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SurgicalManagement of VitiligoEDITED BY

Somesh Gupta, MD, DNBDepartment of Dermatology and VenereologyAll India Institute of Medical SciencesNew Delhi, India

Mats J. Olsson, PhDDepartment of Medical SciencesSection of Dermatology and VenereologyUniversity HospitalUppsala, Sweden

Amrinder J. Kanwar, MDDepartment of Dermatology, Venereology and LeprologyPostgraduate Institute of Medical Education and ResearchChandigarh, India

Jean-Paul Ortonne, MDDepartment of DermatologyNice University HospitalNice, France

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Surgical Management of Vitiligo

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Dedicated to my parents, Dr. Ram Pratap Gupta and Indra Gupta, who nurtured my interest in Medicine, to my wife Dr. Meenu who was with me all along the way, and to my yet unborn children (twins) through whom I seemy vision for the future.

Somesh Gupta

To the patients and to my most highly respected friends, colleagues, and mentorsDr. Aaron B. Lerner (Yale University) and the late Dr. Lennart Juhlin (UppsalaUniversity) for always supporting my thoughts and development and for anabsolutely reliable friendship.

Mats J. Olsson

Dedicated to vitiligo patientsAmrinder J. Kanwar

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SurgicalManagement of VitiligoEDITED BY

Somesh Gupta, MD, DNBDepartment of Dermatology and VenereologyAll India Institute of Medical SciencesNew Delhi, India




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© 2007 by Blackwell Publishing LtdBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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First published 2007

1 2007

Library of Congress Cataloging-in-Publication Data

Surgical management of vitiligo / edited by Somesh Gupta ... [et al.]p. ; cm.

Includes bibliographical references.ISBN-13: 978-1-4051-4521-3 (alk. paper)ISBN-10: 1-4051-4521-8 (alk. paper)

1. Vitilio—Surgery. I. Gupta, Somesh.[DNLM: 1. Vitiligo—Surgery. 2. Cell Transplantation—methods.

3. Skin Transplantation—methods. WR 265 S961 2007]

RL790.S87 2007616.5’5—dc22

2006015410

ISBN-13: 978-1-4051-4521-3ISBN-10: 1-4051-4521-8

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Contents

List of contributors, viii

Foreword, xi

Preface, xiii

Section 1 Pathogenesis and medical treatment

1 Pathogenesis of vitiligo, 3Jean-Paul Ortonne

2 Understanding the mechanism of repigmentation in vitiligo, 14Amrinder J. Kanwar and Davinder Parsad

3 Classification of vitiligo, 20Sang Ju Lee , Sung Bin Cho and Seung-Kyung Hann

4 Medical treatment of vitiligo, 31Thierry Passeron and Jean-Paul Ortonne

Section 2 Overview of surgical management

5 History and chronology of development of surgical therapies for vitiligo, 41Rafael Falabella

6 The concept of stability of vitiligo, 49Koushik Lahiri and Subrata Malakar

7 Patient selection and preoperative information in surgical therapies for vitiligo, 56Nanny van Geel and Jean Marie Naeyaert

8 Classification of surgical therapies for vitiligo, 59Philippe Bahadoran and Jean-Paul Ortonne

9 Surgical management of vitiligo and other leukodermas: evidence-based practice guidelines, 69Somesh Gupta, Tarun Narang, Mats J. Olsson and Jean-Paul Ortonne

10 Evaluation of outcome in surgical therapies for vitiligo, 80Nanny van Geel and Jean Marie Naeyaert

v

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Section 3 Tissue grafting

11 Minigrafting for vitiligo, 87Subrata Malakar and Koushik Lahiri

12 Suction blister epidermal grafting, 96Somesh Gupta and Ashima Goel

13 Thin split-thickness skin grafts for vitiligo, 108Niti Khunger

14 Treatment of leukoderma by transplantation of ultra-thin epidermal sheets 115Mats J. Olsson

15 Transplantation of hair follicles for vitiligo, 123Subrata Malakar, Gun Yoen Na and Koushik Lahiri

16 Mesh grafts for vitiligo, 128C.R. Srinivas, Reena Rai and M. Sinha

17 Flip-top pigment transplantation, 134Brent E. Pennington, Jean L. Bolognia and David J. Leffell

18 Ultrasonic abrasion and seed grafts for vitiligo, 139Katsuhiko Tsukamoto, Reiko Kitamura and Osami Takayama

19 Complications and limitations of melanocyte transplantation, 144Yvon Gauthier

Section 4 Cellular grafting

20 Treatment of leukoderma by transplantation of basal cell layer suspension, 151Mats J. Olsson

21 Setting up a tissue culture laboratory, 161Rafal Czajkowski, Tomasz Drewa and Waldemar Placek

22 Treatment of leukoderma by transplantation of cultured autologousmelanocytes, 168Mats J. Olsson

23 Transplantation of in vitro cultured epithelial grafts for vitiligo and piebaldism, 180Liliana Guerra, Sergio Bondanza and Desanka Raskovic

24 Simplifying the delivery of cultured melanocytes and keratinocytes forgrafting patients with vitiligo, 191Sheila MacNeil and Paula Eves

25 Safety concerns in transplantation of in vitro cultured cellular grafts, 203Liliana Guerra, Elena Dellambra and Patrizia Paterna

Section 5 Special issues

26 Post-surgery patient information, 209Mats J. Olsson

vi Contents

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27 Surgical management of lip vitiligo, 211Somesh Gupta, Ashima Goel and Amrinder J. Kanwar

28 Surgical management of vitiligo of eyelids and genitals: special issues, 220Somesh Gupta

29 Surgical management of acral vitiligo, 225Sharad Mutalik

30 Surgical management of leukotrichia, 229Karoon Agrawal and Aparna Agrawal

31 Surgical treatments of leukodermas other than vitiligo vulgaris, 238Mats J. Olsson

Section 6 Miscellaneous

32 Micropigmentation, 249Gurvinder P. Thami

33 Laser for repigmenting vitiligo, 255Thierry Passeron and Jean-Paul Ortonne

34 Application of lasers in transplantation procedures for vitiligo, 259Cengiz Acikel, Ersin Ulkur and Bahattin Celikoz

35 Combining medical and surgical therapies, 267Alain Taïeb and Yvon Gauthier

36 Surgical depigmentation of vitiligo: bleaching cream, laser and cryosurgery, 273Monique R.T.M. Thissen

37 Future directions in surgical management of vitiligo, 277Yvon Gauthier

38 Informed consent, 281Mats J. Olsson

Index, 283

Color plate section appears after page 114

Contents vii

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EditorsSomesh Gupta, MD, DNBDepartment of Dermatology and VenereologyAll India Institute of Medical SciencesNew Delhi, India




Contributors

Cengiz Acikel, MDDepartment of Plastic Reconstructive and Aesthetic

SurgeryGulhane Military Medical Academy Haydarpasa HospitalIstanbul, Turkey

Aparna Agrawal, MDDepartment of Plastic SurgeryJawaharlal Institute of Postgraduate Medical Education and

ResearchPondicherry, India

Karoon Agrawal, MS, MCh(Plastic Surgery)Department of Plastic SurgeryJawaharlal Institute of Postgraduate Medical Education and

ResearchPondicherry, India

Philippe Bahadoran, MD, PhDDepartment of DermatologyUniversity HospitalNice, France

Jean L. Bolognia, MDDepartment of DermatologyYale UniversityNew Haven, CT, USA

Sergio Bondanza, BScLaboratory of Tissue Engineering and Cutaneous

PhysiopathologyIstituto Dermopatico dell’Immacolata, IDI-IRCCSRome, Italy

Bahattin Celikoz, MDDepartment of Plastic Reconstructive and Aesthetic SurgeryGulhane Military Medical Academy Haydarpasa HospitalIstanbul, Turkey

Sung Bin Cho, MDDepartment of DermatologyYonsei University College of MedicineSeoul, South Korea

Rafal Czajkowski, MD, PhDDepartments of Dermatology and Tissue EngineeringNicolaus Copernicus University in TorunLudwik Rydygier Medical College in BydgoszczBydgoszcz, Poland

List of contributors

viii

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List of contributors ix

Elena Dellambra, PhDLaboratory of Tissue Engineering and Cutaneous


Tomasz Drewa, MD, PhDDepartment of Tissue EngineeringNicolaus Copernicus University in TorunLudwik Rydygier Medical College in BydgoszczBydgoszcz, Poland

Paula Eves, PhDDepartment of Engineering MaterialsThe Kroto Research InstituteUniversity of SheffieldSheffield, UK

Rafael Falabella, MDDepartment of DermatologyUniversidad del Valle and Hospital Universitario del ValleCali, Colombia

Yvon Gauthier, MDDepartment of DermatologyPigmentary Disorders Outpatient ClinicHôpital Saint AndréBordeaux, France

Ashima Goel, MDDepartment of Dermatology, Venereology and LeprologyPostgraduate Institute of Medical Education and ResearchChandigarh, India

Liliana Guerra, MDLaboratory of Tissue Engineering and Cutaneous


Seung-Kyung Hann, MDDrs. Woo & Hann’s Skin ClinicSeoul, South Korea

Niti Khunger, MD, DNB, DDVSafdarjang Hospital & V. M. Medical College New Delhi, India

Reiko Kitamura, MD, PhDDepartment of DermatologyUniversity of YamanashiFaculty of MedicineYamanashi, Japan

Koushik Lahiri, MBBS, DVD, DNBI, FAAD,PhD(Scholar)Pigmentary Disorder UnitRita Skin FoundationSalt Lake, Kolkata, India

Sang Ju Lee, MDDepartment of DermatologyYonsei University College of MedicineSeoul, South Korea

David J. Leffell, MDDepartment of DermatologyYale UniversityNew Haven, CT, USA

Sheila MacNeil, PhDDepartment of Engineering Materials and Division of

Clinical Sciences (North)The Kroto Research InstituteUniversity of SheffieldSheffield, UK

Subrata Malakar, MBBS, DCH, MDPigmentary Disorder UnitRita Skin FoundationSalt Lake, Kolkata, India

Sharad Mutalik, MBBS, DVDConsultant Dermatologist, Dermatologic and Laser SurgeonSkin and Cosmetology ClinicPune, India

Gun Yoen NaDepartment of DermatologySchool of MedicineKyungpook National University HospitalDaegu, South Korea

Jean Marie Naeyaert, MD, PhDDepartment of DermatologyGhent University HospitalGhent, Belgium

Tarun Narang, MDDepartment of Dermatology and VenereologyPostgraduate Institute of Medical Education and ResearchChandigarh, India

Davinder Parsad, MDDepartment of Dermatology, Venereology and LeprologyPostgraduate Institute of Medical Education and ResearchChandigarh, India

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Thierry Passeron, MDDepartment of DermatologyUniversity Hospital of NiceNice, France

Patrizia Paterna, BScLaboratory of Tissue Engineering and Cutaneous


Brent E. Pennington, MDNashville Skin and CancerNashville, TN, USA

Waldemar Placek, MD, PhDDepartment of DermatologyNicolaus Copernicus University in TorunLudwik Rydygier Medical College in BydgoszczBydgoszcz, Poland

Reena Rai, MDDepartment of Dermatology, Venereology, and LeprologyPSG Institute of Medical Sciences and ResearchCoimbatore, Tamil Nadu, India

Desanka Raskovic, MDVI Division of DermatologyIstituto Dermopatico dell’Immacolata, IDI-IRCCSRome, Italy

M. Sinha, MS, MRCSEdDepartment of Plastic and Reconstructive SurgeryCanniesburn Plastic Surgery UnitGlasgow Royal InfirmaryGlasgow, UK

C.R. Srinivas, MDDepartment of Dermatology, Venereology, and

LeprologyPSG Institute of Medical Sciences and ResearchCoimbatore, Tamil Nadu, India

Osami Takayama, MDTakayama Dermatology and Plastic Surgery ClinicYamanashi, Japan

Alain Taïeb, MDDepartment of DermatologyHôpital St AndréCentre Hospitalier et Universitaire de BordeauxBordeaux, France

Gurvinder P. Thami, MDDepartment of Dermatology and VenereologyGovernment Medical College and HospitalChandigarh, India

Monique R.T.M. Thissen, MD, PhDDepartment of Dermatology and VenereologyUniversity Hospital MaastrichtMaastricht, The Netherlands

Katsuhiko Tsukamoto, MD, PhDDepartment of DermatologyYamanashi Prefectural Central HospitalYamanashi, Japan

Ersin Ulkur, MDDepartment of Plastic Reconstructive and

Aesthetic SurgeryGulhane Military Medical Academy Haydarpasa HospitalIstanbul, Turkey

Nanny van Geel, MD, PhDDepartment of DermatologyGhent University HospitalGhent, Belgium

x List of contributors

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Foreword

xi

To raise new questions, new possibilities, to regard old prob-

lems from a new angle, requires creative imagination and

marks real advance in science.

Albert Einstein

Many researchers throughout the world have dedicated their time and lives in search of the etiol-ogy of vitiligo, an important skin pathology thatalthough physically asymptomatic in most patients,provokes profound changes in psychologicalbehavior and social interaction with other individ-uals in daily life. And most important, in spite ofmultiple known factors involved in its pathogenesisthat have been published in many journals devotedto different disciplines – from the laboratory to theambulatory patient – finding the cause of this condition has been elusive.

To our satisfaction, remarkable progress has beenmade in the past two decades. When medical ther-apy is no longer useful for treating depigmentedlesions, melanocyte transplantation, performedjudiciously, provides acceptable repigmentation for

an important proportion of appropriately selectedpatients presenting with stable disease.

We are fortunate that Professors Somesh Gupta,Mats J. Olsson, Amrinder J. Kanwar and Jean-PaulOrtonne have provided the readers with a superbbook consisting of 38 chapters written by 48 inter-national authorities from 13 countries, in theirfields of expertise. This magnificent book is themost comprehensive scientific work written todate, in which all topics of surgical management ofvitiligo are covered by a panel of well knownauthors. Not only are all pertinent surgical topicsdealt with in fine detail, but also the current under-standing of pathogenic mechanisms and clinicalaspects of the disease are described, providing thefoundations for determining which patients may becandidates for surgical repigmentation therapy.

Finally, after reading the contents and conceptsof Surgical Management of Vitiligo, I was inspired toexpress the following words: “Innovation increaseshuman knowledge though sometimes originates contro-versy, which in turn stimulates improvement.”

Rafael Falabella, MD

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Preface

xiii

The concept of surgically treating vitiligo was firstproposed by a few pioneers in the 1960s. Over theyears, this technique has developed considerablyand is becoming progressively more sophisticated.

Vitiligo is characterised by a lack of melanocytes,which are destroyed by various unidentified mech-anisms. Initial attempts to repigment vitiligo skinwere aimed at mobilising melanocytes from unaf-fected skin and/or hair follicles to depigmented skinlesions. This strategy, which is often tedious, doesnot consistently provide the desired results, eventhough a little more is now known about the mech-anisms that control the migration and differentia-tion of melanocyte precursors found in hair follicles.

Several autologous pigmented skin graft tech-niques for vitiligo patients have been developed inorder to facilitate the proliferation and migration ofmelanocytes in grafts so that they colonise thevitiligous skin in which they were implanted. Thesetechniques were micronised in order to reduce andavoid any skin abnormalities that could result fromthe healing of these grafts. They can be used formucous membranes and on sensitive areas such asthe eyelids, and areas that are resistant to repig-mentation, such as the fingers. The transplantationof pigmented hair follicles to vitiligous skin has alsobeen successfully explored.

Cellular grafts of epidermal cell suspensions (keratinocytes and melanocytes) or autologousmelanocytes cultivated prior to grafting have alsobeen used successfully. Several groups even suggestgrafting epidermis that is reconstructed in vitro,

consisting of both melanocytes and epidermal keratinocytes.

What is the future for the surgical treatment of vitiligo?It is likely that these “biotherapies” will becomepart of future vitiligo treatments, either by usingcytokines, or growth factors that facilitate the differ-entiation, proliferation and migration of melanocytes.Melanocyte progenitors and/or human embryonicstem cells will most likely have a role in futurevitiligo biotherapies, to the extent that the toler-ance and efficacy of factors that modulate pigmentcells will have been demonstrated. Also, a U.S.team has recently reported that it is possible togrow functional melanocytes from human embry-onic stem cells in vitro. One can therefore hope thatthe production of melanocytes for the repigmenta-tion of vitiligous skin will become easier and moreproductive in the future.

Cellular graft techniques also need to evolve. It iscurrently possible to prepare the ‘bed’ for melanocytegrafts by destroying the epidermis using lasers, whileavoiding damage to the basal membrane at the epidermal-dermal junction. It is hoped that futuretechniques will improve this step further.

I would like to thank Somesh Gupta andAmrinder J. Kanwar for inviting me to be involvedin the publication of this book with Mats J. Olsson,one of the pioneers in melanocyte grafting for thetreatment of vitiligo. The resulting monograph, thefirst publication that is dedicated to the surgicaltreatment of vitiligo, is a true encyclopedia contain-ing contributions from most of the global teams

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xiv Preface

that surgically treat vitiligo. It will not be the lastand should be regularly updated as progress ismade in this area.

I hope you enjoy reading it and I hope it meetsyour expectations. Perhaps in the future, effectivetherapies that block the processes that cause skin

depigmentation will become available. In themeantime, we need to continue the progress beingmade on repigmenting techniques. For several skinsites, surgical and biotherapeutic approaches will bethe optimal choice.

Jean-Paul Ortonne, MD

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SECTION 1

Pathogenesis and medical treatment

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Introduction

Vitiligo is an acquired cutaneous hypomelanosis witha 0.5–2% incidence worldwide, without predilec-tion for sex or ethnicity. The clinical presentation ischaracterized by well-circumscribed white macules.Several clinical phenotypes have been identified.Generalized vitiligo is characterized by acquireddepigmentation due to melanocyte loss, in a pat-tern that is non-focal and generally bilateral acrossthe midline, though not necessarily symmetric [1].This definition differentiates generalized vitiligo fromsegmental vitiligo and other localized forms of vitiligowhose true pathogenic relationship to generalizedvitiligo is as-yet unknown.

This chapter is a review of the recent develop-ments of vitiligo pathogenesis. There are threemajor hypotheses for the pathogenesis of vitiligothat are not exclusive of each other – the auto-immune hypothesis, the neuronal dysfunctionhypothesis, and the melanocyte self-destructionhypothesis. Several other hypotheses have beenrecently proposed.

Vitiligo: a melanocyte disorder ormore?

Melanocytes present or absent in vitiligomacules?Vitiligo is characterized by a disappearance of epider-mal and/or follicular melanocytes. It is likely thatmelanocytes are destroyed by an as-yet unknownprocess. Indeed, melanocyte destruction has neverbeen clearly demonstrated [2]. One recent studyreports that melanocytes are never completely absentin the skin [3]. Melanocyte cultures were successfullyestablished from depigmented epidermal suction

blister roof of 12 randomly selected vitiligo patients.These “vitiligo” melanocytes produced melanin invitro. Although interesting, these observations in asmall group of patients cannot be generalized. Thepersistence of melanocytes within vitiligo maculeswas already reported in 1956 [4]. Besides the so-called “absolute” type of vitiligo in which there areno dopa-positive melanocytes in the vitiliginous epi-dermis, there are “relative” types of vitiligo in whichmelanocytes remain in the white macules with adecreased dopa-positivity. It is likely that the disap-pearance of epidermal melanocytes in vitiligo maculesis not an immediate process, but is a progressive one.Indeed, it may be suggested that the “relative” typesof vitiligo are considered possible forerunners of the“absolute” types. Thus, it would not be surprising to find melanocytes in the epidermis of the whitemacule of “relative” vitiligo. An immunohistologicalstudy of vitiliginous skin using a panel of melanocytemarkers, related and unrelated to the melanogenicpathway, could not detect identifiable epidermalmelanocytes [5]. From the presently available data,it is generally agreed that there are no longer func-tional melanocytes in vitiligo skin and that this lossof histochemically recognizable melanocytes is theresult of their destruction.

The impact of vitiligo on melanocyte stem cells(MSC) is not known. MSC are present in the bulgeregion of hair follicles in the adult skin in mice.Undifferentiated MSCs in the bulge have beenshown to express the three transcription factors,PAX 3, SOX 10, and MITF. These factors play a keyrole in controlling the balance between MSC main-tenance and differentiation. Studies to evaluateMSCs in vitiligo-pigmented and depigmented hairfollicles are strongly required to better understandthe mechanism of poliosis in vitiligo patients and

3

CHAPTER 1

Pathogenesis of vitiligoJean-Paul Ortonne

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4 Chapter 1

the cellular event underlying perifollicular repig-mentation of vitiligo [6].

KeratinocytesSeveral observations suggest that epidermal cellsother than melanocytes are also altered in vitiligoinvolved and uninvolved skin. Epidermal ker-atinocytes produce several factors that support the growth and differentiation of neighboringmelanocytes, such as basic fibroblast growth factor(b-FGF) and stem cell factors (SCF). A recent studydemonstrated that the expression of SCF (P �

0.001) and b-FGF was usually reduced in the depig-mented compared with the normally pigmentedvitiligo epidermis [7]. SCF has been demonstrated to prevent TRAIL-induced melanocyte apoptosis in vitro. These results suggest that melanocyte celldeath in vitiligo can result from deprivation of keratinocyte-derived SCF.

Cytoplasmic vacuolization and/or the presence ofan extracellular granular material that may bederived from the cytoplasm of altered keratinocyteshave been reported mainly in the adjacent normal-appearing vitiligo skin, but also in the perilesionalskin and rarely in the lesional skin [8]. Focal areasof vacuolar degeneration in the lowest layers of theepidermis, especially in the basal layer in associa-tion with mild mononuclear cell infiltrate, have alsobeen observed [9].

The significance of these morphological observa-tions is not known, but several hypotheses can beproposed. They may be related to architectural dis-turbances induced by a local immunological reaction.They may be due to toxic intermediate metabolites of melanogenesis, which destroy not only the pig-ment cell from which they originate [8], but also theadjoining keratinocytes. The recently proposed the-ory of a breakdown in the detoxification mechanismsin vitiligo skin fits very well with these observations.

Langerhans cellsThe role of Langerhans cells in vitiligo has beenopen to controversy. The Langerhans cell densityevaluated either by histochemical techniques(ATPase) or with the monoclonal antibodies OKT6and anti-HLADR has been variably reported asdecreased, normal, or increased [10]. In addition to

these quantitative changes of Langerhans cells, afunctional impairment of these cells has also beendocumented in vitiligo skin. How this functionalimpairment of Langerhans cells is related to thepathogenesis of vitiligo remains to be established.

All these observations suggest that vitiligo affectsthe entire keratinocyte–Langerhans cell-melanocyteunit (KLM) [11]. In the epidermis there is a complexexchange of messages between these three celltypes that is just beginning to be understood. Nodoubt a better clarification of these epidermal cellinteractions will help in understanding the basicmechanisms involved in vitiligo.

Genetics of vitiligo

Epidemiological dataFamilial studies have shown the increased prevalenceof vitiligo in close relatives of affected individuals. In a large series performed in India, this increase wasabout 4.5-fold in close biological relatives [12].Another study performed on 160 white kindred livingin US shows a relative risk (RR) for vitiligo of about 7 for parents, about 12 for siblings, and about 36 forchildren [13]. The pattern of relationship betweenRR and degree of kinship indicates involvement ofgenetic factors, although it is not consistent with single-locus Mendelian transmission. The majorgenetic component in vitiligo pathogenesis and alsothe role of environmental factors were recentlyemphasized [14]. In this epidemiological study the frequency of vitiligo in probands’ siblings was6.1%, about 18 times that of the population fre-quency. Nevertheless, the concordance of vitiligo inmonozygotic twins was only 23%, indicating that anon-genetic component also plays an important role.Moreover, probands with earlier disease onset tendedto have more relatives affected with vitiligo, sug-gesting a greater genetic component in early onsetfamilies.

One vitiligo or several vitiligos?For most authors, vitiligo is a unique disorder withseveral clinical presentations but one physiopathol-ogy. Indeed, almost all the recent genetic studies haveignored the clinical presentation of patients. However,recent data strongly suggest that there is not one

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vitiligo but several vitiligos. A complex segregationanalysis was performed on 2247 Chinese patientsand their families. For the first time the results wereanalyzed according to the clinical manifestations[15]. The results showed a different age of diseaseonset depending on the subtypes of vitiligo. Moreinterestingly, a polygenetic additive model was foundto be the best model for segmental, localized, acro-facial, and generalized vitiligo whereas the best modelfor universal vitiligo was an environmental model.All of these data suggest that heterogeneous patho-geneses underlie different phenotypes of vitiligo.

Genetic aspects of vitiligoThe earliest genetic studies of vitiligo were case-control association studies of the major histocom-patibility complex (MHC). They were carried out bytesting various different vitiligo phenotypes versuscontrols in many different populations. Genetic asso-ciation of vitiligo with alleles of MHC loci appearedto be strongest in patients and families with variousvitiligo-associated autoimmune/autoinflammatorydisorders versus patients and families with only gen-eralized vitiligo. Thus, it is not clear whether theMHC association is with vitiligo, vitiligo-associatedautoimmune/autoinflammatory disorders, or both.

Allelic association between vitiligo and a numberof other candidate genes has also been described(Table1.1).

Which gene(s) for vitiligo?Two large genome-wide screens for generalizedvitiligo showed significant linkage of an oligogenicautoimmune susceptibility locus, termed AIS1(1p31.3–p32.2) [16,[17]. An additional seven signals on chromosome 1,7,8,11,19, and 22 metgenome-wide criteria for “suggestive linkage.” Inan extended study with a cohort of 102 multiplexfamilies the localization of AIS1 was confirmed andtwo new susceptibility loci have been found. AIS2is located on chromosome 7 and AIS3 on chromo-some 8. Additionally, the locus SLEV1 on chromo-some 17 was confirmed and two new potentiallinkages on chromosome 9q and on 13q are alsoreported (Table 1.1) [18]. Interestingly, all loci exceptAIS3 derive principally from the autoimmunity-associated family subgroup. These loci may predis-pose to a vitiligo-associated autoimmunity diathesis.On the other hand, analyses suggest a linkage to SLEV1 in the autoimmune families and non-linkage in the non-autoimmune families. Thus, link-age to SLEV1 in these families indicates that SLEV1confers susceptibility to a broader range of auto-immune diseases than just lupus and vitiligo. Agenome-wide linkage analysis in Chinese familiesidentified interesting linkage evidence in 1p36,4q13–21, 6p21–p22, 6q24–q25, 14q12–q13, and22q12. These findings in the Chinese populationshared a minimal overlap with the linkage findingsin the Caucasian population. Such little overlapbetween the linkage findings of this two popula-tions may suggest that vitiligo is associated with astrong genetic heterogeneity [19].

Many candidate genes for vitiligo have been pro-posed so far (Table 1.2). However, most of the locidescribed do not correspond to positions of theseproposed biological candidate genes.

Finally, one of the best candidate genes could beFOXD3 (“Forkhead box” D3). FOXD3 is located on chromosome 1 (1p32–p31) and is a transcriptionfactor that suppresses melanoblast developmentfrom the neural crest [20]. Therefore, dysregulated(over-)expression might harm melanocytes.Moreover FOXD3 also regulates endodermal differ-entiation including thyroid, pancreas, adrenal, andgut [21] and other FOX factors are involved inautoimmune syndromes [22]. Mutations in FOXD3

Pathogenesis of vitiligo 5

Table 1.1 Susceptibility loci for vitiligo.

References Susceptibility locus Mapping

[73] SLEV1 17p13

[18]

[16] AIS1 1p31.3–p32.2

[18] AIS2 7p

[18] AIS3 8q

[74] 6p21.3–21.4

[75] 4q13–q21

Modified from Passeron T, J Autoimmun 2005;25:63–8,and Spritz RA, J Dermatol Sci 2006;41:3–10.

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leading to elevated FOXD3 transcription have beenrecently reported in one AIS1-linked family [23].Thus, FOXD3 is worth further investigation andrepresents a serious candidate gene in AIS1-linkedautoimmune disease.

Pathogenesis

The classic hypotheses

Vitiligo is an autoimmune diseaseThis theory is the most long-standing and popularhypothesis for the pathogenesis of vitiligo. It pro-poses that melanocytes are killed by autoimmuneeffector mechanisms.

Association with autoimmune diseaseSporadic generalized vitiligo is associated withautoimmune thyroid disease, pernicious anemia,Addison’s disease, systemic lupus erythematosus[14]. Familial generalized vitiligo is also characterized

by a broad repertoire of associated autoimmune dis-eases, such as thyroiditis, rheumatoid arthritis, pso-riasis, adult-onset-dependent diabetes mellitus,pernicious anemia, and Addison’s disease [24].Furthermore generalized vitiligo is a component ofthe APECED (APS1) and Schmidt (APS2) multipleautoimmune disease syndromes. These same vitiligo-associated autoimmune/autoinflammatory disordersalso occur, at increased frequencies, in patients’ first-degree relatives, regardless of whether or not thoserelatives have vitiligo themselves. These observationssuggest that specific genes predispose to a specificgroup of autoimmune diseases that includes gener-alized vitiligo, autoimmune thyroid disease, rheuma-toid arthritis, psoriasis, adult-onset insulin-dependentdiabetes mellitus, and pernicious anemia.

Cellular immunityRecent evidence has emerged for a role for cell-mediated immunity in vitiligo pathogenesis. The

6 Chapter 1

Table 1.2 Vitiligo candidate genes.

Gene Mapping Product Disease

PTPN 22 1p13 Lymphoid protein tyrosine phosphatase Vitiligo vulgaris

FOXD3 1p32–p31 Transcriptor factor involved in Early and progressive vitiligomelanoblast differentiation

VIT 1/FBX 011 2p21 ? Vitiligo vulgaris

CTLA 4 2q33 Antigen-4 of T-cytotoxic lymphocytes Vitiligo vulgaris

MITF 3p14.1–p12.3 Transcription factor Vitiligo vulgaris

KIT 4q12 Transmembrane tyrosine kinase Vitiligo vulgaris

MHC (HLA-DRB1, 6p21.1 Major MHC Vitiligo vulgarisHLA-DRB4, HLA-DQB1)

ESR 1 6p25.1 Oestrogen receptor 1 Vitiligo vulgaris

CAT 11p13 Catalase Vitiligo vulgaris

GTPCH (GTP-cyclohydoxylase 14q22.1–q22.2 Rate-limiting enzyme of the Vitiligo vulgarisI gene) tetrahydrobiopterin pathway

ACE 17q23 Angiotensin converting enzymes Vitiligo vulgaris

AIRE 21q22.3 Transcriptor factor APECED

COMT 22q11.2 Catecholamine O methyl transferase Vitiligo vulgaris

Modified from Passeron T, J Autoimmun 2005;25:63–8, and Spritz RA, J Dermatol Sci 2006;41:3–10.

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discovery of a T-cell infiltrate in the margin of inflam-matory vitiligo was the first clue for participation of cellular immunity in vitiligo pathogenesis.Infiltrating activated CD4 and CD8 T-cells, but notthe B-cells, have been observed at the periphery ofvitiligo lesions [25]. A more recent study of vitiligolesional skin noted a high frequency of cutaneouslymphocyte antigen-positive-activated cytotoxic T-cells clustered in perilesional skin in the vicinityof disappearing melanocytes [26]. Furthermore,melanocytes in close proximity to activated lym-phocytes focally expressed HLA-DR and intercellu-lar adhesion molecule-1, suggesting a major rolefor skin-homing T-cells in melanocyte death [26]. The reports of an increase of CD45RO memory T-cells, increased levels of soluble interleukin-2receptors and expression of the cutaneous lympho-cyte antigen in number infiltrating T-cells, all sug-gest an activation of circulating T-cells and theirrecruitment to the vitiligo skin [27–29]. In vitiligoskin the CD4/CD8 ratio is reversed with a predom-inant presence of CD8 T-cells.

Further evidence for a role played by cytotoxic T-cells in vitiligo stems from studies of melanomapatients. Vitiligo-like depigmentation has beenobserved following successful immunotherapy ofmelanoma, including high-dose IL-2 therapy, infu-sion of peptide pulsed dendritic cells, and MelanA/MART-1 specific CTL clones [30]. A specific cellu-lar immune response predominantly directed againstthe melanosomal protein Melan-A/MART-1 wasobserved in HLA-A2-positive vitiligo patients whereCD8� T-cells displaying Melan-A/Mart-1-specificreactivity ex vivo were demonstrated in the periph-eral blood of these patients. Another study reportedevidence of an association between CD8 �

T-lymphocyte reactivity to the melanocyte antigengp100 and to a lesser extent Melan-A/MART-1 andvitiligo [30]. These findings support the concept ofan immunopathological mechanism in vitiligo inwhich cell-mediated play a crucial part. Recently,new understanding for the requirements forCD8� T-cell mediated destruction of melanocyteswas brought [31]. CD4� T-cell help induced by sys-temic immunization and a local inflammation areboth required to break MHC class-I-restricted T-celltolerance.

Humoral immunitySeveral circulating autoantibodies (Table 1.3) havebeen found in sera of vitiligo patients. These includeantibodies to non-pigment cell antigens (common tis-sue antigens), cytoplasmic pigment cell antigens, andpigment cell surface antigens [32]. The heterogeneityof this antibody response is surprising and does notfit with a selective destruction of melanocytes. Onereasonable explanation is that this humoral responsecould be secondary to a primary melanocyte destruc-tion mediated by other mechanisms.

The incidence and serum level of antibodies wasfound to correlate with the disease activity and theextent of the cutaneous depigmentation. Functionalin vitro assays have shown the ability of antibodiesto damage melanocytes, both by complement activa-tion and by ADCC [33]. Furthermore injections ofIgG fractions of serum from patients with vitiligohave a destructive effect on melanocytes of thehuman skin grafted onto nude mice [34].

Antibody-dependent immunity against themélanosome membrane protein-1 (TYRP-1) ofmelanocytes leads to autoimmune hypopigmenta-tion. Hypopigmentation occurred in mice deficientin activating FcR containing the common � subunitand in mice deficient in the C3 complement but notin mice doubly deficient in both Fc�R� and C3 [35].

The neural hypothesisThere are several observations, clinical findings,and laboratory evidence that suggest the involve-ment of the nervous system in the pathogenesis of


Table 1.3 Identified target autoantibodies for vitiligoantibodies.

Autoantigen Function

Tyrosinase Melanogenic enzyme

TRP-2 Melanogenic enzyme

TRP-1 Melanogenic enzyme

Pmel-17 Melanocyte-specific protein

MCHR1 Melanin concentrating hormone receptor 1

SOX 9 Transcription factor

SOX 10 Transcription factor

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vitiligo. Embryologically, melanocytes are derivedfrom the neural crest. There are isolated reports ofvitiligo associated with viral encephalitis and trans-verse myelitis. Communication between the nerv-ous system and epidermal melanocytes has beenproved [36]. Ultrastructural studies demonstratefrequent direct contacts between dermal nerveendings and melanocytes in vitiligo skin [37] orstructural alterations (swelling of axons, duplica-tion of the basement membrane, etc.) [38,39], butthe significance of these morphological findings isunknown. The neural hypothesis is based in thefirst place on the presence of segmental vitiligo. Thedistribution of segmental vitiligo is often said to bedermatomal, suggesting the role of regional nervesin this condition. In actuality it is unilateral, but notdermatomal (i.e. it does not follow a specific pattern of cutaneous sensory nerves) [40].

Thus, the role of the nervous system in thepathogenesis of vitiligo is still undefined.

A few physiological studies have demonstratedaltered bleeding times, epinephrine vasoconstrictoreffect, and abnormal sympathetic skin responses inlesions of vitiligo [41,42]. Other studies have shownaltered neuropeptides in vitiligo. Aberrations in �-endorphin and met-enkephalin secretion havebeen reported [43]. The plasma met-enkephalin levels were generally higher in vitiligo patients, espe-cially in those with active vitiligo, than in controls.Immunohistological observations suggest that theimmunoreactivity to neuropeptide Y and vasoactiveintestinal polypeptide is increased at the marginalareas or within vitiligo macules. These observationssupport the hypothesis of neural involvement andneuro-immunomodulation in vitiligo [39]. Stillother studies have demonstrated a reduction in theimmunoreactive nerve growth factors (NGFr-IR)[44] and an absence of Merkel cells [45].

Several studies demonstrating abnormalities of acetylcholine, catecholamines, or related enzymes(catechol-o-methyltransferase (COMT) and mono-amino oxidase [46,47]) have also been reported withconflicting results [48–50]. A reduced acetyl-cholinesterase activity in vitiliginous skin as com-pared to adjacent normal skin has been reported [51].Increased urinary levels of catecholamines have beenfound during the active phase of vitiligo [52,53].

The autocytotoxic theoryIn 1971, Lerner [54] postulated that melanocyteshave a genetically based protective mechanism thateliminates toxic products like DOPA, DOPAchrome,and 5,6-dihydroxyindole, manufactured duringmelanogenesis. Individuals who are deficient in thismechanism have accumulation of these melanotoxicproducts, which results in depigmentation. Anotherpossible mechanism could be damage by geneticmechanisms or by perioxidation [55] to the mem-branes of melanosomes, which prevent leakage ofthese compounds into the cellular milieu [56,57].

The oxidative stress theory proposes thatmelanocyte death results from an intrinsic increasedsensitivity to oxidative stress either from toxic inter-mediates of melanin precursors or from other sources.In vivo and in vitro evidence for hydrogen peroxide(H2O2) accumulation in the epidermis of vitiligopatients has been reported, resulting from low epidermal catalase levels [58]. Several studies sug-gest that (a) cultured vitiligo melanocytes exhibitincreased sensitivity to oxidative stress and (b) cata-lase helps to establish vitiligo melanocyte cultures andto restore melanocyte functions after exposure toH2O2 [2]. According to Schallreuter and her group,the origin of the epidermal H2O2 accumulation andlow epidermal catalase levels within the entire skinof vitiligo patients may arise from several potentialsources: (1) perturbed (6R)-L-erythro-5,6,7,8-tetra-hydrobiopterin (6BH4) de novo synthesis/recy-cling/regulation; the absence of catalase leads toaccumulation of toxic superoxide radicals. One suchmechanism involves a group of compounds calledpteridines. L-tyrosine is the central substrate for cat-echol synthesis in keratinocytes and melanin syn-thesis in melanocytes L-tyrosine itself is producedfrom L-phenylalanine and the reaction is regulatedby the enzyme phenylalanine hydroxylase. Thisenzyme is under the control of pteridines including5,6,7,8-tetrahydrobioopterin (6BH4). Defects in theproduction of pteridines lead to the accumulation ofepidermal phenylalnine and shortage of L-tyrosine.A clinical study using a loading oral dose of L-pheny-lalanine showed slower turnover of L-phenylalanineto L-tyrosine in patients compared with controls[59]. The defective deranged synthesis of pteridinsleads to the concomitant accumulation of H2O2;

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(2) impaired catecholamines synthesis with increasedmonooxidase A activities; (3) low glutathione per-oxidase activities; (4) “oxygen burst” via NADPHoxidase from a cellular infiltrate [58]. Under in vitroconditions, vacuole of vitiligo melanocytes has beendemonstrated which was reversible upon exogenousaddition of bovine catalase to the culture medium[3]. Until now, this interesting concept has not yetbeen validated in vivo in patients with vitiligo.Whether H2O2 is the cause or the consequence ofvitiligo remains to be identified. Another mechanisminvolves the ion calcium. In the epidermis there isan efficient antioxidant mechanism of thiore-doxin/thioredoxin reductase (T/TR) which reducesH2O2 to water. The activity of this system is alloster-ically regulated by ionic calcium and defectiveuptake of calcium could result in altered redox sta-tus and accumulation of H2O2 [60]. Estrogens canalso contribute to hydrogen peroxide [61]. Success-ful removal by a UVB-activated pseudocatalase hasalso been reported. However, this conclusion arisesfrom an open trial including only 33 patients andthe results have not been confirmed by further stud-ies. The efficacy of pseudocatalase to promote vitiligorepigmentation is still a matter of debate. However,there is no abnormality in blood antioxidant statusin patients with vitiligo. Blood levels of superoxi-dase dismutase, glutathione peroxidase, glutathionereductase, non-enzymatic oxidants such as �-toco-pherol (Vit E), retinol (Vit A), ascorbic acid (Vit C)have been found to be normal.

In the context of the oxidative stress theory, selenium is widely prescribed to stabilize and to repigment vitiligo. However, two distinct studiesdemonstrated that there is an increase in total bloodantioxidant status (high serum selenium levels) invitiligo patients [62,63]. As a consequence, oral sup-plementation should not be practiced in patients whoexhibit a spontaneous increase in selenium levels, asit could be potentially harmful (selenium toxicity).

The new hypotheses

A disorder of melanocyte survivalThe active mechanism by which melanocytes aredestroyed in vitiligo skin has not yet been deter-mined. Several morphological observations suggest

the involvement of melanocyte apoptosis and ofthe SCF/c-kit/MITF/Bcl-2 pathway in the patho-genesis of vitiligo. This pathway plays a key role inthe maintenance of melanocyte survival. SCF ofkeratinocyte origin strongly protects melanocytesfrom TNF-related apoptosis inducing ligand (TRAIL)[64]. Bcl-2, a MITF-dependent kit transcriptionaltarget in melanocytes, is essential for the mainte-nance of an appropriate lifetime for melanocytes.The decrease of Bcl-2 expression of melanocytesincreases their susceptibility to apoptosis. Bcl-2�/�

mice develop graying and whitening of hair early in life during the second hair cycle, due to disap-pearance of follicular melanocytes. Levels of SCFexpression (P � 0.001) are reduced in the depig-mented epidermis of vitiligo patients compared tonormally pigmented paired epidermis [7].

A reduction in the number of kit-positivemelanocytes in the perilesional skin of vitiligo patientshas also been reported. Immunohistochemistry with antibodies to melanocyte markers revealedthat at the edges of the lesional vitiligo epidermis,melanocytes do not express the kit-protein and themelanocyte-specific microphthalmia transcriptionfactor (MITF-M) [65]. Western blotting confirmeddown-regulated expression of c-kit and MITF-M pro-teins at the edge of the lesional epidermis in vitiligo.These findings strongly suggest a deficiency of themelanocyte survival pathway SCF/c-kit/MITF/Bcl-2which might be responsible for dysfunction and/orloss of melanocytes in vitiligo epidermis.

Interestingly, we have observed a marked pro-gression of a vitiligo which was stable since manyyears after treatment with tyrosine kinase inhibitorsthat inhibit c-kit [66]. Moreover, several cases ofvitiligo-like depigmentation occurring after treat-ment with new tyrosine kinase inhibitors thatinhibit c-kit (STI-571 and SU 11428) have beenreported [67,68].

The melanocyte growth factor deficienttheoryDefective growth and passage capacities of vitiligomelanocytes derived from uninvolved and peri-lesional skin in vitro have been described [69].Interestingly, these growth defects of vitiligomelanocytes could be partially corrected in vitro by


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the adjunction of fetal lung fibroblast-derived growthfactors. In addition, melanocytes taken from activelyrepigmenting vitiligo macules grow correctly, sug-gesting a correction of the growth defect. Based onthese results, it has been suggested that a decreasedconcentration of melanocyte growth factor(s) couldplay a role in the pathogenesis of vitiligo [70].

Viral infectionsViral infections have been implicated in the patho-genesis of autoimmune diseases. In one study, CMV DNA was detected in the involved and unin-volved skin of 38% of vitiligo patients and 0% of control subjects. EBV, CMV, Herpes simplex,varicella-zoster, and human T-lymphotropic viruswere negative. There are no definitive data to con-firm or refute the viral hypothesis. Additional stud-ies are needed to confirm these results [71].

Melanocyte defective adhesionInteraction between melanocytes and the der-moepidermal basement membrane are mediated byintegrins (�6�1). Interactions between melanocytesand keratinocytes are mediated by cadherins in asso-ciation with �-catenin.

Repeated friction in non-lesional skin of vitiligopatients induces detachment and transepidermalelimination of melanocytes [72]. This suggests thatminor mechanical trauma in non-lesional vitiligoskin is probably the cause of depigmentation occur-ring in the Köbner’s phenomenon. Transepidermalelimination of melanocytes in vitiligo may be a pos-sible mechanism of chronic loss of melanocytes,perhaps previously damaged by another process [2].

Conclusion

From the available data, it is likely that the loss ofepidermal and follicular melanocytes in vitiligoresults in melanocyte death. The identification of at least two different clinical phenotypes of vitiligo suggests that melanocyte destruction may be the result of several different pathogenetic mechanisms.Many different hypotheses have been proposed.Recent developments of the genetics of generalizedvitiligo strongly suggest a role of immunologicalfactors in generalized vitiligo susceptibility. Besides

genetic and immunologic factors, the environmentis likely to be involved in the pathogenesis ofvitiligo in ways that are not yet known. There are now probably too many hypotheses of vitiligo. Allhypotheses are not mutually exclusive. A “conse-quence” theory suggests that genetic factors, stress,accumulation of toxic compounds, infection, autoim-munity, altered cellular environment, and impairedmelanocyte migration and proliferation can all con-tribute to the phenomenon of vitiligo.

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The basic pathogenesis of vitiligo in general, or forany of the putative subsets of vitiligo, is not fullyknown. Upon spontaneous or medically inducedimprovement in vitiligo patches, repigmentationspreads inwards from the borders of lesion. In somecolor appears diffusely in depigmented areas, butmore commonly the pigment spread is perifollicu-lar. The nature of repigmentation can be classifiedinto three types:1 perifollicular when predominant repigmentationis follicular;2 marginal when predominant repigmentation isfrom the borders of patches;3 diffuse pigmentation when there occurs general-ized darkening across the patches of vitiligo.

Melanocytes in human skin reside both in theepidermis and in the matrix and outer root sheath(ORS) of anagen hair follicles. Staricco [1] describedtwo types of melanocytes in hair follicles: the ame-lanotic or inactive type and melanotic or activemelanocytes. Epidermal and amelanotic hair folliclemelanocytes proliferated well in culture, whereasthe melanotic hair follicle melanocytes did not.Amelanotic hair follicle melanocytes have beenshown to differ from epidermal melanocytes inbeing less differentiated, and expressing less maturemelanosome antigens. Nishimura et al. [2] identifiedthe stem cells of melanocyte lineage in the lowerpermanent portion of mouse hair follicle through-out the hair cycle. They also analyzed the repigmen-tation process in Tg/� mice and found that thesebulge stem cells are the source of melanocytes inepidermis. Nishimura et al. [3] suggested in anotherpublication that hair graying is due to loss ofmelanocyte stem cells. Commo et al. [4] also found

specific depletion of bulb and ORS melanocytes ingraying human hair.

Mechanisms of medically inducedrepigmentation

Perifollicular repigmentationThe mechanism of perifollicular repigmentationpattern has been researched extensively and manyauthors believe that it is the only mode of repig-mentation in vitiligo [5]. Repigmentation of vitiligolesions is thought to occur by the migration of undif-ferentiated melanocytes from the ORS of the hairfollicles to the intrafollicular epidermis. Ortonne et al.[6] demonstrated the mechanism of psoralen plusultraviolet A (PUVA)-induced repigmentation ofvitiligo based on a histochemical and ultrastructuralstudy. They divided the repigmentation process intothree stages:1 proliferation of hypertrophic melanocytes in thelower portion of hair follicle; 2 migration of hypertrophic melanocytes along thehair follicle toward the infundibulum; and3 migration of melanocytes to the adjacent epidermis.Similarly Cui et al. [7] have also shown that duringrepigmentation, treatment stimulated the inactivemelanocytes in the middle and/or lower parts ofthe ORS of hair follicles to divide, proliferate, andmigrate upward along the surface of the ORS to thenearby epidermis, where the melanocytes continuedto migrate radially to form the pigmented islandvisible clinically in repigmented vitiligo lesions. It isconceivable that successful repigmentation dependson the availability of migratory factors as well as

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CHAPTER 2

Understanding the mechanism ofrepigmentation in vitiligoAmrinder J. Kanwar and Davinder Parsad

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