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Neuroinflammation
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==Causes== === Microglia activation === The [[blood brain barrier]] (BBB), a membrane that separates the brain from the rest of the body, may become compromised in [[Myalgic encephalomyelitis|ME]] patients. If there are [[Cytokine|cytokines]] circulating in the bloodstream, they may get into the brain through opened sections of the BBB<ref name=":3">{{Cite journal | last = Morris | first = Gerwyn | last2 = Maes | first2 = Michael | date = Dec 2013 | title = A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/22718491|journal=Metabolic Brain Disease|volume=28|issue=4 | pages = 523–540|doi=10.1007/s11011-012-9324-8|issn=1573-7365|pmid=22718491}}</ref>. While this initially starts as a normal brain response so that the brain can get the body back to normal, healthy functioning, this process can be predisposed to dysfunction and activation may be sustained longer than usual. [[Microglia]] are cells that can act as the brain’s primary immune response. If cytokines or immune cells from outside the [[Central nervous system|CNS]] enter the brain through the BBB, the microglia will respond to the immune threat and attempt to clear the infiltrators out. However, this process increases neuron activation and the release of more cytokines potentially leading to a cycle of neuroinflammation<ref name=":3" />. One study used a radioligand, a tracer that lights up in the presence of a specific molecule, in a positron emission tomography (PET) scanner in search of activated microglia in ME patients’ brains. Activated microglia cells are believed to be correlated to neuroinflammation. Increased radioligand presence in ME subjects’ brains was observed; however, further analysis of these data and replication of their results are needed<ref>{{Cite journal | last = Nakatomi | first = Yasuhito | last2 = Mizuno | first2 = Kei | last3 = Ishii | first3 = Akira | last4 = Wada | first4 = Yasuhiro | last5 = Tanaka | first5 = Masaaki | last6 = Tazawa | first6 = Shusaku | last7 = Onoe | first7 = Kayo | last8 = Fukuda | first8 = Sanae | last9 = Kawabe | first9 = Joji | date = Jun 2014 | title = Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study|url=https://www.ncbi.nlm.nih.gov/pubmed/24665088|journal=Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine|volume=55|issue=6 | pages = 945–950|doi=10.2967/jnumed.113.131045|issn=1535-5667|pmid=24665088}}</ref>. ===<span id="ONS_pathway">Oxidative and nitrosative stress</span>=== The '''oxidative and nitrosative stress pathway''' or '''O&NS pathway''' results in tissue damage which could lead to neuroimflammation in [[ME/CFS]]. [[File:CauseofCFSME.jpg|thumb|403x403px|Scheme of cascade events in CFS/ME/SEID showing O&N pathway.Source: Eur Jrnl of Translational Myology 28(3).<ref>{{Cite journal | last = Pietrangelo | first = Tiziana | last2 = Fulle | first2 = Stefania | last3 = Coscia | first3 = Francesco | last4 = Gigliotti | first4 = Paola Virginia | last5 = Fanò-Illic | first5 = Giorgio | date = 2018-09-07 | title = Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome|url=http://dx.doi.org/10.4081/ejtm.2018.7688|journal=European Journal of Translational Myology|volume=28|issue=3|doi=10.4081/ejtm.2018.7688|issn=2037-7460}}</ref> License: CC-BY-NC-4.0]] Neuroinflammation may also be related to excess [[oxygen]] and nitrogen molecules in tissues. This can cause oxidative or nitrosative stress (O&NS), leading to tissue damage. The O&NS pathway helps maintain the blood brain barrier, an important membrane keeping the brain protected from harmful substances present in the blood. When the pathway is dysfunctional, the blood-brain barrier becomes less effective at keeping out particles. Breakdown of this barrier could lead to immune cells entering the brain and trigger an immune response, leading to neuroinflammation. Researchers propose a link between the dysfunction of brain tissues in ME/CFS and the breakdown of the oxidative and nitrosative stress pathway.<ref name=":3" /> {{See also|Nitrogen hypothesis}} === Activation of cyclical neuroinflammation: A self-perpetuating cycle === When a patient gets an infection, the body attempts to return homeostasis. The immune system has regulatory structures called toll-like receptors (TLRs). High amounts of stress or a previous injury can predispose an individual’s TLRs to be more sensitive, releasing inflammatory molecules more readily in response to an immune stressor.<ref>{{Cite journal | last = Gárate | first = Iciar | last2 = Garcia-Bueno | first2 = Borja | last3 = Madrigal | first3 = Jose Luis Muñoz | last4 = Caso | first4 = Javier Rubén | last5 = Alou | first5 = Luis | last6 = Gomez-Lus | first6 = Marisa L. | last7 = Micó | first7 = Juan Antonio | last8 = Leza | first8 = Juan Carlos | date = 2013-01-01 | title = Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway|url=https://www.ncbi.nlm.nih.gov/pubmed/22906518|journal=Biological Psychiatry|volume=73|issue=1|pages=32–43|doi=10.1016/j.biopsych.2012.07.005|issn=1873-2402|pmid=22906518}}</ref> One of the downstream pathways of TLRs, the oxidative and nitrosative stress pathway (O&NS) can get activated. If this pathway is overstimulated, the body will produce a larger-scale response in an effort to return to normal.<ref>{{Cite journal | last = Liu | first = JiaJun | last2 = Buisman-Pijlman | first2 = Femke | last3 = Hutchinson | first3 = Mark R.| date = 2014 | title = Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder |url =https://www.ncbi.nlm.nih.gov/pubmed/25324715|journal=Frontiers in Neuroscience|volume=8|pages=309|doi=10.3389/fnins.2014.00309|issn=1662-4548|pmc=4179746|pmid=25324715}}</ref> In this attempt, a chemical called damage-associated molecular patterns (DAMPs) triggers the release of more inflammatory molecules, some of which activate the TLRs<ref>{{Cite journal | last = Morris | first = Gerwyn | last2 = Berk | first2 = Michael | last3 = Walder | first3 = Ken | last4 = Maes | first4 = Michael | date = 2015-02-06 | title = Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses|url=https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-014-0259-2|journal=BMC Medicine|language=en|volume=13|issue=1|doi=10.1186/s12916-014-0259-2|issn=1741-7015|pmc=4320458|pmid=25856766}}</ref> (Morris et al., 2015). The process of activation from TLRs to the O&NS pathway to the production of more inflammatory molecules then becomes a cycle.<ref name=":4">{{Cite journal | last = Chaudhuri | first = A. | last2 = Condon | first2 = B.R. | last3 = Gow | first3 = J.W. | last4 = Brennan | first4 = D. | last5 = Hadley | first5 = D. M. | date = 2003-02-10 | title = Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12598734|journal=Neuroreport|volume=14|issue=2|pages=225–228|doi=10.1097/01.wnr.0000054960.21656.64|issn=0959-4965|pmid=12598734}}</ref>
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