Editing Vitiligo (section)

==Causes==
Although multiple hypotheses have been suggested as potential triggers that cause vitiligo, studies strongly imply that changes in the [[immune system]] are responsible for the condition.<ref name=Lancet2016>{{cite journal | vauthors = Ezzedine K, Eleftheriadou V, Whitton M, van Geel N | title = Vitiligo | journal = Lancet | volume = 386 | issue = 9988 | pages = 74–84 | date = July 2015 | pmid = 25596811 | doi = 10.1016/s0140-6736(14)60763-7 | s2cid = 208791128 }}</ref><ref>{{cite journal | vauthors = Ongenae K, Van Geel N, Naeyaert JM | title = Evidence for an autoimmune pathogenesis of vitiligo | journal = Pigment Cell Research | volume = 16 | issue = 2 | pages = 90–100 | date = April 2003 | pmid = 12622785 | doi = 10.1034/j.1600-0749.2003.00023.x | doi-access =  }}</ref> Vitiligo has been proposed to be a [[Multifactorial disease|multifactorial disease]] with genetic susceptibility and environmental factors both thought to play a role.<ref name=Lancet2016/> It is hypothesized that damaging environmental factors can disrupt [[Redox|redox]] reactions necessary for [[Protein folding|protein folding]], so skin cells may initiate the unfolded protein response which releases [[Cytokine|cytokines]], thus mounting an immune response.<ref name="Baldini 2017">{{cite journal | vauthors = Baldini E, Odorisio T, Sorrenti S, Catania A, Tartaglia F, Carbotta G, Pironi D, Rendina R, D'Armiento E, Persechino S, Ulisse S | title = Vitiligo and Autoimmune Thyroid Disorders | journal = Frontiers in Endocrinology | volume = 8 | issue = 290 | pages = 290 | date = 27 October 2017 | pmid = 29163360 | pmc = 5663726 | doi = 10.3389/fendo.2017.00290 | doi-access = free }}</ref><ref name="Chang 2021">{{cite journal | vauthors = Chang WL, Lee WR, Kuo YC, Huang YH | title = Vitiligo: An Autoimmune Skin Disease and its Immunomodulatory Therapeutic Intervention | journal = Frontiers in Cell and Developmental Biology | volume = 9 | issue = 797026 | pages = 797026 | date = 14 December 2021 | pmid = 34970551 | pmc = 8712646 | doi = 10.3389/fcell.2021.797026 | doi-access = free }}</ref>

The [[National Institutes of Health]] states that sometimes an event, like a [[sunburn]], emotional distress, or exposure to a chemical, can trigger or exacerbate the condition,<ref>{{cite web|title=Questions and Answers about Vitiligo|url=https://www.niams.nih.gov/health-topics/vitiligo#tab-causes|access-date=29 June 2024|date=30 October 2022|publisher=National Institute of Arthritis and Musculoskeletal and Skin Diseases|archive-date=8 August 2007|archive-url=https://web.archive.org/web/20070808050044/http://www.niams.nih.gov/hi/topics/vitiligo/vitiligo.htm#tab-causes|url-status=live}}</ref> Skin depigmentation in particular areas in vitiligo can also be triggered by mechanical trauma: this is an example of the [[Koebner phenomenon|Koebner phenomenom]].<ref name=":0">{{cite journal | vauthors = Zhang Y, Ding X, Wang F, Li M, Du J | title = Clinical significance of Koebner's phenomenon in vitiligo: a hospital-based epidemiological investigation from China | journal = Chinese Medical Journal | volume = 136 | issue = 4 | pages = 502–504 | date = February 2023 | pmid = 36580639 | pmc = 10106213 | doi = 10.1097/CM9.0000000000002431 }}</ref> Unlike in other skin diseases, this can be caused by daily activities, especially chronic friction on particular areas of the body.<ref name=":0" />

=== Immune ===
[[Melanin]] is the pigment that gives skin its color; it is produced by skin cells called [[melanocyte]]s.

Variations in genes that are part of the immune system or part of melanocytes have both been associated with vitiligo.<ref name="Lancet2016" /> It is also thought to be caused by the immune system attacking and destroying the melanocytes of the skin.<ref>{{cite web|url = http://www.mayoclinic.org/diseases-conditions/vitiligo/basics/causes/con-20032007|title = Vitiligo Causes | author = Mayo Clinic Staff |publisher = Mayoclinic|date = 15 May 2014|access-date = 22 April 2015|url-status=live|archive-url = https://web.archive.org/web/20150430065653/http://www.mayoclinic.org/diseases-conditions/vitiligo/basics/causes/con-20032007|archive-date = 30 April 2015}}</ref> A genome wide association study found approximately 36 independent susceptibility [[locus (genetics)|loci]] for generalized vitiligo.<ref>{{cite journal | vauthors = Spritz RA | title = Modern vitiligo genetics sheds new light on an ancient disease | journal = The Journal of Dermatology | volume = 40 | issue = 5 | pages = 310–318 | date = May 2013 | pmid = 23668538 | pmc = 3783942 | doi = 10.1111/1346-8138.12147 }}</ref>

The TYR gene encodes the protein [[tyrosinase]], which is not a component of the immune system but is an enzyme of the melanocyte that catalyzes melanin biosynthesis, and a major [[autoantigen]] in generalized vitiligo.<ref name="Lancet2016" />

=== Autoimmune associations ===
Vitiligo is sometimes associated with [[autoimmune]] and [[inflammatory disease]]s such as [[Hashimoto's thyroiditis]], [[scleroderma]], [[rheumatoid arthritis]], [[type 1 diabetes mellitus]], [[psoriasis]], [[Addison's disease]], [[pernicious anemia]], [[alopecia areata]], [[systemic lupus erythematosus]], and [[celiac disease]].<ref name=Lancet2016/><ref name=VanDriesscheSilverberg2015>{{cite journal | vauthors = Van Driessche F, Silverberg N | title = Current Management of Pediatric Vitiligo | journal = Paediatric Drugs | volume = 17 | issue = 4 | pages = 303–313 | date = August 2015 | pmid = 26022363 | doi = 10.1007/s40272-015-0135-3 | type = Review | s2cid = 20038695 }}</ref>

Among the inflammatory products of [[NLRP1]] are [[caspase 1]] and [[caspase 7]], which activate the inflammatory [[cytokine]] [[Interleukin-1 beta|interleukin-1β]]. Interleukin-1β and [[interleukin-18]] are expressed at high levels in people with vitiligo.<ref name=LamkanfiVandeWalle2011>{{cite journal | vauthors = Lamkanfi M, Vande Walle L, Kanneganti TD | title = Deregulated inflammasome signaling in disease | journal = Immunological Reviews | volume = 243 | issue = 1 | pages = 163–173 | date = September 2011 | pmid = 21884175 | pmc = 3170132 | doi = 10.1111/j.1600-065X.2011.01042.x | type = Review }}</ref> In one of the mutations, the [[amino acid]] leucine in the NALP1 protein was replaced by [[histidine]] (Leu155&nbsp;→&nbsp;His). The original protein and sequence is highly [[Conserved sequence|conserved in evolution]], and is found in humans, [[Common chimpanzee|chimpanzees]], [[Rhesus macaque|rhesus monkeys]], and [[Galago|bush babies]]. [[Addison's disease]] (typically an autoimmune destruction of the [[adrenal gland]]s) may also be seen in individuals with vitiligo.<ref>{{cite journal | vauthors = Gregersen PK | title = Modern genetics, ancient defenses, and potential therapies | journal = The New England Journal of Medicine | volume = 356 | issue = 12 | pages = 1263–1266 | date = March 2007 | pmid = 17377166 | doi = 10.1056/NEJMe078017 }}</ref><ref name=NALP2>{{cite journal | vauthors = Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, Fain PR, Spritz RA | title = NALP1 in vitiligo-associated multiple autoimmune disease | journal = The New England Journal of Medicine | volume = 356 | issue = 12 | pages = 1216–1225 | date = March 2007 | pmid = 17377159 | doi = 10.1056/NEJMoa061592 | url = http://openaccess.sgul.ac.uk/111251/1/nejmoa061592.pdf | access-date = 16 December 2019 | url-status = live | archive-url = https://web.archive.org/web/20200306115942/http://openaccess.sgul.ac.uk/111251/1/nejmoa061592.pdf | archive-date = 6 March 2020 }}</ref>

=== Oxidative stress ===
Numerous whole-exome sequencing studies have demonstrated that vitiligo is associated with polymorphisms in genes involved in the response to oxidative stress such as CAT, SOD1, SOD2, SOD3, NFE2L2, HMOX1, GST-M1 or GST-T1 supporting the association of elevated levels of reactive oxygen species in melanocytes with the induction of an auto-immune response.<ref>{{Cite journal | vauthors = Chiarella P |date=2019-10-22 |title=Vitiligo susceptibility at workplace and in daily life: the contribution of oxidative stress gene polymorphisms |journal=Biomedical Dermatology |volume=3 |issue=1 |pages=5 |doi=10.1186/s41702-019-0043-1 |doi-access=free |issn=2398-8460}}</ref><ref>{{cite journal | vauthors = Ezzedine K, Eleftheriadou V, Whitton M, van Geel N | title = Vitiligo | journal = Lancet | volume = 386 | issue = 9988 | pages = 74–84 | date = July 2015 | pmid = 25596811 | doi = 10.1016/S0140-6736(14)60763-7 }}</ref>

Thus, diseases presenting with altered mitochondrial function such as MELAS, Vogt-Koyanagi-Harada syndrome and Kabuki syndrome are associated with increased risk of vitiligo.<ref>{{cite journal | vauthors = Karvonen SL, Haapasaari KM, Kallioinen M, Oikarinen A, Hassinen IE, Majamaa K | title = Increased prevalence of vitiligo, but no evidence of premature ageing, in the skin of patients with bp 3243 mutation in mitochondrial DNA in the mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) | journal = The British Journal of Dermatology | volume = 140 | issue = 4 | pages = 634–639 | date = April 1999 | pmid = 10233312 | doi = 10.1046/j.1365-2133.1999.02761.x | first6 = And }}</ref><ref>{{cite journal | vauthors = Liang L, Tan X, Zhou Q, Tian Y, Kijlstra A, Yang P | title = TLR3 and TLR4 But not TLR2 are Involved in Vogt-Koyanagi- Harada Disease by Triggering Proinflammatory Cytokines Production Through Promoting the Production of Mitochondrial Reactive Oxygen Species | journal = Current Molecular Medicine | volume = 15 | issue = 6 | pages = 529–542 | date = 2015-08-19 | pmid = 26238371 | doi = 10.2174/1566524015666150731095611 }}</ref><ref>{{cite journal | vauthors = Margot H, Boursier G, Duflos C, Sanchez E, Amiel J, Andrau JC, Arpin S, Brischoux-Boucher E, Boute O, Burglen L, Caille C, Capri Y, Collignon P, Conrad S, Cormier-Daire V, Delplancq G, Dieterich K, Dollfus H, Fradin M, Faivre L, Fernandes H, Francannet C, Gatinois V, Gerard M, Goldenberg A, Ghoumid J, Grotto S, Guerrot AM, Guichet A, Isidor B, Jacquemont ML, Julia S, Khau Van Kien P, Legendre M, Le Quan Sang KH, Leheup B, Lyonnet S, Magry V, Manouvrier S, Martin D, Morel G, Munnich A, Naudion S, Odent S, Perrin L, Petit F, Philip N, Rio M, Robbe J, Rossi M, Sarrazin E, Toutain A, Van Gils J, Vera G, Verloes A, Weber S, Whalen S, Sanlaville D, Lacombe D, Aladjidi N, Geneviève D | title = Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals | journal = Genetics in Medicine | volume = 22 | issue = 1 | pages = 181–188 | date = January 2020 | pmid = 31363182 | doi = 10.1038/s41436-019-0623-x }}</ref>

In line with these observations, genetic alterations in mitochondrial DNA (mtDNA) of melanocytes associated with altered mitochondrial function lead to a release of mtDNA that can be detected in the skin of vitiligo patients.<ref name=":1">{{cite journal | vauthors = Sant'Anna-Silva AC, Botton T, Rossi A, Dobner J, Bzioueche H, Thach N, Blot L, Pagnotta S, Kleszczynski K, Steinbrink K, Mazure NM, Rocchi S, Krutmann J, Passeron T, Tulic MK | title = Vitiligo auto-immune response upon oxidative stress-related mitochondrial DNA release opens up new therapeutic strategies | journal = Clinical and Translational Medicine | volume = 14 | issue = 8 | pages = e1810 | date = August 2024 | pmid = 39113238 | pmc = 11306283 | doi = 10.1002/ctm2.1810 }}</ref><ref>{{cite journal | vauthors = Bzioueche H, Simonyté Sjödin K, West CE, Khemis A, Rocchi S, Passeron T, Tulic MK | title = Analysis of Matched Skin and Gut Microbiome of Patients with Vitiligo Reveals Deep Skin Dysbiosis: Link with Mitochondrial and Immune Changes | journal = The Journal of Investigative Dermatology | volume = 141 | issue = 9 | pages = 2280–2290 | date = September 2021 | pmid = 33771527 | doi = 10.1016/j.jid.2021.01.036 }}</ref> This mtDNA can be sensed by the cGAS-STING pathway resulting in pro-inflammatory cytokine and chemokines production promoting the recruitment of cytotoxic CD8+ T cells. The use of mitochondrial antioxidants, NRF2 inhibitors, and TBK1 inhibitors is emerging as potential therapeutic options to block this cascade of events.<ref name=":1" />