Posted on Authorea 9 Apr 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161798642.25768292/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. nvriyo hffil,BehHl od hffil 1 R,UK 2RX, S10 Sheffield Road, Hill Beech Sheffield, of Disease, University Cardiovascular and Immunology Infection, of Department Gawkrodger D.J. Prof. Correspondence: Gawkrodger: D.J. Kemp: H. E. [email protected] Faraj: S. addresses: Email 0000-0002-6863-7011 Gawkrodger: D.J. 0000-0002-0313-8916 Kemp: E.H. 0000-0002-5211-6705 Faraj: S. ORCID: UK Sheffield, Sheffield, of Disease, University Cardiovascular and Immunology Infection, of *Department and Metabolism, and Gawkrodger* Oncology J. of D. Department and factors Kemp, the stress H. environmental of E. by understanding Faraj, triggered with S. cur-rent milieu, as the immunogenetic immunities, the outline adaptive of we integration and review an innate this directed. vitiligo: be of In might mechanisms immune attack Patho-immunological innate already vitiligo. therapeutic stress, which has in to cellular vitiligo inhibitors loci in for locate mechanisms Jak-1 basis and aetiological pathogenic the vitiligo, the a in of of mechanisms show use understanding pathological Studies Improved successful cell. in vitiligo. autoreactive pigment of in resulted stim-ulation immun-ity of or to adaptive targeting exposure leads and further chemical melanocytes responses to with stress, presentation emo-tional Antigen responses, molecular to cell damage-associated responses. secrete immune T trauma which innate cells from initiate pigment in then ranging stress that oxidative stresses stimulate patterns can by unknown, triggered the to vitiligo, imbalance, metabolite in loss melanocyte Epidermal Abstract 2021 9, April 3 2 1 Faraj Safa factors stress as environmental immunities, by adaptive triggered and innate the with of milieu, integration immunogenetic an vitiligo: of mechanisms Patho-immunological NVO SHEFFIELD OF UNIV Sheffield of University Sheffield of University The 1 e.h.kemp@sheffield.ac.uk Kemp H E , [email protected] 2 n AI GAWKRODGER DAVID and , 1 3 Posted on Authorea 9 Apr 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161798642.25768292/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. hydsperfo ffce kno iiioa h ies rges[7.Imnhsohmclsuisof studies Immunohistochemical [17]. progress disease the as however, vitiligo using present, by of remain revealed stain, skin as (FM) affected Melanocytes in Masson Fontana melanocytes from [13]. the of stage disappear or numbers disease technique they reduced the antibody or to according monoclonal of varies appropriate absence decrease an and This loss melanin [16]. demonstrates epidermis the vitiligo in skin Degeneration affected Melanocyte The and pho- repigmentation, Vitiligo calcitonin-inhibitors, satisfactory [15]. of achieve steroids, Features promise to shown Histopathological topical failed have frequently including inhibitors has Jak-1 vitiligo, action past the the of the recently, under in target treatment but apoptosis procedure, and ultimately The surgical damage that and to stimulate [14]. vulnerable totherapies, susceptibilities expo- can highly factors chemical genetic are which triggering vitiligo and appropriate hormones, in of trauma or the melanocytes The cytokines physical with [2]. metabolites, stress, individuals the melanocytes factors, emotional in Therefore, neural the including responses, endogenous vitiligo, positively [12]. autoimmune in trigger affect therapy imbalances [13]. may to given may confidence factors sure and a measures self-esteem of to life patient’s variety rate the of A enhance response quality decreased and lower and treatment with a vitiligo intervention patients of face vitiligo psychological outcome that initiation specific sexuality and demonstrated treatment of status have marital at development the reports on life impact previous negative of Furthermore, antagonism, major quality to a have subjected [9-11]. also are patients can patients and Vitiligo leprosy of [7]. with [8]. confused stigma isolation still social is social and vitiligo insult and India, Vitiligo self-esteem as such and low countries anxiety some in [5]. depression, In resulting experience sufferers others often from on vitiligo stigmatisation with impact patients and negative embarrassment, Moreover, psychological discrimination lesions, [6]. vitiliginous serious spreading self-consciousness of a or fear self-image have stress, of no can feelings with experience vitiligo commonly region patients a geographic threatening, to or maps non-life race often Although gender, vitiligo any be Segmental affect can aetiologies. can and [4]. different Vitiligo difference have percent, char- [3]. significant might one disease distribution Differentiat- they dermatomal about skin as 2]. or of important [1, a blaschkoid prevalence vitiligo be vitiligo, unclassifiable/undetermined may worldwide in and subtypes a mixed ing event has segmental, pathological non-segmental, Vitiligo into underlying classified patches. the depigmented is by destruction acterised and damage Melanocyte directed. pathological be Introduction the might of attack understanding therapeutic current which the words: outline to Key we loci successful review locate in this in and resulted In immunity already vitiligo, adaptive vitiligo. has and in in vitiligo mechanisms responses inhibitors in immune Jak-1 mechanisms pigment the innate aetiological of of stress, the targeting use cellular of further for with understanding basis presen- Improved responses, pathogenic Antigen cell vitiligo. a T which responses. autoreactive show cells of immune Studies pigment stimulation innate in cell. to initiate stress leads chemi- oxidative then melanocytes stress, stimulate to that emotional can tation patterns to unknown, trauma molecular the from to damage-associated ranging imbalance, secrete stresses metabolite Ethics by or triggered exposure paper. vitiligo, cal in this loss for melanocyte received Epidermal was funding No interest. Summary of conflicts required. no not was identify approval authors by The and Libya, Statement: in Libya. Education Gharyan, of of Ministry University the the by sponsored was Faraj Dr Acknowledgement: email: [email protected] niois uomuiy yoie,CttxcTCls h/h Cells Th1/Th2 Cells, T Cytotoxic Cytokines, Autoimmunity, Antibodies, 2 Posted on Authorea 9 Apr 2021 | The copyright holder is the author/funder. All rights reserved. No reuse without permission. | https://doi.org/10.22541/au.161798642.25768292/v1 | This a preprint and has not been peer reviewed. Data may be preliminary. l fwihsget htteepgetclsaels aal fdaigwt uhsrsosta hs from those than stressors such with dealing of capable anomalies less are Observed cells pigment stress. structure, these melanosome oxidative that abnormal to suggests an and which vulnerable dysfunction, of mitochondrial melanocytes all reticulum, vitiligo endoplasmic dilated render to a also include leads which may endoplasmic of degradation defects of activation sustained protein Intrinsic restoration folding, misfolded the protein inducing facilitate induces to translation, misfold- turn [2]. chaperons protein protein in apoptosis of of synthesis of This the risk halting accumulation promoting the response. the allowing and increases (TYRP1), protein through melanocytes, products protein-1 unfolded homeostasis vitiligo intermediate to tyrosinase-related the reticulum in of of vulnerable activating observed build-up stability more hence The been the melanocytes ing, has results [37]. in be likewise synthesis, intermediates decrease synthesis to melanin melanin a of its for causing addition, melanocytes radiation, required species, In protects is UV oxygen skin which 36]. absorb reactive the to [35, melanocyte intracellular in ability cross stress of present oxidative its easily amount melanin can through higher anion though keratinocytes superoxide Even in adjacent from as been [33]. created well have peroxide damage catalase as of Hydrogen cellular levels As are low causing E. [34]. and radicals hydro- vitamin membranes dismutase skin free and superoxide and their of Such C, superoxide levels in vitamin high as observed [33]. catalase, patients, such dismutase, vitiligo processes superoxide in radicals pathological above, as free mentioned and such antioxidants oxygen-based physiological by of multiple scavenged number during constantly a formed of peroxide, species consist gen oxygen species reactive oxygen stimulate Reactive (UV) can ultraviolet which e.g., chemicals, stressors oxidising environmental [32]. various and production to microorganisms exposed pollution, regularly are radiation, disorder. epidermis the the for in microscopic sufficient compared Melanocytes complete Vitiligo abnormal be a are to in with melanocytes seem Stress vitiligo lesions not to that vitiligo does certain Responses of abnormality is this edge it but Therefore, the melanocytes, at [31]. healthy skin lymphocytes to lesional only T shows in the of examination melanin not vi- immunohistochemical of number was and human loss defect large Histochemical of melanocyte a [30]. intrinsic engrafting of vitiligo that following infiltration in indicating and skin destruction achieved, morphological the was melanocyte ends show of mouse of dendritic nude cause patients longer regimentation on with vitiligo rapid skin enlarged However, from might lesional be vitiligo Melanocytes to tiligo [29]. seen in melanocytes vitiligo. are balance normal borders of redox peri-lesional than cause, dysregulated in Thus, a Those regulat- not [28]. abnormalities. by patients physiological but lesions vitiligo vitiligo vitiligo consequence, cure from treating to a melanocytes in proposed be ineffective was addition, which was In ROS, (pseudocatalase), ing catalase 25]. by-products of 24, oxidative treatment vi- [22, elevated exogenous from However, and reported to derived peroxide sensitive been melanocytes hydrogen more has culture of were skin compensatory to expression patient required Therefore, increased vitiligo are Also, melanogenesis. catalase within (ROS). 23]. of or [20, species by-product factors patients oxygen dis- as growth tiligo reactive of levels as enzyme from ROS such step catalase cells supplements high then first protecting media synthesise and low the oxygen, peroxide melanocytes and and catalyses hydrogen fact, dismutase water dismutase and In superoxide into oxygen superoxide into peroxide of circumstances, anion hydrogen levels superoxide normal transforms high the Under with converting activity by [22]. mutation antioxidant melanocytes catalase inadequate normal healthy show of to compared they levels proliferate also poorly and to [21]. shown [19] loss were melanocyte subjects vitiligo Defective elucidate melanocytes from may vitiligo Melanocytes degeneration of process. susceptibility remains that increased autoimmune it suggests and skin, or stimuli 20] the [19, exogenous degenerative from vitiligo to loss with a melanocyte individuals through from from derived results occurs melanocytes vitiligo this in depigmentation whether that unclear clear numbers is decreased it in exist though may Even they [18]. but changes layer, degenerative basal the demonstrate from can melanocytes and of absence the show lesions vitiligo nvitro in xdtv hrpe uha ueehdoeoieadUBlgt[6 27]. [26, light UVB and hydroperoxide cumene as such therapies oxidative 3 nvitro in rwhof growth Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. n osqetpgetcl etuto 5] eety eieinlkrtnctsfo iiiosi,under IL-1 cytokine skin, downstream vitiligo and from response (NLRP3) keratinocytes autoimmune 3 perilesional an taining Recently, in resulting [54]. stress cells, destruction oxidative acti- T cell facilitate pigment CD8+ the to consequent melanocyte-specific with noted and activate melanocytotoxic were innate them can phenol, the rendering melanocytes butyl was thus immunity bridging 4-tertiary stressed cell-based cells thus to and dendritic by exposure stress cells, of vitiligo by cellular T vation for between stressed treatment vitiligo cytotoxic melanocytes, potential in recruit a when connection offer illustrated The nodes, may immunity. activating HSP70i lymph innate mutant by recruit- the of local and models altering delivery activation in animal Therefore, cell in and, T [53]. immunity vitiligo inducing skin adaptive initiate cytokines, the synthesise directly activation locally to can HSP70i, cell cells ment dendritic HSP70i, endogenous dendritic with particular Activated, of interfering in pathway by cells. DAMPS, dendritic models signaling Thus, swine the and 52]. with mouse [46, vitiligo interferes in cells which depigmentation dendritic delivery, inhibit of HSP70i could activation mutant the addition, via receptors In probably melanocyte inhibitory model, inducing by [45]. the mouse vitiligo skin vitiligo in destroy trigger the aggravates can can decrease in chemicals alone which a While cells, HSP70i and 51]. dendritic adding [46, cells, of stress, iHSP70 numbers NK by 46]. increased activated ac- of when CD3+CD16+CD56+), demonstrates [44, ligand aberrant melanocytes and also found [43]. activating (CD16+CD56+ show skin been receptors response Vitiligo an cells have activating CLEC2B, innate (CD16+CD158a+). dendritic cells cells in the NK and NK in upregulation pro- activated initiate macrophage increase an iHSP70 (GZMB)-expressing PRRs cells, an granzyme-B and shows (NK) and and skin species killer vitiligo, Vitiligo skin oxygen natural in vitiligo Reactive as DAMPs in such [50]. tivation as cells cells serve immune damaged (PAMPs) melanocytes patterns by Innate molecular stressed released pathogen-associated by DAMPs detect to or duced PRRs pathogens of ability in the found on based onset is the immunity and Innate trigger a as stress and oxidative Immunity generation between Innate vitiligo. neoantigen link in a that both thus reaction likely through is autoimmune is autoimmunity iHSP70 the it of of Therefore, [39]. coactivation immunity instigation 49]. of innate [48, to expression of melanocytes the contribute activation elevate to can to responses from stress immune cells iHSP70 stimulating Secreted melanocyte dendritic CD86, induce [46]. and vitiligo to CD80 in reported markers response was immune melanocytes the initiates vitiligo cells that iHSP70 dendritic stressed signal genetically activate been of inflammatory stress, can has oxidative the that expression of iHSP70 release iHSP70 conditions lacking and peptides-chaperoned [46]. Under Mice melanosomal vitiligo [47]. secrete in properties [45]. melanocytes iHSP70 chaperone compromised loss for and iHSP70 adjuvant role increased melanocytes potent a have shows addition, causes to suggesting in- patients from found In depigmentation, patients vitiligo skin experimental DAMPs vitiligo [44]. of develop in of controls of not skin resulting healthy will release uninvolved skin melanocytes with this, the the comparison stressed with in by in agreement from activated expression lymphocytes In released is of constantly [43]. immunity numbers vitiligo be increased Innate been with to patients has likely [42]. in NLRP1 are study flammation vitiligo Indeed, DAMPs linkage in Toll-like a cells. (NLRs). including detected in stressed receptors pat- (PRRs) been vitiligo (NOD)-like molecular receptors has with domain damage-associated recognition or linked pattern oligomerization which Pathogens via nucleotide (iHSP70), inflammation and [41]. evoke 70 as disease receptors can such active protein which derivatives with shock (DAMP), correlate phenolic they terns heat to to stressed, seen inducible become exposed ROS and melanocytes of melanocytes melanocytes that Once secretion healthy likely hydroquinone[40]. in the of is develop ether promote it monobenzyl to thus and found butylphenol and been 4-tertiary peroxidation, [39]. has neoantigenic with oxidation stress of and correlated ROSCellular carbonylation generation Elevated been protein neoantigens. with has via generate neoantigens linked may subjects melanocyte stress directly vitiligo generates melanocyte likewise of been and melanocytes has [38], cells in stress islet ROS-mediated beta within epitopes [32]. individuals healthy nvitro, in aebe hw oehbticesdepesoso L aiyprndmi con- domain pyrin family NLR of expressions increased exhibit to shown been have β, niflmaoergltrta a ouaeinnate modulate may that regulator inflammasome an 4 nvitro in 4] teshv eosrtdthat demonstrated have Others [48]. Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. iepoencnann AD(S)[7.I diin h LP namsm a lob activated be also intracellular can (TRPM2)-induced inflammasome 2 NLRP3 member H M the in influx induces subfamily requires addition, calcium channel In and signal mitochondrial speck- cation and other cells apoptosis-associated potential [57]. and receptor the (ASC) primes NLRP3 transient CARD while signal through of a [56], first interaction immunity. containing signaling and innate The protein (mtROS) (NF-kB)-mediated the like species in kB signals. oxygen inflammasome factor reactive two the nuclear mitochondrial requires of by constituent inflammasome expression essential NLRP3 an NLRP3 is of and activation NLR The cytoplasmic a is NLRP3 [55]. melanocytes on attack immune e,ifitaetelsoa odr fvtlgnu kn n hi ubrcreae ihdsaeextension disease with correlates number their and skin, vitiligo. in neigh- vitiliginous melanocytes of anti- borders of [63-65]. lymphocyte-association borders dermo-epidermal destruction severity cutaneous the lesional These marker, and the homing in the in skin implicated lesions. infiltrate the are located depigmented express gen, cells preferentially that of T cells Histological cells, CD8+ T border cytotoxic CD8+ T 62]. the Melanocytotoxic [60]. melanocyte-specific [61, + at lymphocytes melanocytes of CD8 lymphocytes the B production of of bouring by mainly the infiltration antibodies showed consist in by melanocyte-specific lesions infiltrates presented resulting of vitiligo and generation node, of processed the lymph studies be and draining can lymphocytes antigens the T melanocyte in skin, cells the dendritic in Vitiligo signalling in proinflammatory Role Following their and NF-kB Cells through ( T [55] CXCR6 Infiltrating lesions and vitiligo CXCR3 into IL1- of cells Immunity T ligands Also, cytotoxic Adaptive CXCL16, of and patients. migration CXCL10 the vitiligo promote of from which expression pathway, cells the IFN- T stimulated and cells also CD8+ T in CD4+ in CXCR3 IL17A/F and IL1- through CXCR6 strengthened of is IL- cell of T synthesis CD4+ promotes and which cleavage caspase-1 mediates γ 2 nbt D+adC4 el 5] IL1- [55]. cells T CD4+ and CD8+ both in O 2 tetdkrtncts[5.Oc ciae,NR3inflammasome NLRP3 activated, Once [55]. keratinocytes -treated β/ L1 inln aha 5] IL1- [55]. pathway signaling IL-1R 5 β 5,5] usqety h ucino CD8+ of function the Subsequently, 59]. [58, β nrae h ytei of synthesis the increased β β nsrse keratinocytes stressed in iue1 Figure lvtdteexpression the elevated ). Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. r-namtr yoierqie o eaoyeseicatratv D+Tcl erimn [69]. recruitment cell interferon- T levels CD8+ high autoreactive secrete skin [68]. melanocyte-specific vitiligo explants for peri-lesional skin required from autologous CD4+ derived cytokine isolated and in cells Importantly, pro-inflammatory skin apoptosis T [68]. a vitiligo melanocyte CD4+ vitiligo and inducing pigmented of pathology CD8+ of healthy clinical of incapable autologous the were to of cells similar cells explants way T T melanocytes infiltrate a CD8+ kill in patients melanocytes melanocyte-specific to vitiligo eliminate ability by of the infiltrated skin have highly peri-lesional cells are individuals these patients healthy and vitiligo to [62], of compared skin blood their peri-lesional the in Moreover, in cells Melan- involved T CD8+ antigens recognise of are patients numbers [64]. elevated which vitiligo showed of patients in Vitiligo all cells protein, melanocyte-specific T [66]. pathway and CD8+ melanogenic (TYR) self-reactive markers tyrosinase activation infiltrating A/MART, cell 2020)[55]. T perilesional al., of et upregulation Furthermore, Li by from demonstrated keratinocytes (Adapted as in CD137 patients activation and vitiligo inflammasome CD69 in NLRP3 function TRPM2-facilitated T-cell CXCL16. stimulates and CXCL10 IFN- of and cells expression T CD4+ caspase-1 TRPM2-mediated in mediates synthesis through inflammasome IL- activated NLRP3 of be activated, IL1- synthesis also Once provoke can interaction which influx. the inflammasome cleavage as calcium NLRP3 well mitochondrial as NLRP3. and signaling intracellular of NF-kB-mediated and by activated mtROS is between keratinocytes stressed in inflammasome 1. Figure β/ L1 inln aha.IL1- pathway. signaling IL-1R ciae LP namsm nkrtnctspooe elrsossi iiio NLRP3 vitiligo. in responses cell T promotes keratinocytes in inflammasome NLRP3 Activated γ β rdcini ohC8 n D+Tcls IL1- cells. T CD4+ and CD8+ both in production umnsCC6adCC3epeso nC8 el,IL17A/F cells, T CD8+ in expression CXCR3 and CXCR6 augments β, eutn nteatvto fD+adC4 el through cells T CD4+ and D8+ of activation the in resulting 6 nvitro in 6,6,6] D+Tclsioae from isolated cells T CD8+ 68]. 67, [62, β lopooe the promotes also nvitro In γ (IFN- culture γ ), Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. n hw iepedatimnt,udriigaciia oefrTe el nmitnneo oeac to tolerance of maintenance cells in Treg cells lack Treg FOXP3 for defective role with critical strain [78]. a mouse self-antigens underlining mutant autoimmunity, widespread scurfy shows Likewise, the and [77]. in and vitiligo lack mutation CD25+ including syndrome a X-linked diseases, CD4+, of enteropathy, polyendocrinopathy, of because dysregulation, cells phenotype immuno- Treg autoimmunity. a immunological from preventing maintaining suffer represent in by who autoimmunity primarily role Patients controlling key that in a role cells playing vital self-antigens, T a to have tolerance. CD4+ They unresponsiveness peripheral of appropriate (Foxp3). maintaining P3 subgroup in box factors a forkhead key are are Depigmentation cells Inhibit cells T effector and Treg and Effectors cells (Treg) Autoreactive T of Regulatory Suppressors are Cells reverses T and Regulatory prevents action [76]. CXCL10 As vitiligo blocking in [39]. or IFN- progression CXCR3 with vitiligo out the interferes [71] induce knocking within vitiligo and as IFN- localisation in cells the IFN- lesions, depigmentation cell progression, T vitiligo produces T the and more established cells to initiation for recruit of T vitiligo compared responsible to to Thus, epidermis is keratinocytes as the CXCL10 from well [71]. in CXCL10 that shown function and signifying cells effector CXCL9 decreased, T their of is and and quantity skin skin incidence [71]. the the the unchanged the CXCL10, that is absent, in of indicating cells is dermis absence T unchanged, CXCL10 [71]. of the remains when recruitment tenfold in contrast, severity bulk by Interestingly, yet In vitiligo decreased decreased, is cells, vitiligo. are absent vitiligo during T vitiligo is of of occurs of it severity skin cells number when lesional T since reduced within of skin, of over-recruitment the cells to spite T cells in autoreactive T However, melanocyte of of recruitment bulk number and for the CXCL9 responsible are [75]. predominantly that keratinocytes cells seems showed that T CXCL9 demonstrated autoreactive mice studies of reporter functional recruitment chemokine and for employing keratinocytes, responsible by primarily Studies produced mostly 74]. are INF- [71, CXCL10 vitiligo since depigmentation of IFN- CXCR3 cause models vitiligo, of express mouse not Neutralization of in predominantly pathogenesis 74]. Studies subjects [71, in [65]. CXCR3 vitiligo development pathway vitiligo vitiligo active for blood for melanocyte- of role and essential biomarker addition, critical skin skin In specific a the a 71-73]. established from is [69, CXCL9 isolated CXCR3+ and cells primarily receptor, T are CD8+ that specific infiltrates lymphocyte prominent show ( 3 CXCL10 type proinflam- receptor of chemokine ανδ C-X-C secretion of Ρεςρυιτμεντ include their expression requires ἓλλ apoptosis increased melanocytes Τ demonstrated trigger ῝Δ8+ cells IFN- T cytokines οφ CD8+ matory which Δριvερ by mechanism Κεψ The α ας ἵτιλιγο Αςτς ιν destruction Φυνςτιον for Πατηωαψ sufficient Σιγναλινγ and essential ΙΦΝ-γ equally are lesions. cells vitiligo T in CD8+ melanocytes that of evidence robust provide findings These xrsino el rvnstemgaino uoecieTclsit h knadteeoedo therefore and skin the into cells T autoreactive of migration the prevents cells T on expression and , CXCL11 γ inligptwytruhpeeeta niiino A1adJK,sospromise shows JAK2, and JAK1 of inhibition preferential through pathway signalling γ rmC8 el 6] nlsso eeepeso nhmnvtlg einlskin lesional vitiligo human in expression gene of Analysis [68]. cells T CD8+ from 7] nareetwt hsfidn,si ipisfo iiioptetlsosalso lesions patient vitiligo from biopsies skin finding, this with agreement In [71]. Fgr 2) (Figure IFRG FOXP3 CXCR3) ned uoiii,ajnskns JK-, niio,which inhibitor, (JAK)-1,2 kinase janus a ruxolitinib, Indeed, . ee[0 1,a ela ee nue yIFN- by induced genes as well as 71], [70, gene eeada osqec ue rmohrautoimmune other from suffer consequence a as and gene elceoiercpo,adisligands: its and receptor, chemokine cell T a , 7 γ- hmkn aha sas eddfrmaintenance for needed also is pathway chemokine γ ihatbd ramn rtelc of lack the or treatment antibody with γ, hc tmltstepouto of production the stimulates which γ, XR,CC1 r all are CXCL10 CXCR3, γ n these and CXCL9 , Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. o h ucino rgi irpe nvtlg ains u ffco elpeoyei ua vitiligo human clear in cell not phenotype T self-reactive therefore cell reduce is T cells Treg It effector occurring but Naturally [88]. patients, cells. cells T . vitiligo Treg these in [85] defective in of skin disrupted pathogenesis presence decrease lesional is vitiligo the significant Treg vitiligo indicates to a also in of contributes showed number function cells, report cell the Treg Treg another how of in Treg whereas of reduction function 87], localization significant diminished cutaneous [86, no than reduced revealed that rather studies suggesting skin, Immunohistochemical skin, the the the in CD8+ to where number inhibit cells decreased to to but ability as Studies patients decreased consensus skin. vitiligo a activation showed the in no and patients to ability is vitiligo proliferation immigration from cells there or isolated T effects, but cells suppressive Treg function, vitiligo cells, peripheral Treg that cells control of reported density Treg to in of helping in lies: disruption exactly therefore cells disruption reported Treg and have of effectors number groups T the Several enhanced by that was driven theory skin depigmentation the the reducing support in for progression. findings accumulation Treg critical cell These cutaneous Treg is [83]. of PD-L1P-Fc, skin reversed number with elevated was injected depigmentation to were led and transfer mice age adoptive prone that of vitiligo revealed weeks When depigmentation report three in Another [81]. at decrease vitiligo mice [82]. a prevented skin prone and and antibodies the vitiligo infiltration cells CD25 in cells cell or induced Treg Treg CD4 was exogenous cutaneous either CCL22 of in using of increase studies depleted the expression an addition, were into the showed In Tregs cells when study Treg of [79]. One when infiltration melanocytes severity 81]. elevated against vitiligo [80, responses an in immune by increase of accompanied an prevention was the reported repigmentation in resulting vitiligo, from possibly (Adapted of skin, receptor model CXCR3 mouse the a through 10, In interferon- CXCL site produce and the 9 cells 2020)[39]. to CXCL al., lymphocytes CD8+T secrete et of to melanocyte-reactive Frisoli recruitment keratinocytes vitiligo, induce additional These of in antigens. resulting phase melanocyte progressive encountering the on gamma In loop. feedback 2. Figure rgeso fvtlg eurscniudrcuteto el hc cusvaapositive- a via occurs which cells T of recruitment continued requires vitiligo of Progression nvitro in 8] oee,aohrsuysoe omlTe elactivity cell Treg normal showed study another However, [84]. 8 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ieetatbde omlnctshv enietfida infiatyeeae eesi h eao vitiligo of sera the in levels elevated significantly at identified been have melanocytes to antibodies patholog- Different a vitiligo. for in evidence autoimmunity supportive of adds role immunity ical (antibody-mediated) [107]. humoral immunity, psoriasis cellular in [69, Besides reported skin previously perilesional cytokine- Vitiligo vitiligo as via in in flare-up, Immunity patients cells a considered Trm Humoral in during are of involved disease disease existence be stable the the may with evidenced of These patients as vitiligo relapse 106]. response, Notably, and immune [39]. continuing maintenance this cells have Trm long-term T to In that circulating the concluded of [105]. mediate recruitment cells therefore to mediated IFN- T was likely synthesise further to It are IFN- shown of cells were the recruitment cells [105]. employing of Trm reversed affected CD8+ probably absence it cells melanocyte-specific CXCL10, not the T model, autoreactive memory in was mouse model, recirculating vitiligo mouse cells vitiligo of vitiligo cytokines, maintain In Trm depletion independently producing or of [39]. skin cannot of number circulation the cells ability to from the migration efficient cells although cell and effector T vitiligo, of activity of blockade recruitment lack cytotoxic that cells in were low found Trm involved response was cells their that be immune target indicating on may the elimination, allogenic Based cells mediate tumour lysing Trm of cells More- on [104]. instead [103].Trm skin [102]. outgrowth ability cells human tumour perforin cytotoxic T inhibiting normal and memory via B from effector melanoma granzyme isolated to circulating of cells than levels Trem contexts, low poorer 2014). CD8+ other demonstrated significantly sufficiently al., of In cells et effect cells Trem (Ariotti the these CD8+ 101]. potential. over, circulation skin models, cytotoxic the [100, human low some from normal have cells In recruitment to In recirculating shown cell for are debate. T cells need effector of Trm for no CD8+ subject However, cytokines with the synthesise evoke re-infection been rapidly mainly and during has they time rapidly lesional of titres long long-term function vitiligo for expression and stimulating viral their cells tissues surface for dermis, in Trm control of candidates cell live papillary considered to known the strongly able [39]. by and are were are defined relapse cells they skin epidermis are these viruses, the As the They against reactions of [99]. surroundings; [98]. immunity CD44 after cells antigen and their tissues Trm CD49a cognate nonlymphoid patrol CD103, Resident their CD69, most encounter 97]. They [39]. within they [96, treatments persist when current skin. cells that respond by cells the T cleared suggesting T by in not long-lived lesions, driven residence is of repigmented infection that subset previously skin a or same are the inflammation the cells in (Trm) exactly role cessation T vitiligo in after a following memory that years plays year occurs showed two memory first study pigment relapse autoimmune new One Notably, the that their within relapses. lost [95]. prevent occurs (NB-UVB) to treatment B and treatment of band-ultraviolet common no narrow is is with there lesions treated date, patients vitiligo To in [94]. relapse cessation treatment repigmentation Vitiligo Indeed, of in [93]. Function [92]. response risk therapy skin their for The inflammatory the targets and the into potential Cells driving cells as T cells touted these in Memory Th1/Th17-Tc1/Tc17 been of IL- Resident cells have migration and and cells Th17 possible patients, Th17/Tc17 Th17 for suggesting vitiligo and Th1/Tc1, vitiligo, role Tc1/Tc17 in with circulating Th1/Th17, a raised patients of are implying in frequencies shown cells, skin, were decreased Th17 their Recently, of mouse Serum in A molecule [73]. elevated CXCL10 [91]. [90]. effector of is controls the role to mRNA dominant (IL-17), compared a 17 17 vitiligo with in interleukin pattern Th1-mediated increased of predominantly are levels a cells shows Th17 vitiligo. vitiligo and for of Th1 treatment model novel circulating a of Vitiligo numbers as in The function Cells cell Treg Helper improving development T the of of to potential contributes Immune-Dysregulation the cells Treg examine of to deficiency and [89]. blood how patients vitiligo, determine peripheral vitiligo reliably of of in to anergy phenotype required escape the are cells of T studies Further CD8+ analysis melanocyte-autoreactive and that anergy, indicates called cells mononuclear phenomenon a activation, and proliferation γ- hmkn aha omiti iiiolsos[0] hs Trm Thus, [105]. lesions vitiligo maintain to pathway chemokine 9 γ and Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. fmlnctsaeapiayo eodr agto h uoa muersos nvtlg.Te might They vitiligo. in response determined immune been humoral not the has of it activity Presently, target antigen-presenting secondary cells. on the T or ICAM-1 enhancing cytotoxic primary [133]. and for By a function targets HLA-DR are melanocyte [134]. become of melanocytes the they melanocytes expression way, if affect from this the could IL-8 in the induce activity of melanocytes of this to of release function how able the the or are and block or if antibodies melanocytes extent to known disease (69%) anti-melanocyte demonstrated not to 9/13 were IgG is related from MCHR1 Moreover, it not However, sera against was antibodies model, [133]. this patient epidermis receptor although Vitiligo reconstructed melanocytes, a of [141]. detachment In activity the [132]. induced patients destruction vitiligo melanocyte induce to shown 140]. 133, vivo demonstrated [131, In been cytotoxicity has cellular melanocytes antibody-dependent destroy and to cytotoxicity antibodies complement-mediated vitiligo-associated of anti- ability regulates down The cell Vitiligo and in B skin Autoimmunity and the of activity in Mechanisms lymphocyte cell Pathogenic [139]. T Langerhans antigens of suppress melanocyte number which vitiligo-associated the corticosteroids, of reduces topical Phototherapy, expression works patients do [138]. calcineurin vitiligo cofactor as responses gene-activating in 137], body cytokine [13]. observed blocking [136, vitiligo by Repigmentation in vitiligo cells process T in [135]. immune-mediated dam- suppresses lymphocyte an melanocytes destruction that B of against reagent cell notion or a response Au- Tacrolimus, T the immune T supports an as the vitiligo. treatments from such immunosuppressive at in or receiving mechanisms, antigens, immunity dysregulation cell other it humoral immune pigment Presently, by the to to [134]. aged of tolerance susceptibility cells of target genetic lack T secondary a with affects cytotoxic level, or from this for primary arise target if might a a known toantibodies are them not (ICAM- make molecule-1 is melanocytes may adhesion it whether intercellular antibodies though unclear and anti-melanocyte receptor, HLA-DR by the of induced expressed of 1) Melanocyte function Melanin- [133]. the 132]. function block [131, melanocyte 1 cytotoxicity melanocytotoxicity cellular receptor Rab27A of antibody-dependent hormone protein by capable concentrating GTP-binding and are and cytotoxicity antibodies protein complement-mediated P by Vitiligo-associated OCA2-encoded receptor, data). 1 (unpublished melanocortin Rab38, b, protein protein protein heat-shock GTP-binding melanoma hydroxylase, 2, tyrosine identified factor 1, has translation-initiation against technology γ- receptor enzyme, display sera, antibodies hormone ubiquitin-conjugating Phage patients’ organ-specific melanin-concentrating osteopontin, vitiligo [127]. circulating 90, in antigens as common melanocyte of such are variety major targets glands, promise as A other adrenal shown recognised and not has [126]. thyroid are surface, patients cells, these cell islet though vitiligo B pancreatic in the cells, trial on parietal response, expressed gastric clinical autoantibody protein this small CD20 Considering a against [123-125]. in L-dopachrome directed prevalence as low monoclonal such de- pathway a a melanogenic extensively at rituximab, the been albeit of have PMEL, proteins protein, other TYRP1, against melanocyte-specific tautomerase, and antibodies on a autoantigens 88, have tyrosinase, expressed as melanocyte-associated 70, Various against [120-122], preferentially 65, tected Antibodies 45, are [119]. of proteins melanocytes reported. targets in kDa been 150-kDa, 150-kDa, antibody expressed have 90- and vitiligo and specifically 75, and identified 90 are 40-45, 35 have of which 75, the reports those 110-kDa, 45, other including whereas to Additionally, proteins, antigens, these 40 [118]. tissue of 35, melanocytes common Some pa- of be [117]. vitiligo weights surface to molecular in cell appear with the antibodies antigens on that found to shown being directed [116]. these have frequently detected extracts subclasses most been protein are also including have tients melanocyte [111], antibodies using class anti-melanocyte studies (IgG) IgA Immunoprecipitation though G [115], immunoglobulin IgG3 ( the and loss to IgG2 (5-10% pigment belong IgG1, depigmentation minimal antibodies extent wider with with anti-melanocyte the patients patients These with of of 50% associated 93% only directly in in are present and being levels [114]. involved) 113], their area 112, and skin [109, [108-111], of vitiligo controls of healthy activity to and opposed as patients enolase, h diitaino g rmvtlg ainsit ua kngatdot uemc a been has mice nude onto grafted skin human into patients vitiligo from IgG of administration the , α- nls n ai 1810,a ela ornvlatatgn lcpoennon-metastatic glycoprotein autoantigens novel four as well as [128-130], A lamin and enolase 10 < %o knae involved) area skin of 2% nvitro in nvitro in and yboth by nvivo in Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. mueratvt gis ainn eaoacls seilyC8 el,i huh opa rtclrole critical a play to thought is cells, the T unclear, CD8+ the still especially Although is cells, vitiligo melanoma melanocytes. malignant melanoma-associated of malignant against growth reactivity of uncontrolled immune pathogenesis from the resulted in cancer implicated skin mechanism exact of type a [76]. is vitiligo melanoma Malignant in depigmentation reverses Vitiligo and prevents Melanoma-Associated IFN- action of Malignant CXCL10 levels lymphocytes, blocking high T or show CD8+ CXCR3 vitiligo, autoreactive out of melanocyte-specific Knocking model of increased mouse IFN- recruitment through a of cutaneous skin and and the vitiligo patients for human in required IFN- Both disrupted to cytokine is [155]. response adhesion cells in the pigment keratinocytes melanocyte of by the that growth lesions produced Expression shown fibroblastic vitiliginous MMP-9, in basic been of levels factor, has [153]. levels lower at cell it cytokines expressed stem Recently are interferon Th1/Th2 endothelin-1, factor [154]. (IL-2, as stimulating of monocyte-colony such 1 ratio granulocyte mediators (Th) and higher melanogenic factor helper of a variety T [151, with a of recruiter whereas elevation examined, basophils TNF- of patients and cytokine revelation vitiligo pro-inflammatory the lymphocytes, 44 by T all to neutrophils, of added IL-8, been synthesis leukocyte–melanocyte of has receptor, increased facilitate (IFN)- levels this IL-2 have could Recently elevated soluble as which melanocytes of reported, as 152]. on levels been well expression have serum as ICAM-1 Elevated patients, induces interaction, vitiligo cytokine [150]. in a skin IL-6, activity vitiligo of disease in with shown correlated which been Pathogenesis has Vitiligo imbalance in [38]. Cytokine as cells Role formation islet their neo-antigen beta and untransformed in These Imbalance in involved Cytokines [38]. neo-antigen been splicing generating ability mRNA have in alternative the processes implicated and have oxidation are not biochemical cells citrullination, do processes T Several carbanylation, melanocytes deamidation, self-reactive untransformed as However, [39]. such since immunogenic DNA well [149]. vitiligo, highly is their generation in of Melanoma neo-antigen mutate proteins formation mutated in to the [148]. target result to neo-antigens to that leads unlikely target mutation This neo-antigen are that DNA cells [148]. called receptors somatic epithelial proteins proteins high-affinity thymic to such owing modified since synthesise with risk not them, cells that significant do against T suggests education a response self-reactive hypothesis cell immune confer T One an presentation for stimulating antigen responsible immunogenic [147]. in extremely vitiligo implicated be of are can development that autoimmune induce skin the Genes may perilesional requires for which from this melanocytes. abnormalities Melanocytes and histological against details. clear, and in yet reaction physiological involved not mechanism demonstrates is exact patients cancer eliminated the vitiligo unveil of are of to that vitiligo order from in in differ communicate melanocyte several studies may they how further how vitiligo fact, Therefore, and autoimmune and cells In cells. in ligand, T mechanism viral-infected by as killing or used F cell-mediated [146]. selectively whereas and are T pathways granzyme Additionally, process cells, these perforin, how [145]. alternative virus-infected via unclear slower-acting or currently killing mainly is cell cells cells as it T T therefore cancer cytotoxic cytotoxic act granzyme, destroying promote that may pathways believed perforin, of signaling is mechanism as intracellular method It such killing fast-acting [145]. proteins as ligand-driven cells effector target granzyne Fas cytotoxic destroy and to Several used perforin once mechanism understood. be exact use that can fully the cytokines but clear, not CD8+ and is T-cells, is immunotherapy cytotoxic ligand Fas melanoma for use as and potential cells such vitiligo the both these cause While in that immune melanocytes melanocytes. might another eliminate vitiligo to to from in destructive cells antibodies themselves T melanocyte cell are pigment the antibodies addition, of the In cell destruction triggered 144]. the [143, to on antibodies expressed secondary by be accessible be can be PMEL can and so lack TYRP1 and antigens surface to melanocyte immune [142]. leading intracellular an mechanism level, normally from other the lymphocyte originate Interestingly, some B might by antibodies or damaged vitiligo T Alternatively, melanocytes the [142]. against at antigens response dysregulation cell pigment immune to to tolerance susceptibility of genetic a from arise γ, TNF- γ- nue yoieCC1,adisrcpo XR,fudo uoecieC8 el [71]. cells T CD8+ autoreactive on found CXCR3, receptor its and CXCL10, cytokine induced β ,T2(L4 L5 L1,I-3 n h7(L1,I-3-naectknsi h serum the in cytokines IL-23)-innate (IL-17, Th17 and IL-13) IL-10, IL-5, (IL-4, Th2 ), α ssgicnl lvtdi einladpr-einlvtlg ain skin, patient vitiligo peri-lesional and lesional in elevated significantly is 11 γ n TNF- and α, n itrigEcdei on E-cadherin disturbing and γ, the Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. al :Asmayo ee soitdwt ucpiiiyt vitiligo to susceptibility with associated genes of summary A anti-melanocyte 1: an Table facilitating vitiligo, in autoantigens vitiligo as as 124]. recognised identified [122, proteins been response or have autoimmune enzymes genes function several for melanocyte genes, include encode in regulatory involved genes These immune and to melanocytes loci. addition in In susceptibility expressed [168]. leucine-rich-repeat only NACHT studies are as association that such genome-wide immunity, innate in in found role been a play ( that 1 genes protein with vitiligo 22; protein; of repeats type association An dipeptide non-receptor acid immunity phosphatase devel- arginine–glutamic adaptive tyrosine and of cell activation) protein mediators T lymphoid have key autoreactive cells), also studies T are to association that lead Genome-wide genes can regulatory GZMB [60]. immune This other population as of Tregs 2012a). such subset result effective al., a ultimately produce et reported that pathways to also (Jin several failure by recognition that and/or elucidated self-antigen shown opment be in have can studies disorders, disruption autoimmune Several in other and susceptibility [147]. associa- vitiligo, vitiligo proteins Genome-wide immune-regulatory and to encode melanocyte-specific contribute genes [166]. encode susceptibility loci factors remainder vitiligo Mendelian multiple rate non-genetic of the a concordance half of show while The approximately involvement not proteins, that [147]. suggesting revealed does loci have vitiligo 23%, susceptibility vitiligo studies multiple of However, is tion with 15-20% twins polygenic [165]. histories: monozygotic the relative family is in first-grade of but affected examination inheritance, simple one of mechanism a least from at obvious have [164]. is patients response vitiligo of the in treatment maintain involvement during and Genetic vitiligo predict to of indication Development clinical Factors [164]. a Genetic patients in as have these used lesions and in be Vitiligo-like factor levels survival can prognostic their longer melanoma vitiligo. good malignant and a a melanoma-associated as low with malignant considered correlated are without cell-mediated are been immunotherapy and antibodies via receiving destruction with melanoma-related patients of patients melanocyte malignant melanoma eradication malignant after in of the response differ titres both immune not to serum secondary do crucial the a are Furthermore, as melanoma cells malignant T arise in effects. driven CD8+ to antibodies Thus, cell-mediated, likely Melanocyte-specific be response. are vitiligo. humoral of to patients pathogenesis a suggested the by is and not melanoma damage and malignant response cells melanocyte to immune T crucial the causes are Therefore, CD8+ which cells by cells vitiligo. patients T of CD8+ T melanoma pathogenesis [162]. Thus, the CD8+ malignant immunotherapy and [163]. in with melanoma patches with malignant vitiligo packed treated of idiopathic eradication are to are the immunotherapy similar malignant both who melanocytes, melanoma malignant by patients to regulate malignant such specific triggered to are by 4% commonly that thought initiated about are is patches in cells vitiligo vitiligo these occurs Notably, New-onset and this [161], and [145]. strategies therapy, both cytolysis tumor melanoma of autologous perforin-dependent effectiveness infiltrate via the that in melanoma cells vital T is expands cells. cells which therapy, T T cell CD8+ adoptive with with and interfere vivo studies which tissues, ex associated melanoma inhibitors, in checkpoint is tolerance Malignant T-cell cell efficacy blocking T involves and enhanced sera. melanoma Following tautomerase malignant patient melanoma, [160]. for cells dopachrome malignant melanoma Immunotherapy T CD8+ metastatic malignant TYRP1, self-reactive by for some [158], recognised immunotherapy were in malignant tyrosinase specific-antigens melanocyte found and to these that been melanocytes reactive showed have both antibodies [159] by Indeed, response Pmel17 expressed immune from antigens cells. arise melanoma-associated may melanoma vitiligo malignant melanoma-associated against Malignant directed 157]. [156, development vitiligo in cttxct fTcls,frha o rti P3; protein box forkhead cells), T of (cytotoxicity o hrpui eneto nomlnm ains[9.Ipraty uorifitainwt CD8+ with infiltration tumour Importantly, [39]. patients melanoma into reinjection therapeutic for CD80 NLRP1 atvto fTcls,cttxcTlmhct antigen-4; lymphocyte T cytotoxic cells), T of (activation ,itreo-nue eiaeCdmi ( 1 domain C helicase interferon-induced ), TYR , PMEL Tbe1) (Table eaootn1rcpo ( receptor 1 melanocortin , 12 FOXP3 nosre soito ewe L types HLA between association observed An . IFIH1 RERE dvlpetadfnto fregulatory of function and (development n aps- ( caspase-7 and ) PTPN22 rglto fcl ppoi)[167]. apoptosis) cell of (regulation CTLA4 MC1R dw-euaino cell T of (down-regulation ihbto fTcells), T of (inhibition ), OCA2 CASP7 19.Such [169]. ,hsalso has ), Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. ln lshodlnsi emna ilg,adteocsoa bevto fatu emtmlappearance, dermatomal true 204]. distribution a [167, the of areas observation included producing trigeminal occasional involvement from dysfunction the the neural released and in autonomic towards vitligo, by catecholamine e.g. pointers segmental or through Clinical in lines melanocytes vitiligo blaschkoid 204]. to in along [203, cytotoxic role destruction be a cell might have pigment which to endings thought nerve originally epidermal were elements Neuronal Theory Neuronal Function genes Metabolism-related function Melanocyte Protein Gene regulatory Immune- HLA Type RNASET2 RERE LPP EDN-1 CAT ZMIZ1 TYR PMEL OCA2 MC1R FOXD3 XBP1 UBASH3A TSLP TOB2 SLA SH2B3 PTPN22 NLRP1 IL2RA IKZF4 IFIH1 GZMB FOXP3 FOXP1 FASLG CXCR5 CTLA4 CLNK CD80 CD44 CCR6 CASP7 C1QTNF6 BACH2 III class HLA DQA1 and HLA-DRB1 ACE ASP AIRE HLA–A 13 aaaePoet el rmoiaiesrs ybekono yrgnperoxide hydrogen regulator of stress breakdown Oxidative by stress oxidative function from and cells growth Protects melanocyte of Regulator melanogenesis of co-activator Regulator Potential transporter Melanosomal melanocytes of survival and function development, Regulates development melanoblast of Regulator apoptosis cell melanogenesis Regulates of Regulator premelanosomes of II organization class tolerance Structural complex cell histocompatibility T major in Involves of Regulator signalling receptor antigen Regulates cells T2 protein T Ribonuclease repeats and dipeptide cells cells acid dendritic killer Arginine–glutamic skin natural lymphocytes of and T maturation partner lymphocytes and of Lipoma-preferred T B regulator cytotoxic of Cytokine of Development contribution Endothelin-1 with death cell immune-induced Catalase of process 1 the type Mediates MIZ activation protein cell finger T Zinc Regulates Tyrosinase apoptosis immune PMEL Regulate protein Melanocyte-specific cells T regulatory system gene immune of OCA2 innate cells function receptor Regulates T and 1 development regulatory signaling Melanocortin Regulates Regulates development receptor cell D3 cell B box T Forkhead Regulates Suppresses response immune development 1 protein innate cell protein A Regulates inflammation T X-box-binding domain–containing and in SH3 Involves apoptosis and of Ubiquitin-associated protein Executor lymphopoietin stromal migration activationThymic lymphocyte cell B T in TOB2 of Involves Protein regulation Negative cells T Src-like-adapter [168] of 3 22 Inhibition cells protein type dendritic adapter non-receptor immunity and SH2B phosphatase and lymphocytes tyrosine tolerance T protein between and Lymphoid balance B 1 the of protein controlling function leucine-rich-repeat by and NACHT disease cells differentiation alpha inflammatory T Regulates subunit prevents of receptor that activation Interleukin-2 differentiation Eos Co-stimulates T-cell protein signalling CD4+ finger immune-receptor 1 of Zinc regulates domain regulator Positively C key helicase a Interferon-induced is which cells, B B Granzyme of P3 repressor protein transcriptional box a Forkhead P1 encodes protein repressor box transcriptional Forkhead cell B ligand 5 FAS production type cytokine receptor and chemokine inflammation C-X-C in 4 Involved protein T-lymphocyte Cytotoxic linker cell hematopoietic Cytokine-dependent CD80 expression antigen IL-10 activation monocyte T-lymphocyte Induces antigen CD44 6 receptor Chemokine-cytokine 6 system protein immune factor-related Caspase-7 the necrosis to tumour presentation C1q antigen Complement Peptide BACH2 protein regulator Transcription antigen DQA1 histocompatibility and III DRB1 class antigen, HLA histocompatibility II class HLA nitni-ovrigezm euao fiflmainadbodpressure blood and inflammation of Regulator MC1R via regulator Melanogenesis enzyme Angiotensin-converting protein signalling Agouti tolerance immune of Maintenance system immune the to presentation antigen Peptide regulator Autoimmune A antigen, histocompatibility I class HLA [174] [171] [171] [202] [199-201] [198] 197] [174, 196] [171, [169] [168] 194] [168, [195] [194] 193] [182, [171] [182] [168] [168] [168] 187-192] [171, 184-186] [42, 171] [169, 169] [168, [168] 183] [171, [182] [181] [180] [169] [177-179] [168] [168] [168] 174] [171, [168] [171] 176] [175, [174] 173] [171, [170-172] References Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. .A bde ..adDJ akogr nertn ernlivleetit h mueadgenetic and immune the into involvement neuronal Integrating Gawkrodger, D.J. and M.S. 2016. Abadie, F1000Res, vitiligo. Al understanding 3. in advances Recent Orlow, S.J. Global and Vitiligo 2234. Elbuluk, the N. P., issues: 2012. Manga, related Res, 2. and Melanoma vitiligo Cell of Pigment classification/nomenclature Conference. Revised Consensus al., Issues et T K., anti-melanocyte Ezzedine, investigation. autoreactive 1. further of merits existence that the play scenario indicate antibodies a References might that melanocytes, but possible destroying is vitiligo, of consequence, it of capable lym- However, In are pathogenesis T vitiligo. clonal [216]. aggravate cells CD4+ the further autoreactive evaded epitopes in activated to which cryptic part by act stimulation cells, against no then cell may tolerised T B which autoreactive been autoreactive [216], following not either phocytes secreted have to be which presented can cells, — be processing antibodies na¨ıve Following T proteins can to [215]. cell proteins or apoptosis pigment antigenic deletion, during intracellular occurring cells, other against modification by dendritic directed protein damage and by melanocyte observed epitopes of been result cryptic have a of as exposure autoantibodies secondarily ul- when occur immune that may as inappropriate immunity responses adaptive underlie factors, immune activate may autoimmunity but turn is to vitiligo, in said predisposition which in genetic be resulting cells, responses A immune melanocytes, can innate in melanocytes. What elicit targets responses that timately elucidation. stress with DAMPs instigate interacts considerable of synthesis defects genetic requires the cell-intrinsic the still in and which system factors by environmental immune interven- modus both the pharmacological exact that targeted with the However, permit and to environment, steps. vitiligo immunological the of appropriate pathogenesis the the at about tion understood now is Sufficient Prospects and Conclusion cellular antibody-dependent by response and or in 133]. complement response activating generated [122, by tyrosinase, immune cytotoxicity cells as pigment on-going such damage proteins the destruction, melanocyte-specific melanocyte to against to contribute Antibodies Tregs [86]. and skin-infiltrating 166]. spread cells disease 135, fully-functional T [54, cytotoxic reduced activation melanocyte-specific or immune of Absent of proliferation in stage resulting the nodes, — lymph dendritic destruction within regional by make-up stress melanocyte presented in oxidative genetic antigens, cells in melanocyte whose T result chaperoned to individual proposed and cells an is HSP70 mechanical in express it factors, subsequently destruction, factors, to which neural melanocyte Such melanocytes due endogenous and 211-214]. activation in perhaps immune 206, imbalances to stage or [5, predisposes hormones exposure elicitation chemical or an stresses, cytokines with emotional metabolites, suggests trauma, beginning It skin pathogenesis [210]. and vitiligo in friction of mechanisms stages causal potential sequential the together multiple link to attempts theory convergence The the Theory in and Convergence account neuropeptides into systems, taken [209]. neuro-endocrine be vitiligo and to (Tc)1 of neural need cell causation the systems, T Th1/cytotoxic immune Hence, the the [208]. alter with vitiligo can interacting destruction and in neurotransmitters, melanocyte skewed polypeptide, to intestinal is central vasoactive as that by seen balance induced cells, local be Treg cells, a system can provoke dendritic 207]. could immune vitiligo, cells, [206, melanocytes, in to the destruction NK to led melanocyte next cells, on release and This T ending effects reaction including nerve immune [205]. has from cells patches released active which macrophages, vitiligo immunologically and Y, several of granulocytes, Changes on neuropeptide margins located 205]. potentially the receptors [203, at neuropeptides, through half evident a that are in postulation damage Y, axonal cells the neuropeptide Schwann and with notably instances cases, of neuropeptides, of 75% 42% in in in nerves membrane cutaneous basement fine thickened of showing degeneration shows skin vitiligo Ultrastructurally 14 25 3:p E1-13. p. (3): 5 p. : Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. pdri fptet ihvtlg n t ucsflrmvlb V-ciae suoaaae Investig J pseudocatalase. UVB-activated the a in by accumulation removal (H2O2) successful 1999. peroxide hydrogen its Proc, for and Symp evidence vitiligo Dermatol vitro with in patients double-blind and vivo of a In epidermis vitiligo: al., of et treatment K.U., Schallreuter, 2007. the 22. Dermatol, in Exp band-UVB narrow Clin and addition trial. Antioxidants controlled the al., by placebo 1989. et corrected Res, M.L., partially Dermatol Dell’Anna, subjects be Arch vitiligo 21. can vitro. from and in culture subjects in factors repigmenting melanocytes growth of in fibroblast-derived defects vivo of Growth from in Ramaiah, corrected obtained A. spontaneously melanocytes and are of Mojamdar, 1987. M. characteristics N., Dermatol, growth Puri, Invest vitro 20. J In subjects. Ramaiah, vitiligo A. and and normal Invest, Mojamdar, Lab adult M. site. N., perilesional the Puri, Destruction at patients. 19. cells vitiligo T generalized CLA+ of of skin histopa- presence in prominent with the response 2000. : with immune associated diseases Local is al., skin melanocytes et common of R., 101 Wijngaard, den of van atlas Scribendi. 2000. 18. Ardor clinical Pathol, S´anchez, York: J A New J. vitiligo. 2000, and duration correlation. Kerl, long thologic H. of skin A.B., Ackerman, lesional in 17. absent not 2020. are Drugs, Melanocytes Emerg al., Opin 191 et Expert D.J., vitiligo. Tobin, of 16. treatment the for drugs 7-24. Emerging p. 2004. al., (1): Res, et Cell P., Pigment Karagaiah, vitiligo. 15. contact/occupational treatment of etiology the the 208-14. on On p. Manga, impact (3): P. 2015. its and Lancet, R.E. and Boissy, The 14. vitiligo Vitiligo. in al., et score K., Index Ezzedine, Quality 13. Life 2003. Dermatol, Dermatology J al., Br et outcome. D., Dermatol, Acad Parsad, life, Am 12. of J quality epidemiology, work-up. Introduction, and J I. etiology, Part patients. histopathology, overview 2011. urticaria associations, comprehensive chronic diagnosis, a and Vitiligo: differential vitiligo al., diagnosis, of et A., functions Alikhan, sexual 11. in problems 2007. inter- The patient-physician Ther, Maner, the Marital F. of Sex and importance M. the Sukan, vitiligo: 10. to patients of 1978. responses Dermatol, Personal Arch Outcomes, al., action. Life et Qual J., Health vitiligo. Porter, with 9. patients in expe- life the of Quality vitiligo: Kanwar, of A.J. and 2003. impact 2009. Dogra, psychological Dermatol, S. the D., J Parsad, in Br 8. factors centre. referral subjective French vs. a Objective from 2009. al., rience Dermatol, et P., Bras An Kostopoulou, emotions. 7. and Vitiligo Azambuja, 41-5. R.D. p. and (1): Zancanaro, P.C. Dermatol, Acad L.S., Am Nogueira, J 6. analysis. incident critical 2016. a One, vitiligo: Plos of effects meta-analysis. Psychologic 1996. a Al’Abadie, M. vitiligo: and of G. Kent, Prevalence 5. The al., 10.1111/ced.14490. et doi: Y., p. Zhang, 2020: 4. Dermatol, Exp Clin vitiligo. of paradigm 4:p 407-16. p. (4): 80 65 1 35 .58. p. : 8:p 1299-309. p. (8): 473-91. p. (3): 895-8. p. (6): 33 1:p 55-64. p. (1): 4 114 1:p 91-6. p. (1): 148 9:p 1384-5. p. (9): 2:p 373-4. p. (2): 32 386 15 6:p 631-6. p. (6): 98) .74-84. p. (9988): 161 88 1:p 128-33. p. (1): 4:p 434-438. p. (4): 281 3:p 178-84. p. (3): 11 9:p e0163806. p. (9): 25 17 84 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1 os .. ta. etsokpoen7 xrsini iiioadisrlto otedsaeactivity. disease the to relation its and vitiligo in expression protein-70 shock 2016. Heat 2012. Dermatol, in al., Dermatol, J. response Invest et Indian protein J R.W., unfolded IL8. Doss, the and Annu activate 41. IL6 phenols of treatment. Vitiligo-inducing upregulation Manga, and P. in pathogenesis and resulting of Orlow, melanocytes S.J. mechanisms S., Toosi, Vitiligo: 40. Harris, J.E. and 2020. Essien, Immunol, K. Rev M.L., Frisoli, 2018. 39. Diabetes, tolerance. of of recognition Immune loss Mamula, the M.J. and in Pietropaolo, melanoma. M. cutaneous E.A., human James, 38. in (TYRP1/gp75) 1 protein oxidative 2011. related Tyrosinase Oncol, from Fabrice, Mol vitiligo: J. clinical and of and G. pathogenesis experimental Ghanem, the 37. of in journal advances medical new international of : 2019. Perspectives monitor research, Li, science Medical C. autoimmunity. and to Li, Dermatol stress S. J autoimmunity? Y., trigger Wang, autoantigens 36. Invest stress-induced oxidative J do processes? how 6BH4-dependent Vitiligo: 2016. al., Sci, all et of H., regulation Xie, 35. in mechanism general recycling a (6BH4) 2001. tetrahydrobiopterin of Dermatol, alters identification accumulation H(2)O(2) vitiligo: Epidermal 2009. in al., Leprol, et Venereol K.U., Schallreuter, Dermatol 34. and J dismutase Indian superoxide skin. measuring by non-vitiliginous vitiligo and in 268-71. vitiliginous stress in oxidative 2017. of levels Clin, Determination catalase Dermatol al., et treatments. P.V., emerging Sravani, 33. and stability pathogenesis determining Vitiligo in 257-65. microscopy Harris, p. confocal J.E. (2): reflectance and vivo 2013. M. in Dermatol, Rashighi, J of 32. Indian Role study. en- Xu, preliminary following A.-e. a and skin vitiligo: Wang, of in S. Repigmentation W., hypomelanosis. Li, guttate 1989. 31. Dermatol, idiopathic Arch and Wilkins:): mice. Vitiligo & nude al., onto Williams graftment et Lippincott 2005(D. Philadelphia, A., Murphy. Skin, Gilhar, F. the 30. G. of and Histopathology Johansson Lever’s L. skin. 705-713. B. the p. Elenitsas, of J R. disorders Br Elder, Pigmentary picture. E. GR., the R.a.K., clearing Spielvogel, vitiligo: 29. for of B ultraviolet expression narrowband abnormal 2009. and and Dermatol, Pseudocatalase stress D.J., oxidative 2001. Gawkrodger, to Dermatol, 28. melanocytes J of Br mela- sensitivity vitiligo. of Increased in factor protein al., pathogenic tyrosinase-related et possible a Exp K., 1997. as Jimbow, vitiligo. Dermatol, agents 27. Invest in peroxidative J to stress vitiligo. sensitivity oxidative in Increased damage supports al., nocyte further et V., allantoin Maresca, epidermal 26. in of degeneration Presence melanocyte al., for 2008. et basis Dermatol, M., possible a Shalbaf, as 25. alterations 2007. lipid Dermatol, Membrane Invest al., J normal vitiligo. et from M.L., obtained Dell’Anna, melanocytes 1990. human 24. Dermatol, adult Invest of J culture donors. Successful Nordlund, vitiligo J.J. and and E.E. Medrano, 23. 81 1:p 3-9. p. (1): 25 17 116 161 5 .1017-1023. p. : 9:p 761-70. p. (9): 2:p 150-55. p. (2): 38 1:p 167-74. p. (1): 721-2. p. (4): .621-648. p. : 61 4:p 408-412. p. (4): 127 5:p 1226-33. p. (5): 67 6:p 1035-1042. p. (6): 95 4:p 441-5. p. (4): 125 109 16 1) .1363-6. p. (10): 3:p 310-3. p. (3): 58 144 6:p 429-32. p. (6): 1:p 55-65. p. (1): β- el:noptpsa e players key as neoepitopes cells: 132 1) .2601-9. p. (11): 75 3:p. (3): 35 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 0 peket .adN a el iiio nudt nptohsooyadtetetotos mJ Am options. treatment and pathophysiology on update an Vitiligo: Geel, van 2017. Dermatol, N. Clin and converting interleukin-1beta R. by Speeckaert, mediated 60. factor inducing interferon-gamma of 1997. Activation Science, al., enzyme. et interleukin-1 Y., for Gu, required 59. is protease cysteine 1992. heterodimeric Nature, novel A monocytes. 2011. al., in Nature, et N.A., activation. Thornberry, inflammasome NLRP3 58. in mitochondria for license role 221-225. A receptors al., p. et cytokine R., and Zhou, Md. (Baltimore, recognition 57. immunology pattern of Journal activating 2009. expression. NF-kappaB 1950), 2020. NLRP3 : al., regulating Immunol, by et activation Clin inflammasome F.G., Allergy NLRP3 J Bauernfeind, keratinocytes in vitiligo. 56. inflammasome with (NLRP3) patients 3 containing in domain pyrin response 632-645. family T-cell NLR Activated cutaneous al., promotes et S., 2011. Li, Acad Dermatol, autoimmunity55. Invest Am T-cell J J potent autophagy. 1240-51. induces melanosome vitiligo. monobenzone and p. agent haptenation of (6): Skin-depigmenting tyrosinase classification by al., cells et and pigmented J.G., pathogenesis toward Boorn, the den van in 54. discoveries J New al., swine. Sinclair et 2017. in M., Dermatol, lesions Rodrigues, vitiligo repigments 53. DNA HSP70i(Q435A)-encoding al., 2018. non-segmental 2008. et Dermatol, Venereol, in Invest S.W., Dermatol receptors Henning, Acad cell killer Eur natural 52. J inhibitory study. and atopic cytometric activatory and flow of psoriasis, a Evaluation defense, al., host vitiligo: skin et P.Y., in Basak, receptors Toll-like 51. of role 2019. stress. The Res, under Zhang, Immunol L.J. melanocytes J and vitiligo Liu, dermatitis. by W. L., HSP70 Sun, inducible cell- 50. of dendritic secretion 2014. to Res, Preferential melanocytes Melanoma vaccine al., Cell human et tumor Pigment sensitizes J.A., 2005. a Dermatol, exposure Mosenson, as Invest phenol acting J 49. butyl TRP2 vitiligo. 4-Tertiary with to al., relevance Hsc70 et killing: of mediated T.M., domain Kroll, ATPase of 48. 2006. protein Lett, Fusion Immunol al., melanoma. et B16 Med, Transl against H., Sci Zhang, vitiligo. in J 47. depigmentation autoimmune vitiligo. reverses autoimmune HSP70 of Mutant al., model 2013. et mouse J.A., a Mosenson, in 46. depigmentation accelerates HSP70i 2008. al., Dermatol, et Invest vitiligo C.J., in immunity Denman, from innate 2012. activated danger 45. ONE, aberrantly PLoS of vitiligo: markers skin. in reveals non-lesional analysis mechanisms and Transcriptome al., immune lesional et Innate R., Yu, Harris, 2013. 44. J.E. A, 2013. increase and Immunol, S Frisoli, autoimmunity Opin U Curr M.L. and Sci within. J.M., vitiligo Acad Richmond, with Natl 43. Proc associated haplotypes inflammasome. NLRP1 NLRP1 2952-6. al., the p. via et processing C.B., interleukin-1beta Levandowski, 42. 5 14:p 174ra28. p. (174): 183 77 2:p 787-791. p. (2): 1:p 1-13. p. (1): 138 275 128 1) .2531-2539. p. (12): 59) .206-9. p. (5297): 356 8:p 2041-8. p. (8): 67) .768-774. p. (6372): 2019 25 27 6:p 676-82. p. (6): 2:p 209-20. p. (2): .1824624. p. : 105 2:p 167-73. p. (2): 7 1) .e51040. p. (12): 17 124 4:p 798-806. p. (4): 22 8:p 970-6. p. (8): 145 469 β processing 110 (7329): 2:p. (2): 131 (8): Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 b,JM,e l,Imn epne namuemdlo iiiowt pnaeu pdra e and de- epidermal spontaneous with vitiligo of Exp model J mouse a disease. 2014. in scurfy-like Res, responses Melanoma a Immune Cell induces Pigment al., cells et repigmentation. T J.M., Clin regulatory Eby, Foxp3+ Allergy 79. of J depletion treatments. Selective novel al., 2007. to et Med, lead K., insights Lahl, vitiligo mechanistic coexistent 78. Vitiligo: with patient Harris, a J.E. in 2017. and Immunol, ruxolitinib M.L. 2016. oral Frisoli, Dermatol, on Acad 77. repigmentation Am skin J (AA). Rapid 2017. areata Dermatol, al., Invest alopecia et J and J.E., epidermis disease. Harris, the of in biomarkers 76. 2012. positioning as IFN- T-cell serve Dermatol, orchestrate requires may Invest chemokines and depigmentation Keratinocyte-derived J vitiligo epidermal al., during et focused J.M., skin. with Richmond, the vitiligo 75. in of accumulation model T-cell mouse CD8(+) A 1869-76. autoreactive al., CXCL10 and for et 2016. vitiligo Dermatol, gamma J.E., with vitiligo. J patients Harris, in Br in ligands response vitiligo. its 74. immune for and marker the CXCR3 clinical of of potential expression initiation Increased a the al., as a et in X.X., in signature Wang, depigmentation interferon 73. of I 2014. maintenance Type Res, and al., Melanoma progression Cell et Pigment the A., for Bertolotti, 2014. Med, critical Transl 72. is Sci CXCL10 messenger vitiligo. skin al., of and et model 2004. responses mouse M., Dermatol, therapeutic Rashighi, Acad vitiligo: Am J 71. for J therapy CXCR3. cytokines. tacrolimus expressing proinflammatory Topical cells of al., T expression et CD8 RNA P.E., memory Grimes, resident from with 70. cells imprinted is T skin perilesional Vitiligo 2018. by al., Dermatol, melanocytes Invest et skin K., of Boniface, destruction 69. 2009. Autoimmune Dermatol, al., Invest et cellular J of J.G., patients. role tyrosinase Boorn, vitiligo 2001. the Melan-A/MART1, den Dermatol, tetramers: Invest van against complex/peptide J responses 68. histocompatibility vitiligo. lymphocyte major of of T etiopathogenesis use the cytotoxic the in Specific by immunity vitiligo al., in et 2010. gp100 Res, and B., Melanoma events Palermo, Cell dynamic Pigment early 67. nevi. of halo analysis with immunophenotypic associated and vitiligo histopathological segmental 375-84. First with of al., patient biomarkers et a useful N.A., in reveals patients Geel, van vitiligo of 2017. au- 66. skin Dermatol, in lesional Acad parallels lymphocytes the Am blistering T skin J Suction activity. cytotoxic vitiligo al., disease melanocyte-specific et inflammatory J.P., skin-homing Strassner, in of 65. 1998. macrophages frequency Med, and High Exp al., J cells et vitiligo. T is toimmune G.S., of type-1-like Ogg, Presence to 1996. 64. al., cells Pathol, et J T Am I.C., CD8+ disappearance. Poole, and 2003. melanocyte Invest, Le CD4+ Lab of vitiligo. 63. human Immunopolarization in 1993. al., loss Pathol, melanocyte et J with vitiligo. A., associated in Wankowicz-Kalinska, lymphocytes cutaneous 62. of study immunohistological An al., 170 et A.M., Badri, 61. 2:p 149-55. p. (2): 204 140 1:p 57-63. p. (1): 3:p 654-662. p. (3): 138 2:p 355-64. p. (2): 27 188 3:p 398-407. p. (3): 6:p 1203-8. p. (6): 129 76 9:p 2220-32. p. (9): 6 148 5:p 847-55. p. (5): 23:p 223ra23. p. (223): 18 27 4:p 1219-28. p. (4): 74 6:p 1075-85. p. (6): 2:p 370-1. p. (2): 174 6:p 1318-26. p. (6): 83 117 5:p 683-95. p. (5): 2:p 326-32. p. (2): 51 1:p 52-61. p. (1): 137 2:p 350-358. p. (2): 132 23 7:p. (7): 3:p. (3): Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9 ohm ..adEC ely isersdn eoyC8 el:fo hntp ofunction. to phenotype from cells: T CD8+ memory Tissue-resident Reilly, 2018. E.C. Immunology, in and Frontiers D.J. Immunology, Nature Topham, skin. human 99. in cells T CD8+ memory resident by patrol 2019. Tissue al., et F.E., 2018. Dijkgraaf, immunology, responses: 98. immune in tissue-restricted Frontiers in worse? cells of T or Review Resident-memory better Merkler, Annual D. for residence. and Vincenti, tissue I. and K., Steinbach, patterns, 97. migration subsets, cell T Memory 2013. repigmentation al., Immunology, the et does S.N., vitiligo: Mueller, for 2007. 96. therapy Venereol, UVB Dermatol Narrowband Acad Ronnevig, Eur J.R. J and randomized, Dermatol, last? Loeb, a M. J ointment: J.C., Br tacrolimus 2015. Sitek, 0.1% Dermatol, 95. Invest with vitiligo? J J vitiligo for study. adult Br option placebo-controlled of blind, therapeutic therapy double vitiligo. Maintenance a al., human cells et Cavali´e, in blood M., 94. cells T T circulating targeting memory Is circulating 2020. T.R., of Matos, function and One, 93. PLoS Phenotype lesions. al., vitiligo et in 2020. C., increased Dermatol, are Martins, cells dendritic 92. activated and cells vitiligo. non-segmental Th17 active al., in 2011. et blood C.Q., peripheral Wang, in 91. responses Th17 individ- and 2016. healthy stable Th1 Res, in Enhanced and phenotype Dermatol al., Arch anergic active et an Y., in with Zhen, cells T-cells 90. T CD8+ CD8+ self-reactive and of 2014. CD4+ Detection Science, al., FoxP3+, uals. et tissue Y., Maeda, of 89. 2014. Assessment Dermatol, skin al., J human Int et healthy vitiligo. in M., nonsegmental with cells Abdallah, T patients regulatory 2014. in FOXP3+ 88. Dermatol, lymphocytes of J T analysis Int Immunohistochemical regulatory dermatoses. al., autoimmune peripheral et and of S., Terras, defects 2012. Functional 87. Res, Res, al., Melanoma Melanoma Cell Cell et Pigment Pigment M., vitiligo. vitiligo. Ahmed, progressive in Ben Treg in functional impairment by 86. homing an skin with Reduced correlates 2012. al., lymphocytes One, et 2010. T PLoS J., cytotoxic Klarquist, vitiligo. CD8+ generalized 85. of with activation patients of Global in abundance cells al., the T et increasing regulatory by Y., mice Lili, vitiligo 2018. Pmel-1 84. Reports, in Scientific depigmentation reverses skin. PD-L1 the al., in Journal Tregs et The X., vitiligo. J Miao, in depigmentation 83. vitiligo. suppress and of migration development Treg 2015. activate controls dermatology, to investigative cells CCL22 of al., T in et regulatory J.M., Eby, vitiligo in 2010. 82. increase autoimmune 1950), quantitative of A : development 2014. al., Dermatol, et temporal Invest Md. S., and (Baltimore, Chatterjee, spatial immunology 81. of of Journal Mechanisms 1909-1917. p. al., mice. (4): et transgenic TCR R.K., tyrosinase-specific Gregg, 80. 20 183 6 23 4:p e18907. p. (4): 6:p 756-764. p. (6): 2:p 276-86. p. (2): 5:p 803. p. (5): 183 346 31 5:p 899-908. p. (5): 134 1:p 137-161. p. (1): 61) .1536-40. p. (6216): 308 5:p 1285-94. p. (5): 1) .703-710. p. (10): 9 (515). 135 6:p 1574-1580. p. (6): 8 21 53 1:p 1605. p. (1): 7:p 891-6. p. (7): 8:p 940-6. p. (8): 9 19 53 .2827-2827. p. : 3:p 294-9. p. (3): 25 1:p 99-109. p. (1): 135 4:p 970-974. p. (4): 7 5:p e37513. p. (5): 184 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 1.Pr,YK,e l,Ietfiaino uonioyt eaoye n hrceiaino iiioantigen vitiligo of 1996. characterization and Sci, 1995. melanocytes Dermatol Res, to J Cell autoantibody patients. of Pigment Identification vitiligo al., antigens. in et vitiligo Y.K., of Park, Characterization 119. Bystryn, J.C. 53-9. and antigens Arita, p. related Y. (1): of J., identification 2015. Cui, and Res, antibodies 118. Mol anti-melanocyte vitiligo Genet serum of vitiligo. of sera with Detection the patients al., in in et antibodies M.C., 1987. anti-melanoma Zhu, Dermatol, IgA 117. Invest ST, of J MAIN Association disease. 350 Hashimoto, active K. and INC with and distribution patients PUBLISHING P.J. subclass BLACKWELL Aronson, of Studies 1991. 116. autoantibodies. Dermatol. USA. Vitiligo Invest 02148 Jordon. MA J MALDEN, R. 2010. in and Rev, Autoimmun Geoghegan, activation. W. complement vitiligo. P., for Xie, remedies cell Current pigment 115. al., et of antimelanocyte 1993. M., and Dermatol, level Tahir, antikeratinocyte Invest Abu and of J relationship 114. incidence vitiligo. and non-segmental-type Coexistence the with Yu, between patients C.L. and in Relation Kao, 1991. antibodies C.H. Bystryn, Dermatol, H.S., Invest J.C. Yu, J Acad 113. and vitiligo. Eur in Cui, J activity J. vitiligo. disease with and R., patients antibodies Iranian Harning, 55 in 112. system immune the of 2005. patients Assessment Venereol, from al., Dermatol sera et in S., present Farrokhi, antibodies with 111. 2000. antigens Dermatol, cell J melanoma extent Int of and Recognition vitiligo. al., antibodies with et 1986. vitiligo I.M., Dermatol, between Rocha, Acad Correlation 110. Am Bystryn, J J.C. vitiligo. and vitiligo. in Reggiardo, in depigmentation D. melanocytes of human G.K., normal Naughton, to 109. Antibodies Bystryn, 1983. J.C. Med, and Exp Eisinger, J reverse M. G.K., IL-17-producing durably 2017. Naughton, psoriasis-specific investigation, to contain 108. clinical potential lesions of psoriatic the Journal resolved The has Clinically clones. signaling al., cell et IL-15 T.R., maintain of Matos, to blockade 107. cooperate Antibody 2018. cells Medicine, al., 2019. Translational dermatology, T et investigative Science melanoma. memory of J.M., vitiligo. to Journal recirculating Richmond, immunity The and durable vitiligo. memory 106. of mediate Resident model skin mouse al., the a et in in J.M., disease cells Richmond, T memory 105. Resident al., 2017. et immunology, B.T., Science Malik, 104. against IFN- protection antigen-specific rapid provide 2015. cells through 1950), T challenge CD8 memory virus 2018. Airway-resident respiratory al., distinct Immunol, et functionally Exp S.R., and McMaster, Clin phenotypically 103. function. are cytotoxic cells immediate T lack CD8(+) 2012. memory and the 79-92. A, resident in populations S Skin cells circulating U al., (TRM) Sci from et T Acad J.A., Natl memory Seidel, Proc tissue-resident 102. presentation. by antigen immunity local epithelial global persisting providing Long-lived of cells al., absence T(RM) et CD8+ L.K., Mackay, memory 101. non-migratory generates infection 2012. Skin Nature, immunity. al., skin et X., Jiang, 100. 195 1:p 203-209. p. (1): 158 1:p 246-51. p. (1): 19 2 6:p 706-11. p. (6): 483 1) .eaam6346. p. (10): 78) .227-31. p. (7388): 39 1) .840-3. p. (11): 11 2:p 111-20. p. (2): 10 14 γ rdcin ora fimnlg Blioe d : Md. (Baltimore, immunology of Journal production. 40:p eaam7710. p. (450): 4:p 16060-73. p. (4): 20 88 127 (475). 15 1) .4031-4041. p. (11): 5P ) .978-81. p. 1): Pt (5 97 6:p 1078-80. p. (6): 9 100 109 7:p 516-20. p. (7): 139 6:p 823-8. p. (6): 1) .7037-42. p. (18): 4:p 769-778. p. (4): 194 1:p. (1): αβ T 8 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 3.Gwrde,DJ,e l,Vtlg:cnieeiec ae udlnso igoi n management. and diagnosis on guidelines based evidence concise Vitiligo: Acta 2010. study. J, al., Med prospective et Postgrad 12-month D.J., placebo-controlled Gawkrodger, 0.1% a tacrolimus 138. of of efficacy results enhances vitiligo: treatment 2008. with Venereol, Occlusive Derm patients Hamm, H. adult 1998. and in Immunol, Brocker, ointment J E.B. responses. A., immune Hartmann, skin 137. primary during cells epidermal in node expression 5331-40. molecule lymph costimulatory draining and cytokine local suppresses FK506 and Topical al., et B., Homey, 2001. Autoimmunity, 136. vitiligo. of aspects Autoimmune Weetman, A.P. and 34 Waterman, E.A. Dermatol, E.H., Invest Kemp, J 135. endothelin-1. secrete and synthesize keratinocytes human Cultured 1993. hormone al., et melanin-concentrating with J.J., Yohn, the patients 2006. 134. Invest, from to Lab serum autoantibodies patients. of Function-blocking vitiligo fraction al., in IgG receptor et the R.V., by Gottumukkala, melanocytes 133. of destruction 1995. vivo Dermatol, induce Invest In sera J al., patients’ vitiligo. et cellular vitiligo: A., antibody-dependent Gilhar, human and 132. damage in complement-mediated mechanisms 1988. by Dermatol, immunologic vitro Invest 2017. for in J Dermatol, cytotoxicity. Evidence melanocytes Invest human J al., to vitiligo. et damage in D.A., autoantibodies Norris, A 131. lamin of investigation An al., (S14). et S., 2010. Faraj, autoantibody phage-displayed Dermatol, 130. a Invest of of selection J target serological library. the novel expression by identified cDNA a vitiligo in melanocyte 1, Autoantigens al., receptor et E.A., Waterman, 2002. hormone 129. Invest, melanin-concentrating Clin The J vitiligo. al., in et responses E.H., Kemp, Dermatol, J 128. Int relatives. their and patients vitiligo in autoantibodies vitiligo 1996. Organ-specific al., of et R.C., sera Mandry, 127. the 2013. in Immunol, detected Exp Clin protein-1 study. 1998. tyrosinase-related Dermatol, Ruiz-Arg J to Br 126. Autoantibodies assay. radiobinding al., quantitative vitiligo et a of using E.H., sera 1998. patients the Immunol, Kemp, in Exp pmel17 Clin protein (RIA). 125. radioimmunoassay melanocyte-specific quantitative human and to sensitive Autoantibodies Exp a al., ev- Clin patients: et E.H., sera: (TRP-2). Kemp, vitiligo protein-2 124. with tyrosinase-related autoantigens and enzyme tyrosinase melanogenic to 1997. of 35S-labeled Immunol, autoantibodies Immunoprecipitation using cross-reactive al., vitiligo for et with idence patients E.H., 1997. Dermatol, in Kemp, Invest 1996. autoantibodies J 123. Immunol, tyrosinase radioimmunoassay. Exp of a Clin Detection in tyrosinase al., vitiligo. human et with recombinant E.H., patients Kemp, in autoantigen 122. an as 1994. Tyrosinase Lancet, al., vitiligo. et 105 autoimmune E., in tyrosinase Baharav, of role 121. The al., et Y.H., Song, 120. 1:p 65-77. p. (1): 1:p 84-8. p. (1): 100 35 1:p 18-21. p. (1): 1:p 23-6. p. (1): els . ta. ramn fvtlg ihaciei oolnlatbd oC2:apilot a CD20: to antibody monoclonal chimeric a with vitiligo of Treatment al., et A., uelles, ¨ 109 3:p 495-500. p. (3): 88 86 5:p 474-9. p. (5): 11) .466-71. p. (1018): 174 105 2:p 229-36. p. (2): 5:p 683-6. p. (5): 90 109 6:p 783-9. p. (6): 7:p 923-30. p. (7): 86 8:p 781-9. p. (8): 21 130 1:p 230-40. p. (1): 139 5:p 798-805. p. (5): 109 344 1:p 69-73. p. (1): 82) .1049-52. p. (8929): 114 3:p 333-8. p. (3): 160 1) p. (11): 137 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 5.Hag .. ta. nioyrsosst eaoamlnct uoniesi eaoapatients. melanoma in autoantigens melanoma/melanocyte to Cancer, responses 1998. Dermatol, Antibody vitiligo. Invest al., and J et melanoma S.K., between Huang, bridge of 159. the variant tyrosinase: effective to the Autoantibodies vitiligo: al., 1997. in et tumor- P., responses of Fishman, cell role 158. T 2005. cytotoxic melanoma: Res, human Cell Melanocyte-specific, Pigment for al., immunity? et model melanoma S., animal Garbelli, an 2004. in Res, 157. vitiligo Cancer Spontaneous to cells. al., disruption T CD8+ E-cadherin et specific and R., production Lengagne, 2020. MMP-9 Insight, and JCI 156. regulate microenvironment cytokines vitiligo. cytokine in Type-1 loss al., epidermis: melanocyte et promote vitiligo N., in Boukhedouni, 2009. dysfunction Histopathol, 155. Keratinocyte Histol al., apoptosis. keratinocyte et to S., correlation cytokines Moretti, pro-inflammatory 2020. innate 154. Res, of role Dermatol Predominant Arch Dastgheib, disease. L. inhibited vitiligo and 2014. Yazdani, is in M.R. Dermatol, which N., Exp interleukin-8, Gholijani, Clin release and 153. vitiligo. express early melanocytes to human relevance Stimulated TNF- luteolin: al., IL-2, by et IL-6, A., of Miniati, concentration 152. Serum 2012. Pandey, Dermatol, S.S. 2019. J Immunol, and Indian Clin Singh, Rev patients. U. Expert S., pathogenesis. Singh, vitiligo of 151. yang Clin and yin J therapy. the Cytokines: gene al., 15 receptor et cell M., T Singh, by 150. neoantigens melanoma human Targeting 2016. al., and Invest, et progress M., immunotherapy: Leisegang, cancer 149. cell-mediated T 2017. Personalized Biotechnol, 2017. Joglekar, Opin Clin, Curr A.V. Faschallenges. Dermatol and when vitiligo. M.T. even of Bethune, concert Genetics 148. Andersen, in G.H. working and ligand 2011. R.A. Fas Immunology, Spritz, and detectable. 147. perforin not still lymphocyte is Clinical T action Cytotoxic cells? lytic al., cancer ligand et kill D., lymphocytes Hassin, cytotoxic 146. do How 2011. Pardo, Chem, 2015. J. Biol Research, and J Cancer Anel, secretion. A. during Mart´ınez-Lostao, L., Pmel17 145. process convertases Proprotein Clin al., therapy. 286 et melanoma for R.M., target Leonhardt, surface 144. cell a is protein 1996. membrane melanosomal Res, A Cancer al., Expert et Y., vitiligo. Takechi, in 143. pathomechanisms stressed, Immunological Weetman, 2001. pigmented, A.P. Med, on and Mol Waterman, tested Rev E.A. vitiligo E.H., of Kemp, 142. hypothesis 2007. melanocytorrhagic Res, Cell The 1993. Pigment al., Cancer, epidermis. et reconstructed melanoma. M., against Cario-Andre, effective residential 141. are skin on autoantibodies effects Vitiligo its al., 2013. and 2365-9. et Sci, P., apoptosis Mol Fishman, J UV-induced Int 140. of phototherapy. UV-Based mechanisms in Molecular implication al., the et cells: C.-H., Lee, 139. 2:p 177-188. p. (2): 1) .9321-37. p. (11): 79 8:p 1461-4. p. (8): 126 2 3:p 854-8. p. (3): 1) .1837-42. p. (11): 3 2) .1-22. p. (20): 21 111 2) .5047. p. (22): 4:p 662-7. p. (4): 57 1:p 12-14. p. (1): 48 64 .142-152. p. : 4:p 1496-501. p. (4): 312 18 20 2:p 123-131. p. (2): 4:p 234-42. p. (4): 22 5:p 385-93. p. (5): 5 (11). 133 24 2:p 190-196. p. (2): 39 7:p 849-57. p. (7): 1:p 54-57. p. (1): 14 3:p 6414-35. p. (3): 35 2:p 245-55. p. (2): α, n IFN and γ 72 nvitiligo in 8:p. (8): Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. L-N(NRi nrn2 eeplmrhssadvtlg.ErJDrao,2009. Dermatol, and J (+49) Eur CTLA4 vitiligo. (Delta32), and CCR5 polymorphisms (I)/(D), ACE gene (-590), 2) IL4 intron between in Association (VNTR meta-analysis al., a IL1-RN et and S., studies 2009. Pehlivan, association Res, genetic 179. Melanoma two Cell vitiligo: Pigment generalized data. and CTLA4 published antigen-4 al., of T-lymphocyte et 1999. cytotoxic S.A., with Dermatol, the Birlea, J of associated 178. Br polymorphism are microsatellite vitiligo. a AIRE with of patients regulator Analysis in autoimmune al., gene et the E.H., in Kemp, mutations 177. 2015. Dominant Immunity, al., diseases. autoimmune Br et organ-specific vitiligo. B.E., common with Oftedal, associated strongly is and 176. (AIRE) 6q27 gene at regulator autoimmune loci 2008. The susceptibility Dermatol, al., identifies J et vitiligo R., Tazi-Ahnini, for study 175. association 2010. Genome-wide Genet, Nat al., general- MHC. et familial 2006. the of C., Res, risk Cell Quan, to Pigment contributes Melanoma 174. onset. DRB1*04-DQB1*0301 Cell disease haplotype Pigment early II Japanese. and class in HLA vitiligo 01 al., ized et 02: P.R., HLA-A* Fain, J with Engl 173. vitiligo N of vitiligo. association generalized Major 2015. in al., Res, loci et susceptibility Y., autoimmunity Jin, 172. and TYR Venereol, of Dermatol Variant Acad al., 2010. Eur Med, et J Y., meta-analysis. Jin, a 171. HLA-A2: with vitiligo of Han Association Chinese al., the 2007. et in J.B., vitiligo generalized Liu, for for 170. Loci susceptibility loci 2013. three Dermatol, susceptibility identify Invest analyses new J Association population. 13 al., et identify X.F., Tang, analyses 169. association Genome-wide 2012. Genet, al., Nat et vitiligo. Y., 1959. Jin, Dermatol, 168. Invest 2015. J Primers, Vitiligo. Dis A.B., Rev pro- Lerner, Nat Caucasian 167. Vitiligo. in al., diseases et autoimmune M., 2003. associated Picardo, Res, and 166. Cell vitiligo Pigment of families. Epidemiology their and al., melanoma bands et malignant A., metastatic with Alkhateeb, patients 165. in response and 2015. vitiligo Tumori, evi- of temozolomide. 2000. Association direct on medicine, al., melanoma: experimental et of of A.M., Tatli, immunotherapy Journal 164. antigen-specific The after vitiligo. cell–mediated destruction T Melanocyte of al., dence et receiving Clinical C., melanoma of Yee, Journal III-IV 163. meta-analysis. stage and review with systematic patients survival a in survival: 2015. improved Oncology, with depigmentation with association Vitiligo-like its associated al., and are immunotherapy et cells H.-E., T Teulings, Clinical 162. + treatment. CD8 anti-PD-1 tumor-resident during 2018. + by significantly Research, CD103 expand Cancer recognized and al., antigens patients et immunotherapy-na¨ıve Melanoma-associated melanoma in J., Zeuthen, Edwards, J. 161. and 1998. Dzhandzhugazyan, Apmis, K. lymphocytes. T A.F., cytotoxic Kirkin, 160. 21 2:p 205-13. p. (2): 28 362 3:p 360-62. p. (3): 1) .1686-97. p. (18): 33 159 7:p 773-781. p. (7): 3:p 591-6. p. (3): 24 44 1) .3036. p. (13): 42 6:p 676-80. p. (6): 7:p 614-8. p. (7): 101 133 2:p e67-9. p. (2): 106 2:p 403-10. p. (2): 7:p 665-79. p. (7): 16 23 140 32 3:p 208-14. p. (3): 22 2 at2:p 285-310. p. 2): Part (2, 1:p 73-8. p. (1): 2:p 230-4. p. (2): 1 19 .15011. p. : 42 1:p 51-7. p. (1): 6:p 1185-96. p. (6): 192 1) .1637-1644. p. (11): 19 2:p 126-8. p. (2): Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. 9.Wo,JM,e l,Cmue iuaino eeoeeu igencetd oyopim nthe in tetramerization and polymorphisms NADPH-binding nucleotide site, single active heterogeneous enzyme of the in simulation in vitiligo changes Computer of structural al., polymorphism indicates et I/D gene J.M., gene catalase enzyme Wood, for converting gene angiotensin 199. 2004. susceptibility of Res, a Cell Association Pigment be al., to population. et Korean ZMIZ1 S.Y., confirms 2014. Jin, analysis Genet, Med 198. association J comprehensive A population. Chinese HLA-A al., in 2012. et and vitiligo Dermatol, Y., TYR Invest Sun, of J variants presentation. 197. common antigen identifies via vitiligo re-sequencing generalized DNA of FOXD3 Next-generation 1730-3. risk the al., the in et modulate variant that Y., 2005. promoter Jin, Med, functional Intern 196. Gen Candidate J Spritz, vitiligo. R.A. dominant 388-91. autosomal and in p. Fain, protein gene P.R. signaling regulator developmental agouti A., 2003. melanoblast and Res, Alkhateeb, (MC1R) Cell receptor Pigment melanocortin-1 195. risk patients. the genetic vitiligo in and Korean Polymorphisms in expression al., genes XBP1 et (ASIP) modulates G.Y., sequence Na, promoter 194. of 2009. variation is Genet, Genetic polymorphism PLoS al., C/T +1858C/T vitiligo. et 1858 for PTPN22 Y., PTPN22 phosphatase 2014. Ren, and Med, tyrosine 193. Ther A/G Protein Exp CT60 al., vitiligo. A/G, active et 2013. +49 with Rep, M.E., CTLA-4 associated Biol Garcia-Melendez, The Mol Lee, meta-analysis. 192. a Y.H. in vitiligo: and susceptibility to Kim, vitiligo susceptibility J.H. with and polymorphisms G.G., polymorphism 1858C/T Song, PTPN22 2008. 191. of Sci, Association Dermatol J al., 2008. et population. Res, Gujarat N.C., Melanoma Laddha, Cell Pigment 190. population. PTPN22-1858C Romanian is The the CTLA4 al., in but et vitiligo vitiligo, generalized G.S., generalized of Laberge, risk with 189. tyrosine associated 2008. genetically protein Dermatol, is lymphoid Invest PTPN22 J encoding al., 2005. not. gene et Immun, the G.S., Genes LaBerge, in Jordanian vitiligo. 188. polymorphism in generalised single-nucleotide to vitiligo A susceptibility generalized confers al., with (PTPN22) et phosphatase NALP1 I., of Canton, association 187. Genetic 2007. 2010. Med, Qarqaz, Res, J F. Dermatol Engl Arch and N Arabs. A. Romanian disease. Alkhateeb, a autoimmune multiple in 186. vitiligo-associated vitiligo in generalized 1216-25. NALP1 with al., p. associated et (12): are Y., NALP1 Jin, in 185. variations 2007. Genetic Dermatol, Invest al., variant J et 55R-94A-247H common population. 2013. Y., the Dermatol, vitiligo Jin, with Invest generalized associated J 184. is B). for vitiligo granzyme genes generalized (encoding of GZMB candidate Risk of of al., haplotype et analysis 2011. T.M., Ferrara, association Dermatol, Invest 183. Comprehensive 2010. J TSLP. Genet, al., and Nat et FOXP3, vitiligo. XBP1, S.A., generalized supports Chinese with Birlea, in associated vitiligo are 182. FOXP1 of in risk variants with Common al., associated et 42 gene FAS Y., 2008. Jin, the Dermatol, Invest of 181. J polymorphisms analysis. Functional case-control al., a et populations: M., Li, 180. 7:p 576-8. p. (7): 128 5 6:p e1000523. p. (6): 302 7:p 1757-62. p. (7): 127 8:p 631-4. p. (8): 1) .2558-62. p. (11): 49 17 3:p 260-2. p. (3): > 1:p 84-6. p. (1): R2W ucinlplmrhs sascae with associated is polymorphism functional (R620W) T 51 24 8 5:p 345-53. p. (5): 5:p 1433-37. p. (5): 128 131 16 1) .2820-4. p. (12): 2:p 371-81. p. (2): 4:p 383-7. p. (4): 133 6:p 1677-9. p. (6): 40 21 4:p 2985-93. p. (4): 2:p 206-8. p. (2): 6 7:p 584-7. p. (7): 132 20 6:p. (6): 356 (5): Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. stress-factors Gawkrodger.pdf immunogenetic-milieu-with-innate-and-adaptive-immunities-as-triggered-by-environmental- Kemp Faraj 406855/articles/517361-patho-immunological-mechanisms-of-vitiligo-an-integration-of-the- review vitiligo 2104 in melanocytorrhagy 2007. and Res, 2007. autoimmunity, Cell file Res, Pigment Hosted stress, Cell interconnected? oxidative Pigment be dysregulation, they place. Neurogenic can in M.R., vitiligo: fall Namazi, pieces the 216. puzzle: Vitiligo 345-59. d’Ischia, M. p. and (5): W. 2017. Westerhof, Clin, Dermatol 215. vitiligo. immunoreactivi- Chemical-induced alpha-melanotropin with J.E., of Harris, patients levels of 214. plasma lower skin present lesional patients 2006. non Vitiligo Neuropeptides, al., in ties. et friction R., skin Pichler, after 213. 2003. detachment nonseg- Dermatol, of Melanocyte J phase Br al., early et vitiligo. the generalized Y., in Gauthier, levels metabolite 212. and 2000. catecholamine Res, 2019. Cell plasma Dermatol, Pigment Higher Exp al., vitiligo. reappraisal. mental et a M.L., Cucchi, vitiligo: for 211. theory convergence other. The each 647-655. al., influence et p. systems R.V., immune Kundu, and 210. nervous the 2019. how Immunol, interactions: Exp Neuroimmune 2015. Clin L.S., (Oxf), effects Taams, Physiol direct Acta 209. peptide: diseases. intestinal autoimmune vasoactive and 442-52. neuropeptide inflammatory The p. in Kong, involvement (2): W. and and system. cells immune immune Hooper, on K.M. the D., in Ganea, Y 208. neuropeptide of mission 1994. intriguing 2013. Dermatol, Stanojevi´c, Acids, The J Amino S. Br and vitiligo. Dimitrijevi´c, M. in 207. studies marker ultrastructural neuronal 160-65. and an Neuropeptide p. vitiligo: al., (2): in et nerves M., 1986, dermal Al’Abadie, the Editor. 206. on L., 1995. observations R. Dermatol, Morphologic J Thiers, al., Int B.H.a.D. et study. diseases, M.S., skin Al’Abadie, of 99-128. 205. Pathogenesis p. In: York. 1983. New in Dermatol, Livingstone: Vitiligo, J Churchill J.J., Int Nordlands, to skin. susceptibility vitiliginous 204. of and Histopathology polymorphisms Mehta, gene L.N. and endothelin-1 477-80. B.B. between 2007. Gokhale, Dermatol, association Exp 203. The altered population. al., to Korean lead a et 2017. variants in J H.J., Dermatol, region vitiligo J 5’-untranslated Kim, people. Br and Chinese vitiligo. promoter 202. in in gene vitiligo activity catalase with enzyme The and associated al., expression is et gene gene M.S., catalase Mansuri, the 201. in variant Promoter 2008. 2010. al., Dermatol, Dermatol, et Exp Invest L., vitiligo? Liu, with patients 200. in catalase altered 366-71. an p. for (4): predisposition genetic a domains: 45 130 1:p 41-53. p. (1): 40 197 1) .2647-53. p. (11): 34 3:p 177-83. p. (3): 3:p 276-277. p. (3): 1) .837-40. p. (12): 13 148 1:p 28-32. p. (1): 1:p 95-101. p. (1): 25 16 7:p 561-6. p. (7): vial at available 20 5:p 360-3. p. (5): 35 2:p 151-161. p. (2): 177 https://authorea.com/users/ 6:p 1590-1600. p. (6): 22 28 8:p. (8): 213 131 (6): 20 17 Posted on Authorea 9 Apr 2021 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.161798642.25768292/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. stress-factors .pdf Gawkrodger immunogenetic-milieu-with-innate-and-adaptive-immunities-as-triggered-by-environmental- Kemp Faraj 406855/articles/517361-patho-immunological-mechanisms-of-vitiligo-an-integration-of-the- review vitiligo 2104 file Hosted 26 vial at available https://authorea.com/users/