Editing Multiple sclerosis (section)

== Pathophysiology ==
{{Main|Pathophysiology of multiple sclerosis}}
[[File:Multiple Sclerosis.png|thumb|Multiple sclerosis]]
Multiple sclerosis is an autoimmune disease, primarily mediated by T-cells.<ref name="Ward 988–1005" /> The three main characteristics of MS are the formation of lesions in the [[central nervous system]] (also called plaques), inflammation, and the destruction of [[myelin sheath]]s of [[neuron]]s. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue, and in turn, the signs and symptoms of the disease.<ref name="pmid1897097722"/> Damage is believed to be caused, at least in part, by attack on the nervous system by a person's own immune system.<ref name="pmid1897097722"/>

=== Immune dysregulation ===
As briefly detailed in the [[Multiple sclerosis#Immune dysregulation|causes section]] of this article, MS is currently thought to stem from a failure of the body's immune system to kill off autoreactive T-cells & B-cells.<ref name="Ward 988–1005"/> Currently, the T-cell subpopulations that are thought to drive the development of MS are autoreactive CD8+ T-cells, CD4+ helper T-cells, and T<sub>H</sub>17 cells. These autoreactive T-cells produce substances called [[cytokine]]s that induce an inflammatory immune response in the CNS, leading to the development of the disease.<ref name="Ward 988–1005"/> More recently, however, the role of autoreactive B-cells has been elucidated. Evidence of their contribution to the development of MS is implicated through the presence of [[oligoclonal bands|oligoclonal IgG bands]] (antibodies produced by B-cells) in the [[cerebrospinal fluid|CSF]] of patients with MS.<ref name="Ward 988–1005"/><ref name="McGinley_2021"/> The presence of these oligoclonal bands has been used as supportive evidence in clinching a diagnosis of MS.<ref name="Thompson-2018">{{cite journal | vauthors = Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BM, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA | title = Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria | journal = The Lancet. Neurology | volume = 17 | issue = 2 | pages = 162–173 | date = February 2018 | pmid = 29275977 | doi = 10.1016/s1474-4422(17)30470-2 | url = https://discovery.ucl.ac.uk/id/eprint/10041020/ | archive-date = 28 May 2023 | access-date = 20 January 2024 | archive-url = https://web.archive.org/web/20230528035839/https://discovery.ucl.ac.uk/id/eprint/10041020/ | url-status = live }}</ref> As similarly described before, B-cells can also produce cytokines that induce an inflammatory immune response via activation of autoreactive T-cells.<ref name="Ward 988–1005"/><ref>{{cite journal | vauthors = Hassani A, Reguraman N, Shehab S, Khan G | title = Primary Peripheral Epstein-Barr Virus Infection Can Lead to CNS Infection and Neuroinflammation in a Rabbit Model: Implications for Multiple Sclerosis Pathogenesis | journal = Frontiers in Immunology | volume = 12 | pages = 764937 | date = 2021 | pmid = 34899715 | pmc = 8656284 | doi = 10.3389/fimmu.2021.764937 | doi-access = free }}</ref> As such, higher levels of these autoreactive B-cells are associated with an increased number of lesions & neurodegeneration as well as worse disability.<ref name="Ward 988–1005"/>

Another cell population that is becoming increasingly implicated in MS is [[microglia]]. These cells are resident to & keep watch over the CNS, responding to pathogens by shifting between pro- & anti-inflammatory states. Microglia are involved in the formation of MS lesions and be involved in other diseases that primarily affect the CNS white matter. However, because of their ability to switch between pro- & anti-inflammatory states, microglia have also been shown to be able to assist in remyelination & subsequent neuron repair.<ref name="Ward 988–1005"/> As such, microglia are thought to be participating in both acute & chronic MS lesions, with 40% of [[phagocytic cell]]s in early active MS lesions being proinflammatory microglia.<ref name="Ward 988–1005"/>

=== Lesions ===
[[File:MS Demyelinisation KB 10x.jpg|thumb|Demyelination in MS: On [[Klüver-Barrera]] myelin staining, decoloration in the area of the lesion can be appreciated.]]
The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the [[white matter]] in the [[optic nerve]], [[brain stem]], [[basal ganglia]], and [[spinal cord]], or white matter tracts close to the lateral [[Ventricular system|ventricles]].<ref name="pmid1897097722"/> The function of white matter cells is to carry signals between [[grey matter]] areas, where the processing is done, and the rest of the body. The [[peripheral nervous system]] is rarely involved.<ref name="pmid119555563"/>

[[File:MRI machine with patient (23423505123).jpg|thumb|MRI machine used as a tool for MS diagnosis]]

To be specific, MS involves the loss of [[oligodendrocyte]]s, the cells responsible for creating and maintaining a fatty layer—known as the [[myelin]] sheath—which helps the neurons carry [[Action potential|electrical signals]] (action potentials).<ref name="pmid1897097722"/> This results in a thinning or complete loss of myelin, and as the disease advances, the breakdown of the [[axons]] of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.<ref name="pmid119555563"/> A repair process, called [[remyelination]], takes place in the early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell's myelin sheath.<ref name="pmid17531860">{{cite book | vauthors = Chari DM  |chapter=Remyelination in Multiple Sclerosis | veditors = Minagar A |title=The Neurobiology of Multiple Sclerosis |series=International Review of Neurobiology |date=2007 |volume=79 |pages=589–620 |pmid=17531860 |pmc=7112255 |isbn=978-0-12-373736-6 |doi=10.1016/S0074-7742(07)79026-8 }}</ref> Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons.<ref name="pmid17531860" /> These scars are the origin of the symptoms and during an attack [[magnetic resonance imaging]] (MRI) often shows more than 10 new plaques.<ref name="pmid1897097722"/> This could indicate that some number of lesions exist, below which the brain is capable of repairing itself without producing noticeable consequences.<ref name="pmid1897097722"/> Another process involved in the creation of lesions is an abnormal [[astrocytosis|increase in the number of astrocytes]] due to the destruction of nearby neurons.<ref name="pmid1897097722"/> A number of [[pathophysiology of multiple sclerosis#Demyelination patterns|lesion patterns]] have been described.<ref name="pmid17351524">{{cite journal | vauthors = Pittock SJ, Lucchinetti CF | title = The pathology of MS: new insights and potential clinical applications | journal = The Neurologist | volume = 13 | issue = 2 | pages = 45–56 | date = March 2007 | pmid = 17351524 | doi = 10.1097/01.nrl.0000253065.31662.37 | s2cid = 2993523 }}</ref>

=== Inflammation ===
Apart from demyelination, the other sign of the disease is [[inflammation]]. Fitting with an [[immunological]] explanation, the inflammatory process is caused by [[T cell]]s, a kind of [[lymphocyte]]s that plays an important role in the body's defenses.<ref name="pmid119555563"/> T cells gain entry into the brain as a result of disruptions in the [[blood–brain barrier]]. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes".<ref name="pmid1897097722"/>

The attack on myelin starts inflammatory processes, which trigger other immune cells and the release of soluble factors like [[cytokine]]s and [[antibodies]]. A further breakdown of the blood-brain barrier, in turn, causes many other damaging effects, such as [[oedema|swelling]], activation of [[macrophages]], and more activation of cytokines and other destructive proteins.<ref name="pmid119555563"/> Inflammation can potentially reduce transmission of information between neurons in at least three ways.<ref name="pmid1897097722"/> The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.<ref name="pmid1897097722"/>

=== Blood-brain barrier ===
The blood-brain barrier (BBB) is a part of the [[capillary]] system that prevents the entry of T cells into the central nervous system.<!--<ref name="pmid11955556" /> --> It may become permeable to these types of cells secondary to an infection by a virus or bacteria.<!--<ref name="pmid11955556" /> --> After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.<ref name="pmid119555563"/><ref>{{cite journal | vauthors = Huang X, Hussain B, Chang J | title = Peripheral inflammation and blood-brain barrier disruption: effects and mechanisms | journal = CNS Neuroscience & Therapeutics | volume = 27 | issue = 1 | pages = 36–47 | date = January 2021 | pmid = 33381913 | doi = 10.1111/cns.13569 | pmc = 7804893 }}</ref> [[Gadolinium]] cannot cross a normal BBB, so gadolinium-enhanced MRI is used to show BBB breakdowns.<ref name="pmid23088946">{{cite journal | vauthors = Ferré JC, Shiroishi MS, Law M | title = Advanced techniques using contrast media in neuroimaging | journal = Magnetic Resonance Imaging Clinics of North America | volume = 20 | issue = 4 | pages = 699–713 | date = November 2012 | pmid = 23088946 | pmc = 3479680 | doi = 10.1016/j.mric.2012.07.007 }}</ref>

===MS fatigue===
The pathophysiology and mechanisms causing MS [[fatigue]] are not well understood.<ref>{{cite journal | vauthors = Manjaly ZM, Harrison NA, Critchley HD, Do CT, Stefanics G, Wenderoth N, Lutterotti A, Müller A, Stephan KE| title = Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 90 | issue = 6 | pages = 642–651 | date = June 2019 | pmid = 30683707 | pmc = 6581095 | doi = 10.1136/jnnp-2018-320050 }}</ref><ref>{{cite journal | vauthors = Ellison PM, Goodall S, Kennedy N, Dawes H, Clark A, Pomeroy V, Duddy M, Baker MR, Saxton JM|title = Neurostructural and Neurophysiological Correlates of Multiple Sclerosis Physical Fatigue: Systematic Review and Meta-Analysis of Cross-Sectional Studies | journal = Neuropsychology Review | volume = 32 | issue = 3 | pages = 506–519 | date = September 2022 | pmid = 33961198 | pmc = 9381450 | doi = 10.1007/s11065-021-09508-1 }}</ref><ref>{{cite journal | pmc=5102292 | date=2016 | title=Central fatigue in multiple sclerosis: A review of the literature | journal=The Journal of Spinal Cord Medicine | volume=39 | issue=4 | pages=386–399 | doi=10.1080/10790268.2016.1168587 | pmid=27146427 | vauthors = Newland P, Starkweather A, Sorenson M }}</ref> MS fatigue can be affected by body heat,<ref name="Heat and cold sensitivity in multiple sclerosis"/><ref name="Davis-2018"/> and this may differentiate MS fatigue from other primary fatigue.<ref name="Multiple Sclerosis Trust"/><ref name="Christogianni-2018"/><ref name="Christogianni-2022"/> Fatigability (loss of strength) may increase perception of fatigue, but the two measures warrant independent assessment in clinical studies.<ref name="loy">{{cite journal |vauthors=Loy BD, Taylor RL, Fling BW, Horak FB |title=Relationship between perceived fatigue and performance fatigability in people with multiple sclerosis: A systematic review and meta-analysis |journal=Journal of Psychosomatic Research |volume=100 |issue= |pages=1–7 |date=September 2017 |pmid=28789787 |pmc=5875709 |doi=10.1016/j.jpsychores.2017.06.017}}</ref>