631927

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Review ArticleOxidative Stress and Immune System in

Vitiligo and Thyroid Diseases

Roberta Colucci Federica Dragoni and Silvia Moretti

Section of Dermatology Department of Surgery and ranslational Medicine University of FlorenceOspedale Piero Palagi Viale Michelangelo 983092983089 983093983088983089983090983093 Florence Italy

Correspondence should be addressed to Roberta Colucci robertacolucci983090983089gmailcom

Received 983090983092 December 983090983088983089983092 Accepted 983090 March 983090983088983089983093

Academic Editor Tomas Kietzmann

Copyright copy 983090983088983089983093 Roberta Colucci et al Tis is an openaccess article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Vitiligo is an acquired dermatological disease requently associated with autoimmune thyroid disorders Several theories have beenproposed so ar to unravel the complex vitiligo pathogenesis Currently the autocytotoxic and the autoimmune theories are themost accredited hypothesis since they are sustained by several important clinical and experimental evidences A growing body o evidences shows that autoimmunity and oxidative stress strictly interact to 1047297nally determine melanocyte loss In this scenarioassociated thyroid autoimmunity mightplay an active and important rolein triggering and maintaining the depigmentation processo vitiligo

1 Introduction

Vitiligo is an acquired dermatological disorder characterizedby circumscribed depigmented macules due to the loss o unctional melanocytes in the epidermis [983089] Tis pigmentary disease is requently associated with some autoimmunecomorbidities and particularly with autoimmune thyroiddisorders (AD) [983090 983091]

Several theories have been proposed so ar to dis-close vitiligo pathogenesis such as the autoimmune the-

ory [983092] the autocytotoxic theory [983093 983094] the neural theory [983095] the ldquoimpaired epidermal cytokinerdquo theory [983096ndash983089983088] themelanocythorragic hypothesis [983089983089] and the recent in1047298amma-tory theory [983089983090] which are currently considered as synergisticin determining the disease [983093]

Among the abovementioned theories however the auto-cytotoxic and the autoimmune theories are at present themost accredited since they are sustained by several impor-tant clinical and experimental evidences Current litera-ture reports several evidences suggesting a strict interplay between oxidative stress and immune system able to triggerand maintain vitiligo depigmentation process and the even-tually associated AD [983089983091]

Tis review ocuses on the most important evidencesregarding the role o autoimmunity and oxidative stressand their interactions in vitiligo and autoimmune thyroiddisorders Moreover we suggest a pathogenetic scenario inwhich the abovementioned autoimmune diseases coexist andsustain each other in a deleterious vicious cycle

2 Vitiligo and Oxidative Stress

In the last decades a lot o studies suggested that an hyper-sensitivity to oxidative stress has a crucial role in determiningmelanocyte degeneration [983089983092] Vitiligo skin o active phasepatients has been demonstrated to display high epidermallevels o reactive oxygen species (ROS) primarily representedby hydrogen peroxide (H

2O2) and peroxynitrite [983089983093 983089983094]

Tese alterations are the result o a local and systemic imbal-ance in enzymatic and nonenzymatic antioxidant systems[983089983095]

Indeed an abnormal unction o the metabolic system o biopterins leading to high levels o the tetrahydrobiopterin(983094BH

4) and its isomer 983095BH

4 has been demonstrated in

vitiligo epidermis [983089983096 983089983097] Biopterins act as inhibitors o theenzymes involved in melanogenesis (namely phenylalanine

Hindawi Publishing CorporationOxidative Medicine and Cellular Longevity Volume 2015 Article ID 631927 7 pageshttpdxdoiorg1011552015631927

7242019 631927

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983090 Oxidative Medicine and Cellular Longevity

hydroxylase and tyrosinase) and stimulate the ormation o H

2O2 [983089983088ndash983090983090]

In addition low levels o enzyme catalase [983090983091ndash983090983093] anantioxidant enzymethatcatalyzes the conversion o hydrogenperoxide in water plus oxygen and other antioxidant agentssuch as glutathione peroxidase glucose-983094-phosphate dehy-

drogenase superoxide dismutase and vitamins C and E havebeen detected both in the epidermis or in the serumo vitiligopatients [983089983093 983090983093ndash983090983095] thus suggesting a systemic redox deectin this disease

An increase o ROS might also be the consequence o animpaired mitochondrial unctioning Indeed ultrastructuralalterations in keratinocytes mitochondria such as swellingo their membranes and a rearrangement o the cristaehave been demonstrated in the epidermis o vitiligo skinbiopsies [983090983096] Such structural deects directly correlate with aconsequent impaired mitochondrial activity thus leading toan increased generation o reactive oxygen species [983090983096]

As a consequence local and systemic high levels o H2O2

are able to alter calcium homeostasis consequently perturb-ing the uptake o L-phenylalanine the amino-acid precursoro tyrosine in melanocytes [983090983097] In addition ROS are ableto oxidize and inhibit the activity o proopiomelanocortin-derived bioactive peptides ACH and a-MSH that havecrucial role in maintaining efficient melanogenesis sincetheir release activates a cascade o intracellular signals leadingto an upregulation o key enzymes or melanin synthesissuch as tyrosinase and tyrosinase-related proteins YRP-983089and YRP-983090 (or dopachrome tautomerase DC) [983091983088]

ROS accumulation is also able to induce lipid perox-idation DNA damage an increased production o proin-1047298ammatory and antimelanogenic cytokines and the loss o

unctionality o enzymes playing a key role in melanogenesis[983091983089]

Most o the unavourable effects o H2O2

accumula-tion are more requently observed in keratinocytes andmelanocytes derived rom perilesional skin thus suggestinga pivotal role o such area in initiating the depigmentationprocess

Moreover recent studies pointed out the importance o the Nr983090-antioxidant response element (ARE) pathway inregulating vitiligo skin homeostasis under oxidative stressand gave the possibility to explain the hypersensitivity o

vitiligo melanocytes to oxidative damage [983091983090ndash983091983092] Te Nr983090-antioxidant response element (ARE) is indeed a major

antioxidant pathway since it regulates the transcription o stress-related cytoprotective genes thus protecting cells romoxidative stress and chemical-induced cellular damage Ithas been demonstrated that the Nr983090-ARE pathway protectshuman melanocytes rom H

2O2-damage through the induc-

tion o downstream antioxidant genes [983091983091] such as hemeoxygenase-983089 (HO-983089) A recent in vitro study showed that

vitiligo melanocytes have reduced Nr983090 nuclear translocationand transcriptional activity which lead to decreased HO-983089expression and aberrant redox balance Accordingly authorsdemonstrated in a clinical setting that serum levels o HO-983089 were signi1047297cantly decreased in vitiligo patients whencompared with healthy controls [983091983092]

Also the Forkhead box class O (FOXO) proteins a classo transcription actors whose activation leads to the indu-ction o gene codiying or antioxidant proteins seem to beinvolved in vitiligo antioxidant impairments [983091983093] Recently some authors reported a signi1047297cant association between aspeci1047297c polymorphism o FOXO983091a gene in active vitiligo

patients together with decreased levels o FOXO983091a proteincompared to a control group [983091983093]

Finally a urther theory sustaining the pathogenic role o oxidative stress in vitiligo called the haptenation theory hasbeen proposed [983091983094] According to this hypothesis high levelso hydrogen peroxide (H

2O2) might lead to increased levels

o ortho-phenols surrogate substrates o tyrosinase Authorssustain that vitiligo tyrosinase due to a genetically controlledpolymorphism could be able to accept the abovementionedsubstrates which covalently bind to the enzyme afer con-

version to reactive ortho-quinone [983091983094] Tis process mightmodiy tyrosinase into a neoantigen possibly recognized by the immune system thus triggering the autoimmune reactionat the basis o the depigmentation process observed in vitiligo[983091983094]

According to all the above reported evidences in the lastdecades some clinical studies showed the bene1047297cial effects o the use o oral and topical antioxidants in association withconventional vitiligo treatment [983091983095ndash983092983088] thus suggesting theimportance to restore the deective antioxidant system in

vitiligo patients

3 Vitiligo and Autoimmunity

With regard to the autoimmune theory it is generally

accepted that autoimmunity is strongly implicated in thedevelopment o the vitiligo [983092983089] so that this pigmentary disorder is widely considered as autoimmune disease Tistheory is sustained by several epidemiological clinical andlaboratory studies [983089 983092 983092983090 983092983091] Elevated organ and non-organ-speci1047297c autoantibodies levels have been reported inthe serum o vitiligo patients [983092983091] Te requency o suchautoantibodies is variable according to different studies con-ducted so ar [983089 983091 983092983091ndash983092983094] and their role in vitiligo patientsis still quite unknown mostly i patients positive or suchautoantibodies do not display clinical signs o autoimmuneassociated diseases However the 1047297nding o elevated organ-speci1047297c autoantibodies in vitiligo patients might represent a

predictive marker o uture overt autoimmune disorders [983092]Te involvement o the humoral response in vitiligo is

documented by the 1047297nding o circulating autoantibodiesdirected towards melanocytic antigens [983092983095ndash983093983088] whose levelscorrelate with disease activity [983092983095] Such autoantibodiespertaining to class G immunoglobulins have been ound alsoin the basal layer o lesional vitiligo epidermis in associationwith complement component 983091 (C983091) deposits [983092983096] Majormelanocytic antigens are the proteins tyrosinase tyrosinase-related protein-983089 (RP-983089) RP-983090 Pmel983089983095 (also called gp983089983088983088)the transcriptional actors SOX 983097 and SOX 983089983088 and the type983089 membrane receptor or melanin-concentrating hormone(MCH-R983089) [983092983097ndash983093983090]

7242019 631927

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Oxidative Medicine and Cellular Longevity 983091

Peripheral blood o patients with vitiligo is also character-ized by high requencies o melanocyte-reactive cytotoxic cells [983091983097] able to release type B granzyme perorin and IFN[983093983091 983093983092] while perilesional -cell in1047297ltration can be oundin vitiligo epidermis [983093983092] It has been demonstrated thatperilesional lymphocytic in1047297ltrate is constituted by cells

appearing as skin-homing polarized toward type-983089 effectorunction and markedly cytotoxic [983093983092ndash983093983094]Moreover recent 1047297ndings pointed out a pathogenetic role

o H983089983095 cells in vitiligo [983093983095ndash983093983097]Namely a population o H983089983095 cells able to release the

cytokine IL-983089983095 has been recently ound in the epidermis o active vitiligo skin [983093983096 983093983097] Accordingly IL-983089983095 levels havebeen ound increased in the serum and in lesional epi-dermis o vitiligo patients [983093983095] Tiscytokine is able to inducethe release o proin1047298ammatory cytokines (namely IL-983089IL-983094 NF1038389 GF1103925 GM-CSF and prostaglandins) romactivated immune cells such as 1047297broblasts keratinocytesendothelial cells and macrophages [983093983097] Tis consequentlocal cytokine network recruits and activates mononuclearlymphocytes or neutrophils which are strongly implicatedin vitiligo pathogenesis In addition in vitro studies showedthat human cultured melanocytes treated with IL-983089983095A dis-played a reduced melanin production a downregulation o the microphthalmia-associated transcription actor (MIF)which is implicated in the transcription o key genes involvedin melanogenesis and a reduced expression o the m-RNAencoding orthe antiapoptotic protein B cell lymphoma gene-983090 (BCL983090) thus suggesting the unavourable effects o IL-983089983095Aon melanocyte unction and survival [983093983097]

Finally a plethora o novel 1047297ndings support the crucialrole o regulatory cells (regs) in vitiligo pathogenesis[983094983088] Indeed circulating regs whose unction is to main-tain peripheral tolerance through the active suppression o sel-reactive -cell activation and prolieration have beenreported to be decreased in vitiligo patients comparedto controls [983094983089 983094983090] Accordingly a remarkable reductionin the number o regs has been observed also in theperilesional and lesional skin o vitiligo patients [983094983091] It isnoteworthy that besides a decrease o circulating reg cellsnumber patients affected by active vitiligo also display animpaired regs unction as demonstrated by their alteredcapacity to inhibit the prolieration o stimulated CD983096+ cellsand their cytokine production [983094983088] Possibly the impairedcytokine network typical o vitiligo might contribute to thereduction and the loss o unction o regs Both GF

beta and IL 983089983088 indeed which are physiological inducers o regs unction and prolieration have been ound to bedecreased in active vitiligo lesions [983096 983094983092 983094983093] thus leading toan impaired peripheral tolerance Future strategies or vitiligotreatment will be probably targeted to improve regs numberand regulatory unctions as shown by recent promisingexperiments conducted in mice [983094983094]

aken together the abovementioned evidences thus sug-gest the pathogenetic role o both humoral and cell mediatedimmunity

Concerning the epidemiological and clinical evidences o an autoimmune theory o vitiligo the requent associationwith organ-speci1047297c autoimmune disorders [983089 983093 983092983091] and

a positive response to immunosuppressive treatments in vitiligo patients [983089983090 983094983095] are the most important proos

4 Interplay between Oxidative Stress and Autoimmunity in Vitiligo

Te role played by autoimmunity and oxidative stress in thepathogenesis o vitiligo until now was considered as mutually exclusive Recent 1047297ndings instead suggested that these twomechanisms are both involved in the depigmentation processand act in synergism [983089983091] In autoimmune disorders such as

vitiligo the immune system develops a chronic in1047298ammatory milieu in which ROS accumulate and exert a toxic effect onsurrounding cells [983089983091]

Structural or unctional melanocytic proteins thereoremay be modi1047297ed by acute and chronic oxidative stresspossibly becoming neoantigens able to trigger autoreactivereactions [983094983096] Hence according to this new theory autoim-munity and oxidative stress interact in initiating andor

ampliying the loss o melanocytes in vitiligoA recent paper [983094983097] suggests that oxidative stress andautoimmunity coexist in vitiligo but might play different rolesin initiating or perpetrating vitiligo Namely in this casecontrol study anti-melanocyte antibody levels suggestive o an autoimmune process and lipid peroxidation levels whichindeed indicate an oxidative stress were evaluated in bothearly onset and late duration vitiligo patients Authors oundthat lipid peroxidation levels were increased in patients withearly onset vitiligo while on the contrary anti-melanocyteantibodies were increased in long duration vitiligo patients[983094983097] Tereore oxidative stress rather than autoantibodiesmight play a major role in initiating vitiligo [983094983097] Possibly the

consequent accumulation o ROS might secondarily triggerautoimmunity and precipitate the depigmenting process o vitiligo since ROS might alter the structure o proteininvolved in melanogenesis such as tyrosinase making themmore antigenic

5 Pathogenetic Interconnections atthe Basis of Vitiligo and AutoimmuneThyroid Comorbidities

Patients with vitiligo have elevated requencies o associatedautoimmune disordersand among them [983095983088 983095983089] autoimmunethyroid disorders (AD) are the most requently ound

comorbidities [983091]AD are a group o disease characterized by the presence

o autoantibodies directed against thyroglobulin thyroper-oxidase or thyroid-stimulating hormone receptor whichare pivotal thyroid-speci1047297c molecules or the productiono thyroid hormones Autoimmune thyroid disorders canbe associated or not with thyroid dysunction A recentsystematic review pointedout that the risk or vitiligo patientsto develop AD diseases is even higher (983090983093 old) compared tononvitiligo patients while the risk to develop elevated thyroidantibodies is more than 983093-old higher in vitiligo patients thanin nonvitiligo patients [983091] Accordingly a screening o AD isrecommended in vitiligo patients [983091]

7242019 631927

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983092 Oxidative Medicine and Cellular Longevity

A recent study perormed by our working group [983095983090] hasinvestigated the presence o an uncommon group o autoanti-bodies directed against thyroid hormones (triiodothyronineandor thyroxine) (HAbs) in patients with vitiligo HAbsrepresent a class o thyroid autoantibodies showing a verylow prevalence in the general population [983095983091 983095983092] but increased

in some thyroid and extra-thyroid autoimmune diseasessuch as Hashimotorsquos thyroiditis Gravesrsquo disease primary Sjogrenrsquos syndrome or rheumatoid arthritis [983095983093] Even i theirpathogenetic role is still quite obscure a study reported thattheir presence in nonthyroid autoimmune diseases seem tobe predictive o overt AD [983095983093]

We showed that HAbs have a surprisingly elevatedprevalence in vitiligo higher than in other disease investi-gated so ar and signi1047297cantly correlate with active vitiligoleukotrichia disease duration and thyroglobulin antibod-ies positivity All together these results suggest a possiblepathogenic role o HAb in vitiligo [983095983090]

As mentioned above a chronic in1047298ammatory milieu ascan be ound in vitiligo can lead to local and systemic ROSaccumulation o explain our 1047297ndings we suggest that ROSincrease might be toxic or thyroid leading the release o large amounts o thyroglobulin proteins that can be moreaccessible to immune system attack [983095983090]

At the same time in patients with thyroid autoimmunity increased ROS levels [983095983094] have been demonstrated whichmight contribute to modiy tyrosinase or other melanogenicproteins into neoantigens leading to the appearance o

vitiligo Tus melanocytic and thyroid system might interactcreating a vicious cycle in which thyroid autoimmune pro-cesses give rise to vitiligo lesions and in turn vitiligo sustains

the ormation o thyroid autoantibodies such as HAbs [983095983094]We suggest that an important role in determining these

events might be played also by heavy metals pollutantsionizing radiations and other chemical substances [983095983095] thatinduce the production o ROS and are considered endocrinedisruptors [983095983096] Tese agents indeed are able to unavorably affect thyroid or other endocrine gland unctions through awide range o molecular toxic mechanisms [983095983096] Tereore anincreased ROS accumulation due to environmental exposurecould induce modi1047297cations o both melanocytic structuresand thyroid proteins leading to the requently reportedassociation o vitiligo and thyroid diseases [983095983095]

6 Conclusions

Overall according to the evidences and theories discussedabove we can state that vitiligo has complex pathogenesis inwhich a pivotal role is played by oxidative stress and immunesystem A growing body o evidences indeed shows thatautoimmunity and oxidative stress interact and worktogetherin creating a pathway 1047297nally able to determine melanocyteloss In this scenario thyroid autoimmunity which was soar considered simply as a comorbidity might instead play anactive and importantrole possibly contributing to triggerandmaintain the depigmentation process o vitiligo

Conflict of Interests

Te authors declare that they have no con1047298ict o interests

References

[983089] A aıeb and M Picardo ldquoVitiligordquo Te New England Journal of Medicine vol 983091983094983088 no 983090 pp 983089983094983088ndash983089983094983097 983090983088983088983097

[983090] V Ingordo S Cazzaniga B Raone et al ldquoCirculating autoan-tibodies and autoimmune comorbidities in vitiligo patients amulticenter Italian studyrdquo Dermatology vol 983090983090983096 no 983091 pp 983090983092983088ndash983090983092983097 983090983088983089983092

[983091] C Vrijman M W Kroon J Limpens et al ldquoTe prevalence o thyroid disease in patients with vitiligo a systematic reviewrdquoBritish Journal of Dermatology vol 983089983094983095 no 983094 pp 983089983090983090983092ndash983089983090983091983093983090983088983089983090

[983092] K Ongenae N van Geel and J-M Naeyaert ldquoEvidence oran autoimmune pathogenesis o vitiligordquo Pigment Cell Research vol 983089983094 no 983090 pp 983097983088ndash983089983088983088 983090983088983088983091

[983093] K U Schallreuter P Bahadoran M Picardo et al ldquoVitiligo

pathogenesis autoimmune disease genetic deect excessivereactive oxygen species calcium imbalance or what elserdquoExperimental Dermatology vol 983089983095 no 983090 pp 983089983091983097ndash983089983092983088 983090983088983088983096

[983094] M Eskandani J Golchai N Pirooznia and S HasannialdquoOxidative stress level and tyrosinase activity in vitiligopatientsrdquo Indian Journal of Dermatology vol 983093983093 no 983089 pp 983089983093ndash983089983097 983090983088983089983088

[983095] M S K Al Abadie H J Senior S S Bleehen and D JGawkrodger ldquoNeuropeptide and neuronal marker studies in vitiligordquo British Journal of Dermatology vol 983089983091983089 no 983090 pp 983089983094983088ndash983089983094983093 983089983097983097983092

[983096] S Moretti A Spallanzani L Amato et al ldquoNew insights intothe pathogenesis o vitiligo imbalance o epidermal cytokines

at sites o lesionsrdquo Pigment Cell Research vol 983089983093 no 983090 pp 983096983095ndash983097983090 983090983088983088983090

[983097] S Moretti A Spallanzani L Amato G Hautmann I Galleraniand P Fabbri ldquoVitiligo and epidermal microenvironment pos-sible involvement o keratinocyte-derived cytokinesrdquo Archivesof Dermatology vol 983089983091983096 no 983090 pp 983090983095983091ndash983090983095983092 983090983088983088983090

[983089983088] A BirolU Kisa G S Kurtipek et al ldquoIncreased tumor necrosisactor alpha (NF-1038389) and interleukin 983089 alpha (IL983089-1038389) levelsin the lesional skin o patients with nonsegmental vitiligordquoInternationalJournalof Dermatology vol 983092983093no 983096 pp 983097983097983090ndash983097983097983091983090983088983088983094

[983089983089] Y Gauthier M C Andre and A aıeb ldquoA critical appraisalo vitiligo etiologic theories Is melanocyte loss a melanocytor-rhagyrdquo Pigment Cell Research vol 983089983094 no 983092 pp 983091983090983090ndash983091983091983090 983090983088983088983091

[983089983090] A aıeb ldquoVitiligo as an in1047298ammatory skin disorder a thera-peutic perspectiverdquo Pigment Cell and Melanoma Research vol983090983093 no 983089 pp 983097ndash983089983091 983090983088983089983090

[983089983091] N C Laddha M Dwivedi M S Mansuri et al ldquoVitiligointerplay between oxidative stress and immune systemrdquo Exper-imental Dermatology vol 983090983090 no 983092 pp 983090983092983093ndash983090983093983088 983090983088983089983091

[983089983092] V Maresca M Roccella F Roccella et al ldquoIncreased sensi-tivity to peroxidative agents as a possible pathogenic actoro melanocyte damage in vitiligordquo Journal of InvestigativeDermatology vol 983089983088983097 no 983091 pp 983091983089983088ndash983091983089983091 983089983097983097983095

[983089983093] K U Schallreuter J M Wood and J Berger ldquoLow catalaselevels in the epidermidis o patients with vitiligordquo Journal of Investigative Dermatology vol 983097983095 no 983094 pp 983089983088983096983089ndash983089983088983096983093 983089983097983097983089

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httpslidepdfcomreaderfull631927 58

Oxidative Medicine and Cellular Longevity 983093

[983089983094] K U Schallreuter J Moore J M Wood et al ldquoIn vivo and in vitro evidence or hydrogen peroxide (H

2O

2) accumulation in

theepidermis o patientswith vitiligo and its successulremovalby a UVB-activated pseudocatalaserdquo Journal of InvestigativeDermatology Symposium Proceedings vol 983092 no 983089 pp 983097983089ndash983097983094983089983097983097983097

[983089983095] E M Shajil and R Begum ldquoAntioxidant statuso segmental andnon-segmental vitiligordquo Pigment Cell Research vol983089983097 no 983090pp983089983095983097ndash983089983096983088 983090983088983088983094

[983089983096] K U Schallreuter J M Wood I Ziegler et al ldquoDeectivetetrahydrobiopterin and catecholamine biosynthesis in thedepigmentation disorder vitiligordquo Biochimica et Biophysica Acta vol 983089983090983090983094 no 983090 pp 983089983096983089ndash983089983097983090 983089983097983097983092

[983089983097] S Hasse N C J Gibbons H Rokos L K Marles and KU Schallreuter ldquoPerturbed 983094-tetrahydrobiopterin recycling viadecreased dihydropteridine reductasein vitiligo moreevidenceor H

2O

2 stressrdquo Journal of Investigative Dermatology vol 983089983090983090

no 983090 pp 983091983088983095ndash983091983089983091 983090983088983088983092

[983090983088] K U Schallreuter J M Wood M R Pittelkow et al ldquoReg-ulation o melanin biosynthesis in the human epidermis by

tetrahydrobiopterinrdquo Science vol 983090983094983091 no 983093983089983093983090 pp 983089983092983092983092ndash983089983092983092983094983089983097983097983092

[983090983089] J M Wood K U Schallreuter-Wood N J Lindsey SCallaghan and M L G Gardner ldquoA speci1047297c tetrahydro-biopterin binding domain on tyrosinase controls melanogene-sisrdquo Biochemical and Biophysical Research Communications vol983090983088983094 no 983090 pp 983092983096983088ndash983092983096983093 983089983097983097983093

[983090983090] J M Wood B Chavan I Haeez and K U SchallreuterldquoRegulation o tyrosinase by tetrahydropteridines and H

2O

2rdquo

Biochemical and Biophysical Research Communications vol983091983090983093no 983092 pp 983089983092983089983090ndash983089983092983089983095 983090983088983088983092

[983090983091] R Khan A Satyam S Gupta V K Sharma and A SharmaldquoCirculatory levels o antioxidants and lipid peroxidation in

Indian patients with generalized and localized vitiligordquo Archivesof Dermatological Research vol 983091983088983089 no 983089983088 pp 983095983091983089ndash983095983091983095 983090983088983088983097

[983090983092] O Arican and E B Kurutas ldquoOxidative stress in the blood o patients with active localized vitiligordquo Acta Dermatovenerolog-ica Alpina Pannonica et Adriatica vol 983089983095 no 983089 pp 983089983090ndash983089983094 983090983088983088983096

[983090983093] P V Sravani N K Babu K V Gopal et al ldquoDeterminationo oxidative stress in vitiligo by measuring superoxide dismutaseand catalase levels in vitiliginous and non-vitiliginous skinrdquoIndian Journal of Dermatology Venereology and Leprology vol983095983093 no 983091 pp 983090983094983096ndash983090983095983089 983090983088983088983097

[983090983094] I Dammak S Boudaya F Ben Abdallah H urki H Attiaand B Hentati ldquoAntioxidant enzymes and lipid peroxidationat the tissue level in patients with stable and active vitiligordquoInternationalJournalof Dermatology vol983092983096no983093pp983092983095983094ndash983092983096983088983090983088983088983097

[983090983095] A Farahi-Jahromy M K Fallahzadeh S Ashkani-Esahani NHamidizadeh M Ghavipisheh and M R Namazi ldquoDecreasedglucose-983094-phosphate dehydrogenase levels in vitiligo patientsurther evidence o oxidative stressrdquo Advanced Biomedical Research vol 983091 no 983089 article 983091983092 983090983088983089983092

[983090983096] F Prignano L Pescitelli M Becatti et al ldquoUltrastructural andunctional alterations o mitochondria in perilesional vitiligoskinrdquo Journal of Dermatological Science vol 983093983092 no 983091 pp 983089983093983095ndash983089983094983095 983090983088983088983097

[983090983097] K U Schallreuter N C J Gibbons C Zothner M MAbou Elloo and J M Wood ldquoHydrogen peroxide-mediatedoxidative stress disrupts calcium binding on calmodulin more

evidence or oxidative stress in vitiligordquo Biochemical and Bio- physical Research Communications vol 983091983094983088 no 983089 pp 983095983088ndash983095983093983090983088983088983095

[983091983088] M achibana ldquoMIF a stream 1047298owing or pigment cellsrdquoPigment Cell Research vol 983089983091 no 983092 pp 983090983091983088ndash983090983092983088 983090983088983088983088

[983091983089] L Denat A L Kadekaro L Marrot S A Leachman and ZA Abdel-Malek ldquoMelanocytes as instigators and victims o oxidative stressrdquo Journal of Investigative Dermatology vol 983089983091983092no 983094 pp 983089983093983089983090ndash983089983093983089983096 983090983088983089983092

[983091983090] L Qiu Z Song and V Setaluri ldquoOxidative stress and vitiligothe Nr983090-ARE signaling connectionrdquo Journal of InvestigativeDermatology vol 983089983091983092 no 983096 pp 983090983088983095983092ndash983090983088983095983094 983090983088983089983092

[983091983091] Z Jian K Li L Liu et al ldquoHeme oxygenase-983089 protects humanmelanocytes rom H

2O

2-induced oxidative stress via the Nr983090-

ARE pathwayrdquo Journal of Investigative Dermatology vol 983089983091983089 no983095 pp 983089983092983090983088ndash983089983092983090983095 983090983088983089983089

[983091983092] Z Jian K LiP Song et al ldquoImpaired activation othe Nr983090-AREsignaling pathway undermines H

2O

2-induced oxidative stress

response a possible mechanism or melanocyte degeneration in vitiligordquo Journal of Investigative Dermatology vol 983089983091983092 pp 983090983090983090983089ndash983090983090983091983088 983090983088983089983092

[983091983093] U Ozel urkcu N Solak ekin Gokdogan Edgunlu SKarakas Celik and S Oner ldquoTe association o FOXO983091A genepolymorphismswith serum FOXO983091A levels and oxidative stressmarkers in vitiligo patientsrdquo Gene vol 983093983091983094 no 983089 pp 983089983090983097ndash983089983091983092983090983088983089983092

[983091983094] W Westerho P Manini A Napolitano and M DrsquoIschia ldquoTehaptenation theory o vitiligo and melanoma rejection a close-uprdquo Experimental Dermatology vol 983090983088 no 983090 pp 983097983090ndash983097983094 983090983088983089983089

[983091983095] M L DellrsquoAnna A Mastrorancesco R Sala et al ldquoAntioxidantsand narrow band-UVB in the treatment o vitiligo a double-blind placebo controlled trialrdquo Clinical and Experimental Der-matology vol 983091983090 no 983094 pp 983094983091983089ndash983094983091983094 983090983088983088983095

[983091983096] M Akyol V K CelikS OzcelikM PolatM Maru1047297hah and A

Atalay ldquoTe effects o vitamin E on the skin lipid peroxidationand the clinical improvement in vitiligo patients treated withPUVArdquo European Journal of Dermatology vol 983089983090 no 983089 pp 983090983092ndash983090983094 983090983088983088983090

[983091983097] M A Middelkamp-Hup JD Bos F Rius-diaz S GonzalezandW Westerho ldquoreatment o vitiligo vulgaris with narrow-bandUVB and oral polypodium leucotomos extract a randomizeddouble-blind placebo-controlled studyrdquo Journal of the European Academyof Dermatology and Venereology vol983090983089 no 983095 pp 983097983092983090ndash983097983093983088 983090983088983088983095

[983092983088] R Colucci F Dragoni R Conti L Pisaneschi L Lazzeriand S Moretti ldquoEvaluation o an oral supplement containingPhyllanthus emblica ruit extracts vitamin E and carotenoidsin vitiligo treatmentrdquo Dermatologic Terapy vol 983090983096 no 983089 pp

983089983095ndash983090983089 983090983088983089983093[983092983089] I C le Poole and R M Luiten ldquoAutoimmune etiology o

generalized vitiligordquo Current Directions in Autoimmunity vol983089983088 pp 983090983090983095ndash983090983092983091 983090983088983088983096

[983092983090] M Sandoval-Cruz M Garcıa-Carrasco R Sanchez-Porras etal ldquoImmunopathogenesis o vitiligordquo Autoimmunity Reviews vol 983089983088 no 983089983090 pp 983095983094983090ndash983095983094983093 983090983088983089983089

[983092983091] C Betterle A Caretto A de Zio et al ldquoIncidence and signi-icance o organ-speci1047297c autoimmune disorders (clinical latentor onlyautoantibodies) in patientswith vitiligordquo Dermatologica vol 983089983095983089 no 983094 pp 983092983089983097ndash983092983090983091 983089983097983096983093

[983092983092] V M Sheth Y Guo and A A Qureshi ldquoComorbidities associ-ated with vitiligo a ten-year retrospective studyrdquo Dermatology vol 983090983090983095 no 983092 pp 983091983089983089ndash983091983089983093 983090983088983089983092

7242019 631927

httpslidepdfcomreaderfull631927 68

983094 Oxidative Medicine and Cellular Longevity

[983092983093] J Sawicki S Siddha and C Rosen ldquoVitiligo and associatedautoimmune disease retrospective review o 983091983088983088 patientsrdquo Journal of Cutaneous Medicine and Surgery vol 983089983094 no 983092 pp983090983094983089ndash983090983094983094 983090983088983089983090

[983092983094] Y Yang G Huang X Yan and Z Qing ldquoClinical analysis o thyroglobulin antibody and thyroid peroxidase antibody andtheir association with vitiligordquo Indian Journal of Dermatology

vol 983093983097 no 983092 pp 983091983093983095ndash983091983094983088 983090983088983089983092

[983092983095] R Harning J Cui and J-C Bystryn ldquoRelation between theincidence and level o pigment cell antibodies and diseaseactivity in vitiligordquo Journal of Investigative Dermatology vol 983097983095no 983094 pp 983089983088983095983096ndash983089983088983096983088 983089983097983097983089

[983092983096] H Uda M akei and Y Mishima ldquoImmunopathology o vitiligo vulgaris Suttonrsquos leukoderma and melanoma-associated vitiligo in relation to steroid effects II Te IgG and C983091 depositsin the skinrdquo Journal of Cutaneous Pathology vol 983089983089 no 983090 pp983089983089983092ndash983089983090983092 983089983097983096983092

[983092983097] Okamoto R F Irie S Fujii et al ldquoAnti-tyrosinase-relatedprotein-983090 immune response in vitiligo patients and melanomapatients receiving active-speci1047297c immunotherapyrdquo Journal of Investigative Dermatology vol 983089983089983089 no 983094 pp 983089983088983091983092ndash983089983088983091983097 983089983097983097983096

[983093983088] E H Kemp D J Gawkrodger P F Watson and A P WeetmanldquoAutoantibodies to human melanocyte-speci1047297c protein Pmel983089983095in the sera o vitiligo patients a sensitive and quantitativeradioimmunoassay (RIA)rdquo Clinical and Experimental Immunol-ogy vol 983089983089983092 no 983091 pp 983091983091983091ndash983091983091983096 983089983097983097983096

[983093983089] H Hedstrand O Ekwall M J Olsson et al ldquoTe transcriptionactor SOX983097 and SOX983089983088 are vitiligo autoantigens in autoim-mune polyendocrine syndrome type 983089rdquo Te Journal of Biological Chemistry vol 983090983095983094 no 983091983096 pp 983091983093983091983097983088ndash983091983093983091983097983093 983090983088983088983089

[983093983090] E Helen Kemp E A Waterman B E Hawes et al ldquoTemelanin-concentrating hormone receptor 983089 a novel target o autoantibody responses in vitiligordquo Journal of Clinical Investi- gation vol 983089983088983097 no 983095 pp 983097983090983091ndash983097983091983088 983090983088983088983090

[983093983091] Y Lili W Yi Y Ji S Yue S Weimin and L Ming ldquoGlobalactivation o CD983096+ cytotoxic lymphocytes correlates with animpairment in regulatory cells in patients with generalizedVitiligordquo PLoS ONE vol 983095 no 983093 Article ID e983091983095983093983089983091 983090983088983089983090

[983093983092] J G van den Boorn D Konijnenberg A M Dellemijn et alldquoAutoimmunedestruction o skin melanocytes by perilesional cellsrom vitiligo patientsrdquo Journalof InvestigativeDermatology vol 983089983090983097 no 983097 pp 983090983090983090983088ndash983090983090983091983090 983090983088983088983097

[983093983093] A Wankowicz-Kalinska R M J G J Van den Wijngaard B Jigges et al ldquoImmunopolarization o CD983092+ andCD983096+ cellstotype-983089-like is associated with melanocyte loss in human vitiligordquoLaboratory Investigation vol 983096983091 no 983093 pp 983094983096983091ndash983094983097983093 983090983088983088983091

[983093983094] R van den Wijngaard A Wankowicz-Kalinska C Le Poole Bigges W Westerho and P Das ldquoLocal immune response in

skin o generalized vitiligo patients destruction o melanocytesis associated with the prominent presence o CLA+ cells atthe perilesional siterdquo Laboratory Investigation vol 983096983088 no 983096 pp983089983090983097983097ndash983089983091983088983097 983090983088983088983088

[983093983095] D A Bassiouny and O Shaker ldquoRole o interleukin-983089983095 in thepathogenesis o vitiligordquo Clinical and Experimental Dermatol-ogy vol 983091983094 no 983091 pp 983090983097983090ndash983090983097983095 983090983088983089983089

[983093983096] C Q F Wang A E Cruz-Inigo J Fuentes-Duculan et alldquoT983089983095 cells and activated dendritic cells are increased in vitiligolesionsrdquo PLoS ONE vol 983094 no 983092 Article ID e983089983096983097983088983095 983090983088983089983089

[983093983097] Y Kotobuki A anemura L Yang et al ldquoDysregulation o melanocyte unction by T983089983095-related cytokines signi1047297cance o T983089983095 cell in1047297ltration in autoimmune vitiligo vulgarisrdquo Pigment Cell and Melanoma Research vol 983090983093 no 983090 pp 983090983089983097ndash983090983091983088 983090983088983089983090

[983094983088] M Dwivedi E H Kemp N C Laddha M S Mansuri AP Weetman and R Begum ldquoRegulatory cells in vitiligoimplications or pathogenesis and therapeuticsrdquo Autoimmunity Reviews vol 983089983092 no 983089 pp 983092983097ndash983093983094 983090983088983089983093

[983094983089] Y Lili W Yi Y Ji S Yue S Weimin and L Ming ldquoGlobalactivation o CD983096+ cytotoxic lymphocytes correlates with animpairment in regulatory cells in patients with generalizedVitiligordquo PLoS ONE vol 983095 no 983093 Article ID e983091983095983093983089983091 983090983088983089983090

[983094983090] M Dwivedi N C Laddha P Arora Y S Maratia and RBegum ldquoDecreased regulatory -cells and CD983092+CD983096+ ratiocorrelate with disease onset and progression in patients withgeneralized vitiligordquo Pigment Cell amp Melanoma Research vol983090983094 no 983092 pp 983093983096983094ndash983093983097983089 983090983088983089983091

[983094983091] M Abdallah R Lot1047297 W Othman and R Galal ldquoAssessmento tissue FoxP983091+ CD983092+ and CD983096+ -cells in active and stablenonsegmental vitiligordquo International Journal of Dermatology vol 983093983091 no 983096 pp 983097983092983088ndash983097983092983094 983090983088983089983092

[983094983092] F Shi and G F Er ldquoIFN- IL-983090983089 and IL-983089983088 co-expression inevolving autoimmune vitiligo lesions o smyth line chickensrdquo Journalof InvestigativeDermatology vol 983089983091983090 no 983091 pp 983094983092983090ndash983094983092983097

983090983088983089983090[983094983093] R Khan S Gupta and A Sharma ldquoCirculatory levels o -

cell cytokines (interleukin [IL]-983090 IL-983092 IL-983089983095 and transorminggrowth actor-1103925) in patients with vitiligordquo Journal of the Amer-ican Academy of Dermatology vol 983094983094 no 983091 pp 983093983089983088ndash983093983089983089 983090983088983089983090

[983094983094] J M Eby H K Kang S ully et al ldquoCCL983090983090 to activate tregmigration and suppress depigmentation in vitiligordquo Journal of Investigative Dermatology 983090983088983089983093

[983094983095] R Colucci Lotti and S Moretti ldquoVitiligo an update on cur-rent pharmacotherapy and uture directionsrdquo ExpertOpiniononPharmacotherapy vol 983089983091 no 983089983091 pp 983089983096983096983093ndash983089983096983097983097 983090983088983089983090

[983094983096] B Kurien K Hensley M Bachmann and R H Sco1047297eldldquoOxidatively modi1047297ed autoantigens in autoimmune diseasesrdquoFree Radical Biology and Medicine vol 983092983089 no 983092 pp 983093983092983097ndash983093983093983094

983090983088983088983094[983094983097] N C Laddha M Dwivedi M S Mansuri et al ldquoRole o

oxidative stress and autoimmunity in onset and progression o vitiligordquo Experimental Dermatology vol 983090983091 no 983093 pp 983091983093983090ndash983091983093983091983090983088983089983092

[983095983088] A Alkhateeb P R Fain A Tody D C Bennett and R ASpritz ldquoEpidemiology o vitiligo and associated autoimmunediseases in Caucasian probandsand theiramiliesrdquo Pigment Cell Research vol 983089983094 no 983091 pp 983090983088983096ndash983090983089983092 983090983088983088983091

[983095983089] K U Schallreuter R Lemke OBrandt et al ldquoVitiligo andotherdiseases coexistence or true association Hamburg study on 983091983090983089patientsrdquo Dermatology vol 983089983096983096 no 983092 pp 983090983094983097ndash983090983095983093 983089983097983097983092

[983095983090] R Colucci F Lotti F Dragoni et al ldquoHigh prevalence o

circulating autoantibodies against thyroid hormones in vitiligoand correlation with clinical and historical parameters o patientsrdquo British Journal of Dermatology vol 983089983095983089 no 983092 pp 983095983096983094ndash983095983097983096 983090983088983089983092

[983095983091] S Sakata S Nakamura and K Miura ldquoAutoantibodies againstthyroid hormones or iodothyronine implications in diagnosisthyroid unction treatment and pathogenesisrdquo Annals of Inter-nal Medicine vol 983089983088983091 no 983092 pp 983093983095983097ndash983093983096983097 983089983097983096983093

[983095983092] S Benvenga F rimarchi and J Robbins ldquoCirculating thyroidhormone autoantibodiesrdquo Journal of Endocrinological Investiga-tion vol 983089983088 no 983094 pp 983094983088983093ndash983094983089983097 983089983097983096983095

[983095983093] R M Ruggeri M Galletti M G Mandol1047297no et al ldquoTyroidhormone autoantibodies in primary Sjogren syndrome andrheumatoid arthritis are more prevalent than in autoimmune

7242019 631927

httpslidepdfcomreaderfull631927 78

Oxidative Medicine and Cellular Longevity 983095

thyroid disease becoming progressively more requent in thesediseasesrdquo Journal of Endocrinological Investigation vol 983090983093 no983093 pp 983092983092983095ndash983092983093983092 983090983088983088983090

[983095983094] R Rostami M R Aghasi A Mohammadi and J Nourooz-Zadeh ldquoEnhanced oxidative stress in Hashimotorsquos thyroiditisinter-relationships to biomarkers o thyroid unctionrdquo Clinical Biochemistry vol 983092983094 no 983092-983093 pp 983091983088983096ndash983091983089983090 983090983088983089983091

[983095983095] R Colucci M Bohm and S Moretti ldquoCommentary rom theEditorial Board to Vitiligo interplay between oxidative stressand immune system (Laddha et al)rdquo Experimental Dermatol-ogy vol 983090983090 no 983094 pp 983091983097983095ndash983091983097983096 983090983088983089983091

[983095983096] M B Murthy and B K Murthy ldquoTyroid disruptors and theirpossible clinical implicationsrdquo Indian Journal of Pharmacology vol 983092983092 no 983092 pp 983093983092983090ndash983093983092983091 983090983088983089983090

7242019 631927

httpslidepdfcomreaderfull631927 88

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