. |author5=Ritson G.P. |author6=Nedelsky N.B. |author7=Schwartz S.L. |author8=DiProspero N.A. |author9=Knight M.A. | year = 2007 | title = HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS | url = | journal = Nature | volume = 447 | issue = 7146| pages = 859–863 | doi=10.1038/nature05853 | pmid=17568747|bibcode=2007Natur.447..860P |s2cid=4365061 |display-authors=etal}}</ref> Other findings show that additional mechanisms are responsible for the "underlying transcriptional and post-transcriptional dysregulation and complex chromatin abnormalities in Huntington's disease".<ref>{{cite journal |author1=Ballas N. |author2=Mandel G. | year = 2005 | title = The many faces of REST oversee epigenetic programming of neuronal genes | url = | journal = Current Opinion in Neurobiology | volume = 15 | issue = 5| pages = 500–506 | doi=10.1016/j.conb.2005.08.015 | pmid=16150588|s2cid=32596790 }}</ref>

The nervous and immune systems have many interactions that dictate overall body health. The nervous system is under constant monitoring from both the [[Adaptive immune system|adaptive]] and [[innate immune system]]. Throughout development and adult life, the immune system detects and responds to changes in [[cell identity]] and neural connectivity.<ref>Bailey, S.L., Carpentier, P.A., McMahon, E.J., Begolka, W.S., Miller, S.D., 2006. Innate and adaptive immune responses of the central nervous system. [[Critical Reviews in Immunology]]. 26, 149–188.</ref> Deregulation of both adaptive and acquired immune responses, impairment of crosstalk between these two systems, as well as alterations in the deployment of innate immune mechanisms can predispose the [[central nervous system]] (CNS) to autoimmunity and neurodegeneration.<ref>{{cite journal |author1=Hauser S.L. |author2=Oksenberg J.R. | year = 2006 | title = The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration | url = | journal = Neuron | volume = 52 | issue = 1| pages = 61–76 | doi=10.1016/j.neuron.2006.09.011|pmid=17015227 | doi-access = free }}</ref> Other evidence has shown that development and deployment of the innate and acquired immune systems in response to stressors on functional integrity of cellular and systemic level and the evolution of autoimmunity are mediated by [[epigenetic mechanisms]].<ref>{{cite journal | author = Sawalha A.H. | year = 2008 | title = Epigenetics and T-cell immunity | url = https://zenodo.org/record/1234451| journal = Autoimmunity | volume = 41 | issue = 4| pages = 245–252 | doi=10.1080/08916930802024145| pmid = 18432405 | s2cid = 46300553 }}</ref> Autoimmunity has been increasingly linked to targeted deregulation of epigenetic mechanisms, and therefore, use of epigenetic therapeutic agents may help reverse complex pathogenic processes.<ref>Gray, S.G., Dangond, F., 2006. Rationale for the use of histone [[deacetylase]] inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics 1, 67–75.</ref> [[Multiple sclerosis]] (MS) is one type of neuroimmunological disorder that affects many people. MS features CNS inflammation, immune-mediated demyelination and neurodegeneration.

Myalgic Encephalomyelitis (also known as [[Chronic fatigue syndrome]]), is a multi-system disease that causes dysfunction of neurological, immune, endocrine and energy-metabolism systems. Though many patients show neuroimmunological degeneration, the correct roots of ME/CFS are unknown. Symptoms of ME/CFS include significantly lowered ability to participate in regular activities, stand or sit straight, inability to talk, sleep problems, excessive sensitivity to light, sound or touch and/or thinking and memory problems (defective cognitive functioning). Other common symptoms are muscle or joint pain, [[sore throat]] or [[night sweats]]. There is no treatment but symptoms may be treated. Patients that are sensitive to [[Mold (fungus)|mold]] may show improvement in symptoms having moved to drier areas. Some patients in general have less severe ME, whereas others may be bedridden for life.<ref>{{cite web |title=WHAT IS ME? |url=https://www.meaction.net/about/what-is-me/ |website=MEAction |accessdateaccess-date=21 August 2018}}</ref>

The interaction of the CNS and immune system are fairly well known. Burn-induced organ dysfunction using vagus nerve stimulation has been found to attenuate organ and serum cytokine levels. Burns generally induce abacterial cytokine generation and perhaps parasympathetic stimulation after burns would decrease cardiodepressive mediator generation. Multiple groups have produced experimental evidence that support proinflammatory cytokine production being the central element of the burn-induced stress response.<ref>{{cite journal |author1=Oke S.L. |author2=Tracey K.J. | year = 2008 | title = From CNI-1493 to the immunological homunculus: physiology of the inflammatory reflex | url = | journal = Journal of Leukocyte Biology | volume = 83 | issue = 3| pages = 512–517 | doi=10.1189/jlb.0607363 | pmid=18065685|s2cid=612157 }}</ref> Still other groups have shown that vagus nerve signaling has a prominent impact on various inflammatory pathologies. These studies have laid the groundwork for inquiries that vagus nerve stimulation may influence postburn immunological responses and thus can ultimately be used to limit organ damage and failure from burn induced stress.

Basic understanding of neuroimmunological diseases has changed significantly during the last ten years. New data broadening the understanding of new treatment concepts has been obtained for a large number of neuroimmunological diseases, none more so than multiple sclerosis, since many efforts have been undertaken recently to clarify the complexity of pathomechanisms of this disease. Accumulating evidence from animal studies suggests that some aspects of depression and fatigue in MS may be linked to inflammatory markers.<ref>Gold, Stefan M, Irwin, Michael R, 2009. Depression and Immunity: Inflammation and Depressive Symptoms in Multiple Sclerosis. 29, 309.</ref> Studies have demonstrated that Toll like-receptor (TLR4) is critically involved in neuroinflammation and T cell recruitment in the brain, contributing to exacerbation of brain injury.<ref>{{Cite journal|title = Lipopolysaccharide from Rhodobacter sphaeroides Attenuates Microglia-Mediated Inflammation and Phagocytosis and Directs Regulatory T Cell Response|journal = International Journal of Inflammation|date = 2015-01-01|issn = 2090-8040|pmc = 4589630|pmid = 26457222|pages = 361326|volume = 2015|doi = 10.1155/2015/361326|firstfirst1 = Sagar|lastlast1 = Gaikwad|first2 = Reena|last2 = Agrawal-Rajput|doi-access = free}}</ref> Research into the link between smell, depressive behavior, and autoimmunity has turned up interesting findings including the facts that inflammation is common in all of the diseases analyzed, depressive symptoms appear early in the course of most diseases, smell impairment is also apparent early in the development of neurological conditions, and all of the diseases involved the amygdale and hippocampus. Better understanding of how the immune system functions and what factors contribute to responses are being heavily investigated along with the aforementioned coincidences.

The nervous system and immune system require the appropriate degrees of cellular differentiation, organizational integrity, and neural network connectivity. These operational features of the brain and nervous system may make signaling difficult to duplicate in severely diseased scenarios. There are currently three classes of therapies that have been utilized in both animal models of disease and in human clinical trials. These three classes include DNA methylation inhibitors, HDAC inhibitors, and RNA-based approaches. DNA methylation inhibitors are used to activate previously silenced genes. HDACs are a class of enzymes that have a broad set of biochemical modifications and can affect DNA demethylation and synergy with other therapeutic agents. The final therapy includes using RNA-based approaches to enhance stability, specificity, and efficacy, especially in diseases that are caused by RNA alterations. Emerging concepts concerning the complexity and versatility of the epigenome may suggest ways to target genomewide cellular processes. Other studies suggest that eventual seminal regulator targets may be identified allowing with alterations to the massive epigenetic reprogramming during gametogenesis. Many future treatments may extend beyond being purely therapeutic and may be preventable perhaps in the form of a vaccine. Newer high throughput technologies when combined with advances in imaging modalities such as in vivo optical nanotechnologies may give rise to even greater knowledge of genomic architecture, nuclear organization, and the interplay between the immune and nervous systems.<ref>{{cite journal |author1=Rauch J. |author2=Knoch T.A. |author3=Solovei I. |author4=Teller K. |author5=Stein S. |author6=Buiting K. |author7=Horsthemke B. |author8=Langowski J. |author9=Cremer T. |author-link9=Thomas Cremer| year = 2008 | title = Light optical precision measurements of the active and inactive [[Prader–Willi syndrome]] imprinted regions in human cell nuclei | doi =10.1111/j.1432-0436.2007.00237.x | journal = Differentiation | volume = 76 | issue = 1| pages = 66–82 |pmid=18039333 |display-authors=etal}}</ref>

*{{cite book |author=Visser A, Goodkin K (eds) |title=Psychoneuroimmunology: stress, mental disorders, and health |publisher=American Psychiatric Press |location=Washington, DC |year=2000 |isbn=0-88048-171-4 }}<br/>technical.

*{{cite book |authoreditor=Ransohoff RM (ed) |title=Universes in delicate balance: chemokines and the nervous system |publisher=Elsevier |location=Amsterdam |year=2002 |isbn=0-444-51002-8 }}

*{{cite book |author=Sternberg EM |title=The Balance Within : The Science Connecting Health and Emotions |date=7 May 2001 |publisher=W. H. Freeman |location=San Francisco |pages= |isbn=0-7167-4445-7 }}<br/>(Written for the general public)

[[Category:Mind–bodyClinical interventionsneuroscience]]