Editing Multiple sclerosis (section)

== Causes ==
MS is an autoimmune disease with a combination of genetic and environmental causes underlying it. Both T-cells and B-cells are involved, although T-cells are often considered to be the driving force of the disease. The causes of the disease are not fully understood. The [[Epstein–Barr virus|Epstein-Barr Virus]] (EBV) has been shown to be directly present in the brain of most cases of MS and the virus is transcriptionally active in infected cells.<ref>{{cite journal | vauthors = Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F | title = Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain | journal = The Journal of Experimental Medicine | volume = 204 | issue = 12 | pages = 2899–2912 | date = November 2007 | pmid = 17984305 | pmc = 2118531 | doi = 10.1084/jem.20071030 }}</ref><ref name="Hassani-2018">{{cite journal | vauthors = Hassani A, Corboy JR, Al-Salam S, Khan G | title = Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells | journal = PLOS ONE | volume = 13 | issue = 2 | pages = e0192109 | date = 2018 | pmid = 29394264 | pmc = 5796799 | doi = 10.1371/journal.pone.0192109 | doi-access = free | bibcode = 2018PLoSO..1392109H }}</ref> EBV nuclear antigens are believed to be involved in the pathogenesis of multiple sclerosis, but not all people with MS have signs of EBV infection.<ref name="Ward 988–1005" /> Dozens of human [[peptide]]s have been identified in different cases of the disease, and while some have plausible links to infectious organisms or known environmental factors, others do not.<ref>{{cite journal | vauthors = Lutterotti A, Hayward-Koennecke H, Sospedra M, Martin R | title = Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients | journal = Frontiers in Immunology | volume = 12 | pages = 640935 | date = 2021 | pmid = 33828551 | pmc = 8019937 | doi = 10.3389/fimmu.2021.640935 | doi-access = free }}</ref>

=== Immune dysregulation ===
Failure of both central and peripheral nervous system clearance of autoreactive immune cells is implicated in MS development.<ref name="Ward 988–1005"/> The thymus is responsible for the immune system's central tolerance, where autoreactive T-cells are killed without being released into circulation. A similar mechanism kills autoreactive B-cells in the bone marrow. Some autoreactive T-cells & B-cells may escape these defense mechanisms, which is where peripheral immune tolerance defenses take action by preventing them from causing disease. However, these additional lines of defense can still fail.<ref name="Ward 988–1005"/><ref name="McGinley_2021"/> Further detail on immune dysregulation's contribution to MS risk is provided in the [[Multiple sclerosis#Pathophysiology|pathophysiology]] section of this article as well as the standalone article on the [[Pathophysiology of multiple sclerosis|pathophysiology of MS]].

=== Infectious agents ===

Early evidence suggested the association between several viruses with human demyelinating [[encephalomyelitis]], and the occurrence of demyelination in animals caused by some viral infections.<ref name="pmid15721830">{{cite journal | vauthors = Gilden DH | title = Infectious causes of multiple sclerosis | journal = The Lancet. Neurology | volume = 4 | issue = 3 | pages = 195–202 | date = March 2005 | pmid = 15721830 | doi = 10.1016/S1474-4422(05)01017-3 | pmc = 7129502 }}</ref> One such virus, [[Epstein–Barr virus|Epstein-Barr]] [[Herpesviridae#Human herpesvirus types|virus]] (EBV), can cause [[infectious mononucleosis]] and infects about 95% of adults, though only a small proportion of those infected later develop MS.<ref>{{cite journal | vauthors = Soldan SS, Lieberman PM | title = Epstein-Barr virus and multiple sclerosis | journal = Nature Reviews. Microbiology | volume = 21 | issue = 1 | pages = 51–64 | date = January 2023 | pmid = 35931816 | pmc = 9362539 | doi = 10.1038/s41579-022-00770-5 }}</ref><ref name="Aloisi20222" /><ref name="Bjornevik2022">{{cite journal | vauthors = Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A | title = Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis | journal = Science | volume = 375 | issue = 6578 | pages = 296–301 | date = January 2022 | pmid = 35025605 | doi = 10.1126/science.abj8222 | s2cid = 245983763 | bibcode = 2022Sci...375..296B }} See lay summary: {{cite news |vauthors=Gallagher J |title=Is a virus we all have causing multiple sclerosis? |url=https://www.bbc.com/news/health-61042598 |work=BBC |date=13 April 2022 |archive-date=25 April 2022 |access-date=14 April 2022 |archive-url=https://web.archive.org/web/20220425142547/https://www.bbc.com/news/health-61042598 |url-status=live }}</ref><ref name="Hassani-2018" /> A study of more than 10 million US military members compared 801 people who developed MS to 1,566 matched controls who did not. The study found a 32-fold increased risk of MS development following EBV infection. It did not find an increased risk after infection with other viruses, including the similar [[cytomegalovirus]]. These findings strongly suggest that EBV plays a role in MS onset, although EBV alone may be insufficient to cause it.<ref name="Aloisi20222" /><ref name="Bjornevik2022" />

The [[Epstein–Barr virus nuclear antigen 1|nuclear antigen of EBV]], which is the most consistent marker of EBV infection across all strains,<ref>{{cite journal | vauthors = Münz C | title = Epstein-barr virus nuclear antigen 1: from immunologically invisible to a promising T cell target | journal = The Journal of Experimental Medicine | volume = 199 | issue = 10 | pages = 1301–1304 | date = May 2004 | pmid = 15148332 | pmc = 2211815 | doi = 10.1084/jem.20040730 }}</ref> has been identified as a direct source of autoreactivity in the human body. These antigens appear more likely to promote autoimmunity in vitamin D-deficient persons. The exact nature of this relationship is poorly understood.<ref>{{cite journal | vauthors = Miclea A, Bagnoud M, Chan A, Hoepner R | title = A Brief Review of the Effects of Vitamin D on Multiple Sclerosis | journal = Frontiers in Immunology | volume = 11 | pages = 781 | date = 2020-05-06 | pmid = 32435244 | pmc = 7218089 | doi = 10.3389/fimmu.2020.00781 | doi-access = free }}</ref><ref name="Ward 988–1005" />

=== Genetics ===
[[File:HLA.svg|thumb|HLA region of chromosome&nbsp;6: Changes in this area increase the probability of getting MS.]]

MS is not considered a [[hereditary disease]], but several [[genetics|genetic variations]] have been shown to increase its risk.<ref name="pmid14747002">{{cite journal | vauthors = Dyment DA, Ebers GC, Sadovnick AD | title = Genetics of multiple sclerosis | journal = The Lancet. Neurology | volume = 3 | issue = 2 | pages = 104–10 | date = February 2004 | pmid = 14747002 | doi = 10.1016/S1474-4422(03)00663-X | s2cid = 16707321 | citeseerx = 10.1.1.334.1312 }}</ref> Some of these genes appear to have higher expression levels in [[microglia|microglial cells]] than expected by chance.<ref name="SkeneGrant2016">{{cite journal | vauthors = Skene NG, Grant SG | title = Identification of Vulnerable Cell Types in Major Brain Disorders Using Single Cell Transcriptomes and Expression Weighted Cell Type Enrichment | journal = Frontiers in Neuroscience | volume = 10 | pages = 16 | year = 2016 | pmid = 26858593 | doi = 10.3389/fnins.2016.00016 | pmc = 4730103 | doi-access = free }}</ref> The probability of developing MS is higher in relatives of an affected person, with a greater risk among those more closely related.<ref name="pmid119555563"/> An [[identical twin]] of an affected individual has a 30% chance of developing MS, 5% for a nonidentical twin, 2.5% for a sibling, and an even lower chance for a half-sibling.<ref name="pmid1897097722"/><ref name="pmid119555563"/><ref>{{cite journal | vauthors = Hassan-Smith G, Douglas MR | title = Epidemiology and diagnosis of multiple sclerosis | journal = British Journal of Hospital Medicine | volume = 72 | issue = 10 | pages = M146-51 | date = October 2011 | pmid = 22041658 | doi = 10.12968/hmed.2011.72.Sup10.M146 }}</ref> MS is also more common in some ethnic groups than others.<ref name="pmid11603614">{{cite journal | vauthors = Rosati G | title = The prevalence of multiple sclerosis in the world: an update | journal = Neurological Sciences | volume = 22 | issue = 2 | pages = 117–39 | date = April 2001 | pmid = 11603614 | doi = 10.1007/s100720170011 | s2cid = 207051545 }}</ref>

Specific [[gene]]s linked with MS include differences in the [[human leukocyte antigen]] (HLA) system—a group of genes on [[chromosome 6 (human)|chromosome 6]] that serves as the [[major histocompatibility complex]] (MHC).<ref name="pmid1897097722"/> The contribution of HLA variants to MS susceptibility has been known since the 1980s,<ref name="pmid21247752">{{cite journal | vauthors = Baranzini SE | title = Revealing the genetic basis of multiple sclerosis: are we there yet? | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 3 | pages = 317–24 | date = June 2011 | pmid = 21247752 | pmc = 3105160 | doi = 10.1016/j.gde.2010.12.006 }}</ref> and it has also been implicated in the development of other autoimmune diseases, such as [[diabetes type I|type 1 diabetes]] and [[systemic lupus erythematosus]].<ref name="pmid21247752" /> The most consistent finding is the association between higher risk MS development and the MHC [[allele]] ''[[HLA-DR15|DR15]]'', which is present in 30% of the U.S. and Northern European population.<ref name="Ward 988–1005"/><ref name="pmid1897097722"/> Other [[Locus (genetics)|loci]] exhibit a protective effect, such as ''[[HLA-C554]] ''and ''[[HLA-DRB1]]*11''.<ref name="pmid1897097722"/> HLA differences account for an estimated 20 to 60% of the [[genetic predisposition]].<ref name="pmid21247752" /> [[Genome-wide association study|Genome-wide association studies]] have revealed at least 200 MS-associated variants outside the HLA locus.<ref name="pmid31604244">{{cite journal| author=International Multiple Sclerosis Genetics Consortium| title=Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. | journal=Science | year= 2019 | volume= 365 | issue= 6460 | pmid=31604244 | doi=10.1126/science.aav7188 | pmc=7241648 }}</ref>

=== Geography ===
[[File:MS Risk.svg|thumb|Geographic risk distribution of MS]]

The prevalence of MS from a geographic standpoint resembles a gradient, with it being more common in people who live farther from the [[equator]] (e.g., those who live in northern regions of the world), although exceptions exist. The cause of this geographical pattern is not clear, although exposure to [[Ultraviolet|ultraviolet B]] (UVB) radiation and [[vitamin D]] levels may be a possible explanation.<ref name="Milo2010"/><ref name="Ward 988–1005"/> For example, those who live in northern regions of the world have less exposure to UVB radiation and lower levels of vitamin D, and a higher risk for developing MS.<ref name="Ward 988–1005"/> Inversely, those who live in areas of higher sun exposure and increased UVB radiation have a decreased risk of developing MS.<ref name="Ward 988–1005"/> As of 2019, the north–south gradient of incidence is still present and is increasing.<ref name="pmid31217172">{{cite journal | vauthors = Simpson S, Wang W, Otahal P, Blizzard L, van der Mei IA, Taylor BV | title = Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 90 | issue = 11 | pages = 1193–1200 | date = November 2019 | pmid = 31217172 | doi = 10.1136/jnnp-2018-320189 }}</ref>

On the other hand, MS is more common in regions with northern European populations,<ref name="pmid1897097722"/> so the geographic variation may simply reflect the distribution of these higher-risk populations.<ref name=Milo2010 />

A relationship between season of birth and MS lends support to this idea, with fewer people born in the Northern Hemisphere in winter than in spring.<ref name="pmid19897699">{{cite journal |vauthors= Kulie T, Groff A, Redmer J, Hounshell J, Schrager S |title= Vitamin D: an evidence-based review |journal= Journal of the American Board of Family Medicine |volume= 22 |issue= 6|pages= 698–706 |year= 2009 |pmid= 19897699 |doi= 10.3122/jabfm.2009.06.090037 |doi-access= free}}</ref>

Environmental factors during childhood may play a role, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region's risk of MS. If migration takes place after age 15, the person retains the risk of their childhood region.<ref name="pmid1897097722"/><ref name="pmid15556803" /> However, some evidence indicates that the effect of moving may apply to people older than 15.<ref name="pmid1897097722"/>

There are some exceptions to the above-mentioned geographic pattern. These include ethnic groups that are at low risk and that live far from the equator, such as the [[Sami people|Sami]], [[Indigenous peoples of the Americas|Amerindians]], Canadian [[Hutterite]]s, New Zealand [[Māori people|Māori]],<ref name="pmid121276522">{{cite journal |vauthors=Pugliatti M, Sotgiu S, Rosati G |date=July 2002 |title=The worldwide prevalence of multiple sclerosis |journal=Clinical Neurology and Neurosurgery |volume=104 |issue=3 |pages=182–91 |doi=10.1016/S0303-8467(02)00036-7 |pmid=12127652 |s2cid=862001}}</ref> and Canada's [[Inuit]],<ref name="Milo2010" /> as well as groups that have a relatively high risk and that live closer to the equator such as [[Sardinian people|Sardinians]],<ref name="Milo2010" /> inland [[Sicily|Sicilians]],<ref>{{cite journal |vauthors=Grimaldi LM, Salemi G, Grimaldi G, Rizzo A, Marziolo R, Lo Presti C, Maimone D, Savettieri G |date=November 2001 |title=High incidence and increasing prevalence of MS in Enna (Sicily), southern Italy |journal=Neurology |volume=57 |issue=10 |pages=1891–3 |doi=10.1212/wnl.57.10.1891 |pmid=11723283 |s2cid=34895995}}</ref> [[Palestinians]], and [[Parsi]].<ref name="pmid121276522" />

===Impact of temperature===
MS symptoms may increase if body temperature is dysregulated.<ref name="Heat and cold sensitivity in multiple sclerosis">{{Cite journal|url=https://www.msard-journal.com/article/S2211-0348(22)00583-1/fulltext|title=Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices - Multiple Sclerosis and Related Disorders|date=2022 |pmid=35963205 |access-date=15 March 2024|archive-date=15 March 2024|archive-url=https://web.archive.org/web/20240315165409/https://www.msard-journal.com/article/S2211-0348(22)00583-1/fulltext|url-status=live |journal=Multiple Sclerosis and Related Disorders |volume=67 |doi=10.1016/j.msard.2022.104075 | vauthors = Christogianni A, O'Garro J, Bibb R, Filtness A, Filingeri D }}</ref><ref name="Davis-2010">{{cite journal | vauthors = Davis SL, Wilson TE, White AT, Frohman EM | title = Thermoregulation in multiple sclerosis | journal = Journal of Applied Physiology | volume = 109 | issue = 5 | pages = 1531–1537 | date = November 2010 | pmid = 20671034 | pmc = 2980380 | doi = 10.1152/japplphysiol.00460.2010 }}</ref><ref name="Davis-2018">{{cite book | vauthors = Davis SL, Jay O, Wilson TE |chapter=Thermoregulatory dysfunction in multiple sclerosis | veditors = Romanovsky AA |title=Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II |series=Handbook of Clinical Neurology |date=2018 |volume=157 |pages=701–714 |isbn=978-0-444-64074-1 |pmid=30459034 |doi=10.1016/B978-0-444-64074-1.00042-2 }}</ref> Fatigue is particularly affected.<ref name="Multiple Sclerosis Trust"/><ref name="Christogianni-2018"/><ref name="Heat Sensitivity"/><ref name="Multiple Sclerosis Trust-2"/><ref name="Staff-2014">{{Cite web|url=https://multiplesclerosisnewstoday.com/multiple-sclerosis-news/2014/08/11/higher-body-temperature-in-rrms-patients-could-cause-increased-fatigue/|title=Higher Body Temperature in RRMS Patients Could Cause Increased Fatigue|first=BioNews|last=Staff|date=August 11, 2014|website=multiplesclerosisnewstoday.com|access-date=15 March 2024|archive-date=15 March 2024|archive-url=https://web.archive.org/web/20240315125742/https://multiplesclerosisnewstoday.com/multiple-sclerosis-news/2014/08/11/higher-body-temperature-in-rrms-patients-could-cause-increased-fatigue/|url-status=live}}</ref><ref name="Sumowski-2014">{{cite journal | vauthors = Sumowski JF, Leavitt VM | title = Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure | journal = Archives of Physical Medicine and Rehabilitation | volume = 95 | issue = 7 | pages = 1298–1302 | date = July 2014 | pmid = 24561056 | pmc = 4071126 | doi = 10.1016/j.apmr.2014.02.004 }}</ref><ref>{{cite journal | vauthors = Leavitt VM, De Meo E, Riccitelli G, Rocca MA, Comi G, Filippi M, Sumowski JF | title = Elevated body temperature is linked to fatigue in an Italian sample of relapsing-remitting multiple sclerosis patients | journal = Journal of Neurology | volume = 262 | issue = 11 | pages = 2440–2442 | date = November 2015 | pmid = 26223805 | doi = 10.1007/s00415-015-7863-8 }}</ref><ref name="Christogianni-2022">{{cite journal | vauthors = Christogianni A, O'Garro J, Bibb R, Filtness A, Filingeri D | title = Heat and cold sensitivity in multiple sclerosis: A patient-centred perspective on triggers, symptoms, and thermal resilience practices | journal = Multiple Sclerosis and Related Disorders | volume = 67 | pages = 104075 | date = November 2022 | pmid = 35963205 | doi = 10.1016/j.msard.2022.104075 }}</ref>

=== Other ===
[[Tobacco smoking|Smoking]] may be an independent risk factor for MS.<ref name="pmid17492755" /> [[Stress (biological)|Stress]] may also be a risk factor, although the evidence to support this is weak.<ref name="pmid15556803" /> 

Environmental risk factor reviews have correlated lower sun exposure with higher MS rates though the effect does not completely align with earth's [[solar irradiance]] [[latitude]] gradient.  Regional perturbations exist indicating involvement of additional, more influential localized MS risk factors.<ref name="FPH-2023">{{cite journal |last1=Vitturi |first1=Bruno Kusznir |last2=Montecucco |first2=Alfredo |last3=Rahmani |first3=Alborz |last4=Dini |first4=Guglielmo |last5=Durando |first5=Paolo |title=Occupational risk factors for multiple sclerosis: a systematic review with meta-analysis |journal=Frontiers in Public Health |date=November 15, 2023 |volume=11 |issue=2023 |page=Introduction, Results |doi=10.3389/fpubh.2023.1285103 |doi-access=free|pmid=38054069 |pmc=10694508 }}</ref> See also: [[Multiple sclerosis#Geography]].

A 2023 meta-analysis screened data from 4,183,166 individuals identifying environmental and occupational risks associated with MS development. High environmental risks were found from oil well fumes, pesticides and [[Extremely low frequency|low-frequency magnetic fields]], e.g., [[electric power transmission]] towers and passageways. Cleaning agents, solvents and animal contact did not appear to elevate MS risks.<ref name="FPH-2023" /> The highest occupational risks were observed for hairdressers, having a 8.25-fold increased risk versus the general population (GP) ([[Odds ratio|OR]] = 8.25, 95% [[Confidence interval|CI]] 1.02–66.52); offshore workers with a 3.56-fold risk (OR = 3.56, 95% CI 2.74–4.61); and agricultural workers with a 1.44-fold risk, (OR = 1.44, 95% CI 1.13–1.83).<ref name="FPH-2023" /> Occupational risks for MS development, relative to GP, were not observed for shoe and leather workers, construction and tradesmen, healthcare aides, chemical industry workers, food industry staff, cleaning company technicians or military servicepersons.<ref name="FPH-2023" /> 

[[vaccine|Vaccinations]] were studied as causal factors; most studies, though, show no association.<ref name="pmid15556803" /><ref>{{cite journal | vauthors = Stowe J, Andrews N, Miller E | title = Do Vaccines Trigger Neurological Diseases? Epidemiological Evaluation of Vaccination and Neurological Diseases Using Examples of Multiple Sclerosis, Guillain-Barré Syndrome and Narcolepsy | journal = CNS Drugs | volume = 34 | issue = 1 | pages = 1–8 | date = January 2020 | pmid = 31576507 | pmc = 7224038 | doi = 10.1007/s40263-019-00670-y }}</ref> Several other possible risk factors, such as [[Diet (nutrition)|diet]] and [[hormone]] intake, have been evaluated, but evidence on their relation with the disease is "sparse and unpersuasive".<ref name="pmid17492755" /> [[Gout]] occurs less than would be expected and lower levels of [[uric acid]] have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown.<ref name="pmid18219824">{{cite book | vauthors = Spitsin S, Koprowski H | chapter = Role of Uric Acid in Multiple Sclerosis | veditors = Rodriguez M | title = Advances in multiple Sclerosis and Experimental Demyelinating Diseases | series = Current Topics in Microbiology and Immunology | volume = 318 | pages = 325–342 | year = 2008 | pmid = 18219824 | doi = 10.1007/978-3-540-73677-6_13 | isbn = 978-3-540-73676-9 }}</ref> Obesity during adolescence and young adulthood is a risk factor for MS.<ref name="Nourbakhsh2019RisksPathogenesis">{{cite journal | vauthors = Nourbakhsh B, Mowry EM | title = Multiple Sclerosis Risk Factors and Pathogenesis | journal = Continuum | volume = 25 | issue = 3 | pages = 596–610 | date = June 2019 | pmid = 31162307 | doi = 10.1212/CON.0000000000000725 | s2cid = 174806511 }}</ref>