Acessibilidade / Reportar erro

Vitiligo - Part 1* * Work performed at Santa Casa de Misericórdia de Curitiba Hospital - Paraná Pontifical Catholic University (PUCPR) - Curitiba (PR), Brazil.

Abstract

Vitiligo is a chronic stigmatizing disease, already known for millennia, which mainly affects melanocytes from epidermis basal layer, leading to the development of hypochromic and achromic patches. Its estimated prevalence is 0.5% worldwide. The involvement of genetic factors controlling susceptibility to vitiligo has been studied over the last decades, and results of previous studies present vitiligo as a complex, multifactorial and polygenic disease. In this context, a few genes, including DDR1, XBP1 and NLRP1 have been consistently and functionally associated with the disease. Notwithstanding, environmental factors that precipitate or maintain the disease are yet to be described. The pathogenesis of vitiligo has not been totally clarified until now and many theories have been proposed. Of these, the autoimmune hypothesis is now the most cited and studied among experts. Dysfunction in metabolic pathways, which could lead to production of toxic metabolites causing damage to melanocytes, has also been investigated. Melanocytes adhesion deficit in patients with vitiligo is mainly speculated by the appearance of Köebner phenomenon, recently, new genes and proteins involved in this deficit have been found.

Autoimmunity; Epidemiology; Genetic association studies; Genetic linkage; Vitiligo


INTRODUCTION

Vitiligo is a chronic systemic acquired disease that has an unpredictable clinical course, characterized by the appearance of macules and achromic or hypochromic patches on the skin and mucous membranes due to the disappearance of melanocytes in the affected area. These lesions can appear in different shapes and sizes and may be present in any area of the tegument.

Along with the skin and mucosal involvement, melanocytes in the ocular (predominantly in the uveal tract) and auditory apparatus (in vascular streaking and in the modiolus of the cochlea) can be decreased, ocular diseases such as uveitis or even neurosensorial hearing loss may also occur, being detected in 13 to 16% of patients in previous studies.1Sharma L, Bhawan R, Jain RK. Hypoacusis in vitiligo. Indian J Dermatol Venereol Leprol. 2004;70:162-4.

Albert DM, Nordlund JJ, Lerner AB. Ocular abnormalities occurring with vitiligo. Ophthalmology. 1979;86:1145-60.
-3Orecchia G, Marelli MA, Fresa D, Robiolio L. Audiologic disturbances in vitiligo. J Am Acad Dermatol. 1989;21:1317-8. However, one of the major consequences of the disease is its psychological impact, since vitiligo can have strong effects on patients' self-esteem, with a subsequent increase in severe depression cases and a sharp sense of social discrimination resulting in quality of life deterioration.4Porter J, Beuf A, Nordlund JJ, Lerner AB. Personal responses of patients to vitiligo: the importance of the patient-physician interaction. Arch Dermatol. 1978;114:1384-5.

Porter JR, Beuf AH, Lerner A, Nordlund J. Psychosocial effect of vitiligo: a comparison of vitiligo patients with "normal" control subjects, with psoriasis patients, and with patients with other pigmentary disorders. J Am Acad Dermatol. 1986;15(2 Pt 1):220-4.
-6Radtke MA, Schafer I, Gajur A, Langenbruch A, Augustin M. Willingness-to-pay and quality of life in patients with vitiligo. Br J Dermatol. 2009;161:134-9.

HISTORICAL ASPECTS

The oldest texts about a disease similar vitiligo as it is known today, date back to 1.500 BC and are present in Hindu sacred writings ("Vedas"), under the name kilăsa, and in texts (papyrus) from ancient Egypt.7Millington GW, Levell NJ. Vitiligo: the historical curse of depigmentation. Int J Dermatol. 2007;46:990-5. There are several references in the Old Testament, especially in Leviticus XIII, to the term Zoráat or Tzaraat, which in classical Hebrew means "white spots", but there is controversy as to whether this disease is really vitiligo.

The Latin term vitiligo was first used in the first century AD by Celsus in the classic treatise De Medicina, however, the Latin root of the word is unknown, and between the cited ones are some words with similar meanings, as vitelius and vituli, comparing the achromic or hypochromic lesions with vitiligo's white patches observed in calves, or vitium which means defect or flaw.8Freilich AR. Tzaraat--"biblical leprosy". J Am Acad Dermatol. 1982;6:131-4.

In the nineteenth century, Brocq and Kaposi were among the first to describe both the clinical aspects, as achromia and hyperpigmentation at the borders of lesions, as well as its histopathology, in which Kaposi reported the absence of pigment granules in the basal layer cells of the epidermis.9Kopera D. Historical aspects and definition of vitiligo. Clin Dermatol. 1997;15:841-3.

EPIDEMIOLOGICAL ASPECTS

The disease affects both genders equally, it can appear at any age, and the average age of onset is somewhat variable in different geographic regions.1010 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol. 1993;129:994-8. The mean age ranging from 22 years in the U.S. and India, 24 in Brazil and 25 years old in England. Furthermore, differences in the mean age of onset have been reported among cases of sporadic and familial vitiligo.1111 Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-14.

12 Das SK, Majumder PP, Chakraborty R, Majumdar TK, Haldar B. Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet Epidemiol. 1985;2:71-8.
-1313 Silva de Castro CC, do Nascimento LM, Olandoski M, Mira MT. A pattern of association between clinical form of vitiligo and disease-related variables in a Brazilian population. J Dermatol Sci. 2012;65:63-7.

The prevalence of vitiligo has been estimated between 0.093% in China, 0.34% on the island of Martinique, 0.38% in Denmark, 1% in U.S. and 0.5% to 1.13% in India.1212 Das SK, Majumder PP, Chakraborty R, Majumdar TK, Haldar B. Studies on vitiligo. I. Epidemiological profile in Calcutta, India. Genet Epidemiol. 1985;2:71-8.,1414 Lu T, Gao T, Wang A, Jin Y, Li Q, Li C. Vitiligo prevalence study in Shaanxi Province, China. Int J Dermatol. 2007;46:47-51.

15 Boisseau-Garsaud AM, Garsaud P, Cales-Quist D, Helenon R, Queneherve C, Claire RC. Epidemiology of vitiligo in the French West Indies (Isle of Martinique). Int J Dermatol. 2000;39:18-20.

16 Howitz J, Brodthagen H, Schwartz M, Thomsen K. Prevalence of vitiligo. Epidemiological survey on the Isle of Bornholm, Denmark. Arch Dermatol. 1977;113:47-52.

17 Lerner AB. Vitiligo. J Invest Dermatol. 1959;32(2 Part 2):285-310.
-1818 Mehta NR, Shah KC, Theodore C, Vyas VP, Patel AB. Epidemiological study of vitiligo in Surat area, South Gujarat. Indian J Med Res. 1973;61:145-54. Brazil has no updated epidemiological data on the incidence and prevalence of this disease.

With the disappearance of melanocytes in individuals affected by vitiligo, one would expect an increased incidence of non-melanoma cancer and actinic keratoses; however, experimental data show the opposite, leading some authors to hypothesize that this low incidence of skin cancer might be due to an overexpression in p53 protein which would have an anticancer effect, and immunohistochemical studies have already demonstrated the greater expression of p53 both in the affected and normal skin sections of vitiligo patients, compared to the skin of controls with a history of basal cell carcinoma.1919 Calanchini-Postizzi E, Frenk E. Long-term actinic damage in sun-exposed vitiligo and normally pigmented skin. Dermatologica. 1987;174:266-71.

20 Schallreuter KU, Behrens-Williams S, Khaliq TP, Picksley SM, Peters EM, Marles LK, et al. Increased epidermal functioning wild-type p53 expression in vitiligo. Exp Dermatol. 2003;12:268-77.

21 Bakry OA, Hammam MA, Wahed MM. Immunohistochemical detection of P53 and Mdm2 in vitiligo. Indian Dermatol Online J. 2012;3:171-6.

22 Schallreuter KU, Tobin DJ, Panske A. Decreased photodamage and low incidence of non-melanoma skin cancer in 136 sun-exposed caucasian patients with vitiligo. Dermatology. 2002;204:194-201.
-2323 Le Poole IC, Stennett LS, Bonish BK, Dee L, Robinson JK, Hernandez C, et al. Expansion of vitiligo lesions is associated with reduced epidermal CDw60 expression and increased expression of HLA-DR in perilesional skin. Br J Dermatol. 2003;149:739-48. Moreover, the reduced expression of GD3 (which contributes to keratinocyte apoptosis) induces a compensatory mechanism of epidermal thickening to protect the affected skin from UV radiation damage.2323 Le Poole IC, Stennett LS, Bonish BK, Dee L, Robinson JK, Hernandez C, et al. Expansion of vitiligo lesions is associated with reduced epidermal CDw60 expression and increased expression of HLA-DR in perilesional skin. Br J Dermatol. 2003;149:739-48.Finally, two recent retrospective studies have not detected a statistically significant increase of non- melanoma skin cancer (first study) or non-melanoma and melanoma skin cancers (second study) in patients with vitiligo, compared to the general population. Moreover, this last retrospective study, did not found a trend of increasing prevalence of these skin cancers in the subgroup of patients treated with PUVA and Narrow-Band UVB, adjusted for age and time of exposure during life.2424 Hexsel CL, Eide MJ, Johnson CC, Krajenta R, Jacobsen G, Hamzavi I, et al. Incidence of nonmelanoma skin cancer in a cohort of patients with vitiligo. J Am Acad Dermatol. 2009;60:929-33.,2525 Teulings HE, Overkamp M, Ceylan E, Nieuweboer-Krobotova L, Bos JD, Nijsten T, et al. Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners. Br J Dermatol. 2013;168:162-71.

VITILIGO GENETICS

Most human diseases result from an interaction between genetic variants and environmental factors, and to establish the actual contribution of genetic factors is the first step of genetic studies that evaluate complex diseases. In general terms, the scrutiny of complex diseases genetic components begins through observational studies, such as: analyzes of pools of familial cases, comparative studies of concordance rates of disease occurrence among monozygotic (MZ) and dizygotic (DZ) twins and complex segregation analyzes (CSA). However, these studies do not provide information on the exact nature of the genetic component in question, as the location and identity of the involved genes. In order to advance it is necessary to perform different studies involving molecular genetic markers, as it is done in linkage and association analysis.

Genetic epidemiological studies have demonstrated that vitiligo can be considered a complex genetic disease because: (i) the disease varies in symptom severity and age of onset, which hinders the definition of the appropriate phenotype and the selection of the optimum study population; early age of onset was associated with familial occurrence of generalized vitiligo.1111 Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-14.,2626 Laberge G, Mailloux CM, Gowan K, Holland P, Bennett DC, Fain PR, et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 2005;18:300-5. In addition, early onset vitiligo is associated with more severe disease;1111 Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-14. (ii) the etiological mechanisms of the disease can vary; vitiligo's etiopathogenesis has not yet been fully clarified, and several theories have been proposed; (iii ) complex genetic diseases are often oligogenic or even polygenic and each gene contributes to a fraction of the overall relative risk; linkage analysis performed using vitiligo phenotype identified susceptible loci located on chromosomes 1, 4, 6, 7 , 8, 17 e 22 co-segregating with the disease.2727 Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol. 2007;21:865-76.

28 Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol. 1997;15:845-51.

29 Morelli JG, Norris DA. Influence of inflammatory mediators and cytokines on human melanocyte function. J Invest Dermatol. 1993;100(2 Suppl):191S-5S.

30 Gauthier Y, Cario Andre M, Taieb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy? Pigment Cell Res. 2003;16:322-32.

31 Dell'anna ML, Picardo M. A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;19:406-11.

32 Huang CL, Nordlund JJ, Boissy R. Vitiligo: a manifestation of apoptosis? Am J Clin Dermatol. 2002;3:301-8.

33 Spritz RA, Gowan K, Bennett DC, Fain PR. Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am J Hum Genet. 2004;74:188-91.

34 Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG, et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005;76:1057-65.
-3535 Liang Y, Yang S, Zhou Y, Gui J, Ren Y, Chen J, et al. Evidence for Two Susceptibility Loci on Chromosomes 22q12 and 6p21-p22 in Chinese Generalized Vitiligo Families. J Invest Dermatol. 2007;127:2552-7. For these regions, some genes consistently associated with vitiligo have been reported, such as NLRP1 (17p13) and XBP1 (22q12).3636 Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216-25.,3737 Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T, et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 2009;5:e1000523.

OBSERVATIONAL EPIDEMIOLOGICAL GENETICS IN VITILIGO

The involvement of genetic factors in the susceptibility to vitiligo became evident in familial studies, which demonstrated that vitiligo segregates with a complex standard of multifactorial and polygenic inheritance.1010 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol. 1993;129:994-8. A study, involving 160 American Caucasian families, confirmed familial aggregation of cases with 20% of the affected individuals presenting at least one first-degree relative with vitiligo.1010 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol. 1993;129:994-8. The relative risk of vitiligo in Denmark and India populations was seven for parents, 12 for siblings, and 36 for off-spring.1010 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol. 1993;129:994-8. The relative risk of vitiligo in first-degree relatives was estimated at between seven to 10 times higher than in general population.3838 Nath SK, Majumder PP, Nordlund JJ. Genetic epidemiology of vitiligo: multilocus recessivity cross-validated. Am J Hum Genet. 1994;55:981-90. A study about vitiligo conducted in twins showed 23% agreement rate of generalized vitiligo for 22 pairs of MZ twins compared with 0% in 24 pairs of DZ twins.1111 Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-14.However, the lack of complete agreement for vitiligo between MZ twins suggests the importance of non-genetic factors.

Additional evidence for a genetic susceptibility component in vitiligo has been gathered from CSA, the main statistical tool used to determine, from familial information, the inheritance model that best explains the pattern of segregation on a particular phenotype.3939 Elston RC, Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21:523-42. Results of CSA held in 56 multigenerational Colombian families containing individuals affected by vitiligo indicated as the most appropriate model, the one that assumes the existence of a dominant major gene with strong influence of environmental factors acting on the recessive genotypes.4040 Arcos-Burgos M, Parodi E, Salgar M, Bedoya E, Builes J, Jaramillo D, et al. Vitiligo: complex segregation and linkage disequilibrium analyses with respect to microsatellite loci spanning the HLA. Hum Genet. 2002;110:334-42. Another CSA involving 2.247 Chinese vitiligo patients and their families demonstrated that different types of vitiligo are regulated by different sets of genes, reinforcing the oligogenic/polygenic nature of the disease.4141 Zhang XJ, Liu JB, Gui JP, Li M, Xiong QG, Wu HB, et al. Characteristics of genetic epidemiology and genetic models for vitiligo. J Am Acad Dermatol. 2004;51:383-90.

LINKAGE STUDIES IN VITILIGO

Linkage analysis is a tool that allows the screening of the entire human genome, using multigenerational families in order to identify genomic regions that harbor loci responsible for the observed phenotype, even without prior assumptions about the disease pathogenesis. The principle of linkage analysis is based on the premise that if a polymorphic marker is near the locus that harbors the disease predisposing gene, they will co-segregate in families over generations, more intensively than expected under the hypothesis of aleatory transmission expected in an independent heritage of unconnected loci.4242 Lander ES, Schork NJ. Genetic dissection of complex traits. Science. 1994;265(5181):2037-48.

The first evidence of linkage was between vitiligo associated with systemic lupus erythematosus (SLE) and chromosome 17p13 markers, a locus denominated by authors as SLEV1, in 16 Euro-American families affected by both diseases.4343 Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, et al. Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus. Am J Hum Genet. 2001;69:1401-6. This result suggests the existence of a probable common genetic autoimmunity determinant of vitiligo and SLE in these families. A subsequent independent study detected linkage between 1p31 locus, termed by the authors "AIS1" (Autoimmunity Susceptibility Locus 1) and vitiligo in a large multigenerational family presenting multiple cases of vitiligo and Hashimoto's thyroiditis.4444 Alkhateeb A, Stetler GL, Old W, Talbert J, Uhlhorn C, Taylor M, et al. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-p32.2. Hum Mol Genet. 2002;11:661-7.,4545 Fain PR, Gowan K, LaBerge GS, Alkhateeb A, Stetler GL, Talbert J, et al. A genomewide screen for generalized vitiligo: confirmation of AIS1 on chromosome 1p31 and evidence for additional susceptibility loci. Am J Hum Genet. 2003;72:1560-4. In a subsequent complementary study, in which the original collection of families was expanded to a total of 102 pedigrees, additional evidence of the connection with vitiligo was detected on chromosomes 7 and 8. Furthermore, the evidence of linkage to 17p13 locus previously described was confirmed.3434 Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG, et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005;76:1057-65.Thus, the suggestive linkage signal to four loci on chromosomes 9, 13, 19 and 22 was detected.3333 Spritz RA, Gowan K, Bennett DC, Fain PR. Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am J Hum Genet. 2004;74:188-91. The authors suggest that linkage signals detected for chromosomes 7q and 17p seem to derive primarily from families segregating vitiligo and epidemiologically related autoimmune diseases. On the other hand, the linkage signal detected for chromosome 8p derived from families that segregate only vitiligo.3333 Spritz RA, Gowan K, Bennett DC, Fain PR. Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am J Hum Genet. 2004;74:188-91. More recently, a genomic scan conducted in Chinese multiplex families affected by generalized vitiligo identified the connection between the disease and markers of region 4q13-q21, 22q12 and 6p21-p22.3434 Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG, et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005;76:1057-65.,3535 Liang Y, Yang S, Zhou Y, Gui J, Ren Y, Chen J, et al. Evidence for Two Susceptibility Loci on Chromosomes 22q12 and 6p21-p22 in Chinese Generalized Vitiligo Families. J Invest Dermatol. 2007;127:2552-7.

Linkage analyzes performed in populations with different ethnic backgrounds, using generalized vitiligo as phenotype, showed that the main susceptibility locus co-segregating with the disease is not the same in each population, except for 22q11. This suggests that different genes may be involved in the pathogenesis of vitiligo in different populations around the world, characterizing a polygenic disease.3333 Spritz RA, Gowan K, Bennett DC, Fain PR. Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis. Am J Hum Genet. 2004;74:188-91.

34 Chen JJ, Huang W, Gui JP, Yang S, Zhou FS, Xiong QG, et al. A novel linkage to generalized vitiligo on 4q13-q21 identified in a genomewide linkage analysis of Chinese families. Am J Hum Genet. 2005;76:1057-65.
-3535 Liang Y, Yang S, Zhou Y, Gui J, Ren Y, Chen J, et al. Evidence for Two Susceptibility Loci on Chromosomes 22q12 and 6p21-p22 in Chinese Generalized Vitiligo Families. J Invest Dermatol. 2007;127:2552-7. The exact definition of the gene or genes involved in controlling the phenotype in question depends on further studies, usually association ones, involving target genes located in genomic regions identified in the linkage analysis.

ASSOCIATION STUDIES IN VITILIGO

There are two main design types of association studies: population-based and family-based. Population-based studies (case-control) primarily compare the allele frequencies of a genetic marker among affected and unaffected individuals (controls); a particular allele is considered associated with the studied phenotype when it occurs with different frequencies amongst the groups. The big challenge in this type of study is the correct selection of the population segment and the sample size, in order to have sufficient power to detect the genetic effect, if it really exists. Family-based association studies use the basic trio design, consisting of two parents and an affected offspring. The analysis assesses the frequency with which a particular allele is transmitted from a heterozygous parent to the affected child: a deviation in the expected aleatory transmission, according to the first law of Mendel, suggests an association. It is important to emphasize that, association studies have greater power to detect moderate to weak genetic effects when compared to linkage studies, which makes them ideal for fine mapping of previously detected chromosomal regions connected with the disease.4646 Cordell HJ, Clayton DG. Genetic association studies. Lancet. 2005;366:1121-31.

Currently, over 50 candidate genes were already investigated in association studies for susceptibility to vitiligo. However, few genes, including DDR1, XBP1, NLRP1, PTPN22 and COMT, were consistently associated with the disease, either by being located in a region previously identified in a linkage study (positional) or by having been replicated in populations of different geographic regions, as described in table 1. In addition to the genes listed above, an evidence of association with vitiligo phenotypes was found for markers of ACE, AIRE, CD4, COX2, ESR1, EDN1, FAS, FOXD3, FOXP3, IL1 - RN, IL - 10, MBL2, MC1R, MYG1, Nrf2, PDGFRA, PRO2268, SCF, SCGF, TXNDC5, UVRAG and VDR genes, but these associations were not replicated in independent populations.4747 Birlea SA, Jin Y, Bennett DC, Herbstman DM, Wallace MR, McCormack WT, et al. Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol. 2011;131:371-81. Nevertheless, several genetic studies for CAT and CTLA - 4 genes in populations of different ethnic origins, have produced conflicting results.4747 Birlea SA, Jin Y, Bennett DC, Herbstman DM, Wallace MR, McCormack WT, et al. Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol. 2011;131:371-81.

48 Casp CB, She JX, McCormack WT. Genetic association of the catalase gene (CAT) with vitiligo susceptibility. Pigment Cell Res. 2002;15:62-6.

49 Liu L, Li C, Gao J, Li K, Zhang R, Wang G, et al. Promoter variant in the catalase gene is associated with vitiligo in Chinese people. J Invest Dermatol. 2010;130:2647-53.

50 Em S, Laddha NC, Chatterjee S, Gani AR, Malek RA, Shah BJ, et al. Association of catalase T/C exon 9 and glutathione peroxidase codon 200 polymorphisms in relation to their activities and oxidative stress with vitiligo susceptibility in Gujarat population. Pigment Cell Res. 2007;20:405-7.

51 Birlea SA, Laberge GS, Procopciuc LM, Fain PR, Spritz RA. CTLA4 and generalized vitiligo: two genetic association studies and a meta-analysis of published data. Pigment Cell Melanoma Res. 2009;22:230-4.

52 Kemp EH, Ajjan RA, Waterman EA, Gawkrodger DJ, Cork MJ, Watson PF, et al. Analysis of a microsatellite polymorphism of the cytotoxic T-lymphocyte antigen-4 gene in patients with vitiligo. Br J Dermatol. 1999;140:73-8.
-5353 Deeba F, Syed R, Quareen J, Waheed MA, Jamil K, Rao H. CTLA-4 A49G gene polymorphism is not associated with vitiligo in South Indian population. Indian J Dermatol. 2010;55:29-32. In general, associations between variants of HLA genes with susceptibility to vitiligo, considering different ethnic groups, have not been consistent, however, there are notable exceptions, such as the association signs observed for HLA - A2, HLA - DR4 and HLA - DR7 alleles.2727 Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol. 2007;21:865-76.,5454 Tastan HB, Akar A, Orkunoglu FE, Arca E, Inal A. Association of HLA class I antigens and HLA class II alleles with vitiligo in a Turkish population. Pigment Cell Res. 2004;17:181-4.

55 Buc M, Fazekasova H, Cechova E, Hegyi E, Kolibasova K, Ferencik S. Occurrence rates of HLA-DRB1, HLA-DQB1, and HLA-DPB1 alleles in patients suffering from vitiligo. Eur J Dermatol. 1998;8:13-5.

56 Wang J, Zhao YM, Wang Y, Xiao Y, Wang YK, Chen HD. [ssociation of HLA class I and II alleles with generalized vitiligo in Chinese Hans in north China]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007;24:221-3.

57 Singh A, Sharma P, Kar HK, Sharma VK, Tembhre MK, Gupta S, et al. HLA alleles and amino-acid signatures of the peptide-binding pockets of HLA molecules in vitiligo. J Invest Dermatol. 2012;132:124-34.
-5858 Hu DY, Ren YQ, Zhu KJ, Lv YM, Cheng H, Zhang Z, et al. Comparisons of clinical features of HLA-DRB1*07 positive and negative vitiligo patients in Chinese Han population. J Eur Acad Dermatol Venereol. 2011;25:1299-303.

TABLE 1:
Non-HLA genes consistently associated to vitiligo

Candidate genes identified from linkage genomic scans generated interesting results. The first was NLRP1, located in chromosome region 17p13, which encodes an innate immune system regulatory protein. NLRP1 gene polymorphisms were first investigated and associated to American families affected with generalized vitiligo and autoimmune diseases epidemiologically associated to vitiligo; later, the association signal was replicated in independent case-control populations from Romania and Jordan, using the generalized vitiligo phenotype.3636 Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216-25.,5959 Jin Y, Birlea SA, Fain PR, Spritz RA. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol. 2007;127:2558-62.,6060 Alkhateeb A, Qarqaz F. Genetic association of NALP1 with generalized vitiligo in Jordanian Arabs. Arch Dermatol Res. 2010;302:631-4.

Successful fine mapping of 22q12 locus identified XBP1 gene associated with vitiligo. XBP1 encodes a transcription factor that regulates the expression of MHC class II genes. The identification of genetic variant rs2269577, located in XBP1 gene promoter region associated with vitiligo per se, was possible due to the progressive realization of association analyzes in three independent population samples, both case-control and families. Furthermore, a functional study showed high expression of XBP1 in the injured skin of patients who carry the risk allele C of rs2269577 polymorphism.3737 Ren Y, Yang S, Xu S, Gao M, Huang W, Gao T, et al. Genetic variation of promoter sequence modulates XBP1 expression and genetic risk for vitiligo. PLoS Genet. 2009;5:e1000523. Interestingly, the same risk allele of variant rs2269577 was replicated in a European population in a case-control association study.5959 Jin Y, Birlea SA, Fain PR, Spritz RA. Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population. J Invest Dermatol. 2007;127:2558-62.

Another approach is the selection of genes involved in important biological pathways in the disease pathogenesis, as is the case with DDR1 gene, located on chromosome region 6p21. DDR1 gene encodes a transmembrane tyrosine kinase receptor; mutations in this gene can lead to alterations in melanocyte adhesion to basal membrane via integrin CCN3. Association between DDR1 gene polymorphisms and vitiligo per se has been reported in a population from southern Brazil. Interestingly, the association signal observed was strongly dependent on age, suggesting a more pronounced genetic effect in patients affected with vitiligo that were aged ≤ 18 and 25.6161 Silva de Castro CC, do Nascimento LM, Walker G, Werneck RI, Nogoceke E, Mira MT. Genetic variants of the DDR1 gene are associated with vitiligo in two independent Brazilian population samples. J Invest Dermatol. 2010;130:1813-8. It is important to note that, one study in a Korean population sample replicated the association between vitiligo and DDR1 variants, although the statistical signal has not withstood correction for multiple testing.6262 Kim HJ, Uhm YK, Yun JY, Im SH, Yim SV, Chung JH, et al. Association between polymorphisms of discoidin domain receptor tyrosine kinase 1 (DDR1) and non-segmental vitiligo in the Korean population. Eur J Dermatol. 2010;20:231-2. Another independent study failed to replicate the same association; however, the authors did not evaluate the population sample stratified by age of vitiligo onset.4747 Birlea SA, Jin Y, Bennett DC, Herbstman DM, Wallace MR, McCormack WT, et al. Comprehensive association analysis of candidate genes for generalized vitiligo supports XBP1, FOXP3, and TSLP. J Invest Dermatol. 2011;131:371-81. Recent functional studies have shown that the decreasing of melanocyte adhesion in the basal lamina is due in part to decreased expression of DDR1.6363 Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A, et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol. 2012;21:411-6.,6464 Reichert-Faria A, Jung JE, Neto VM, de Castro CC, Mira MT, Noronha L. Reduced immunohistochemical expression of Discoidin Domain Receptor 1 (DDR1) in vitiligo skin. J Eur Acad Dermatol Venereol. 2013;27:1057-9.

GENOME WIDE ASSOCIATION STUDIES - GWAS

GWAS involve hundreds of thousands of genetic markers, enough for complete genome coverage, which are tested in combination to determine their association with a particular disease. This method is free of functional or positional hypotheses, since the only goal in selecting the collection of markers to be tested is to achieve the most substantial coverage possible, including all genes in the genome that are investigated in a single experiment. Thus, GWAS allow the identification of genes previously unsuspected of participating in the pathogenesis control of the studied disease.

The first GWAS in vitiligo was conducted in a genetically isolated population sample under strong founder effect (thus presenting lower genetic variability) in northwestern Romania, with a high prevalence of generalized vitiligo, the authors found an association between the disease and SMOC2 gene marker rs13208776 (p=3.13×108Freilich AR. Tzaraat--"biblical leprosy". J Am Acad Dermatol. 1982;6:131-4.); yet, this finding was not replicated.6565 Birlea SA, Gowan K, Fain PR, Spritz RA. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J Invest Dermatol. 2010;130:798-803. Subsequently, two independent GWAS for generalized vitiligo, conducted in Caucasian and Chinese samples, found many signs of vitiligo associated with polymorphisms of several loci, including the MHC.6666 Jin Y, Birlea SA, Fain PR, Gowan K, Riccardi SL, Holland PJ, et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med. 2010;362:1686-97.,6767 Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, et al. Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet. 2010;42:614-8. Only 2 of these signals for LPP and IKZF4 genes were replicated in population samples different from the original ones.3636 Jin Y, Mailloux CM, Gowan K, Riccardi SL, LaBerge G, Bennett DC, et al. NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med. 2007;356:1216-25.,6565 Birlea SA, Gowan K, Fain PR, Spritz RA. Genome-wide association study of generalized vitiligo in an isolated European founder population identifies SMOC2, in close proximity to IDDM8. J Invest Dermatol. 2010;130:798-803.,6767 Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, et al. Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. Nat Genet. 2010;42:614-8.,6868 Tang XF, Zhang Z, Hu DY, Xu AE, Zhou HS, Sun LD, et al. Association analyses identify three susceptibility Loci for vitiligo in the Chinese Han population. J Invest Dermatol. 2013;133:403-10.

ETIOPATHOGENESIS

The etiopathogenesis of vitiligo has not been fully elucidated and several theories have been proposed. Among those, the autoimmune hypothesis is currently the most accepted by experts.6969 Sandoval-Cruz M, Garcia-Carrasco M, Sanchez-Porras R, Mendoza-Pinto C, Jimenez-Hernandez M, Munguia-Realpozo P, et al. Immunopathogenesis of vitiligo. Autoimmun Rev. 2011;10:762-5.,7070 Schallreuter KU, Bahadoran P, Picardo M, Slominski A, Elassiuty YE, Kemp EH, et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Exp Dermatol. 2008;17:139-40; discussion 41-60. Besides this theory, others have been intensively studied, such as epidermal adhesion defect, biochemical and neural hypotheses. This article will discuss the adhesion defect, autoimmune and biochemical theories.

AUTOIMMUNE THEORY

The initial perception that autoimmunity was involved in patients with non-segmental vitiligo was based on the frequent co-occurrence of autoimmune diseases in these patients and their relatives, such as lupus erythematosus, psoriasis, alopecia areata, halo nevi and mainly autoimmune thyroid diseases, besides the favorable response to immunosuppressive therapies such as photochemotherapy with UVA (PUVA) and topical and oral corticosteroids.7171 Clayton R. A double-blind trial of 0-05% clobetasol proprionate in the treatment of vitiligo. Br J Dermatol. 1977;96:71-3.

72 Schallreuter KU, Lemke R, Brandt O, Schwartz R, Westhofen M, Montz R, et al. Vitiligo and other diseases: coexistence or true association? Hamburg study on 321 patients. Dermatology. 1994;188:269-75.

73 British Photodermatology Group guidelines for PUVA. Br J Dermatol. 1994;130:246-55.

74 Kim SM, Lee HS, Hann SK. The efficacy of low-dose oral corticosteroids in the treatment of vitiligo patients. Int J Dermatol. 1999;38:546-50.

75 Radakovic-Fijan S, Furnsinn-Friedl AM, Honigsmann H, Tanew A. Oral dexamethasone pulse treatment for vitiligo. J Am Acad Dermatol. 2001;44:814-7.
-7676 Cockayne SE, Messenger AG, Gawkrodger DJ. Vitiligo treated with topical corticosteroids: children with head and neck involvement respond well. J Am Acad Dermatol. 2002;46:964-5. In this regard, it has been determined that therapy with systemic corticosteroids decreased antibody mediated cytotoxicity against melanocytes in patients with vitiligo.7777 Hann SK, Kim HI, Im S, Park YK, Cui J, Bystryn JC. The change of melanocyte cytotoxicity after systemic steroid treatment in vitiligo patients. J Dermatol Sci. 1993;6:201-5.

In addition, two large epidemiological studies found different prevalence rates of autoimmune comorbidities in patients with vitiligo, especially thyroid diseases, in this case, 7.7% in Chinese subjects, contrasting with a higher prevalence of 20% in Caucasians.1111 Alkhateeb A, Fain PR, Thody A, Bennett DC, Spritz RA. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families. Pigment Cell Res. 2003;16:208-14.,7878 Zhang Z, Xu SX, Zhang FY, Yin XY, Yang S, Xiao FL, et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch Dermatol Res. 2009;301:167-73. A recent systematic review of thyroid diseases in patients with vitiligo identified average prevalence rates of thyroid diseases, autoimmune thyroid diseases, and the presence of thyroid-specific autoantibodies, respective-ly 15.1%, 14.3% and 20.8%, and a corresponding relative risk (RR) for those affected of 1.9, 2.5 and 5.2.7979 Vrijman C, Kroon MW, Limpens J, Leeflang MM, Luiten RM, van der Veen JP, et al. The prevalence of thyroid disease in patients with vitiligo: a systematic review. Br J Dermatol. 2012;167:1224-35.

Vitiligo is accompanied by abnormal humoral and cellular immunity and high levels of serum circulating autoantibodies have been detected in 5 to 10% of patients, predominantly of the IgG class and particularly anti-tyrosinase one and two (TRP-1 and TRP-2), however the role of anti-melanocyte antibodies in vitiligo pathogenesis remains uncertain and it has been suggested that their presence may be secondary to keratinocyte and melanocyte damages.7070 Schallreuter KU, Bahadoran P, Picardo M, Slominski A, Elassiuty YE, Kemp EH, et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Exp Dermatol. 2008;17:139-40; discussion 41-60.,8080 Kemp EH, Gawkrodger DJ, Watson PF, Weetman AP. Immunoprecipitation of melanogenic enzyme autoantigens with vitiligo sera: evidence for cross-reactive autoantibodies to tyrosinase and tyrosinase-related protein-2 (TRP-2). Clin Exp Immunol. 1997;109:495-500.

81 Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP. Autoantibodies to tyrosinase-related protein-1 detected in the sera of vitiligo patients using a quantitative radiobinding assay. Br J Dermatol. 1998;139:798-805.

82 Kemp EH, Waterman EA, Gawkrodger DJ, Watson PF, Weetman AP. Molecular mapping of epitopes on melanocyte-specific protein Pmel17 which are recognized by autoantibodies in patients with vitiligo. Clin Exp Immunol. 2001;124:509-15.

83 Kemp EH, Waterman EA, Hawes BE, O'Neill K, Gottumukkala RV, Gawkrodger DJ, et al. The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. J Clin Invest. 2002;109:923-30.

84 Okamoto T, Irie RF, Fujii S, Huang SK, Nizze AJ, Morton DL, et al. Anti-tyrosinaserelated protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol. 1998;111:1034-9.
-8585 Bystryn JC. Serum antibodies in vitiligo patients. Clin Dermatol. 1989;7:136-45.

Melanocytes are capable of presenting antigens in the presence of MHC class II, which would allow HLA-DR+ cells present in the perilesional vitiligo area to present antigens in response to trauma or local inflammation, in the latter case leading to autoimmune destruction of melanocytes.8686 Le Poole IC, Luiten RM. Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmun. 2008;10:227-43.,8787 Steitz J, Bruck J, Lenz J, Buchs S, Tuting T. Peripheral CD8+ T cell tolerance against melanocytic self-antigens in the skin is regulated in two steps by CD4+ T cells and local inflammation: implications for the pathophysiology of vitiligo. J Invest Dermatol. 2005;124:144-50. Several studies have demonstrated the presence of CD4+ and CD8+ lymphocytic infiltrates in the dermo-epidermal junction in perilesional vitiligo skin.8787 Steitz J, Bruck J, Lenz J, Buchs S, Tuting T. Peripheral CD8+ T cell tolerance against melanocytic self-antigens in the skin is regulated in two steps by CD4+ T cells and local inflammation: implications for the pathophysiology of vitiligo. J Invest Dermatol. 2005;124:144-50.,8888 Oyarbide-Valencia K, van den Boorn JG, Denman CJ, Li M, Carlson JM, Hernandez C, et al. Therapeutic implications of autoimmune vitiligo T cells. Autoimmun Rev. 2006;5:486-92. It has been observed experimentally that in some patients with common vitiligo, there was infiltration of CLA+T cells in the perilesional skin, thus being possible that the recruitment of these T cells occurred through dendritic cells activation, and these in turn are activated at the epidermal trauma region.8989 van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+ T cells at the perilesional site. Lab Invest. 2000;80:1299-309.,9090 Le Poole IC, Wankowicz-Kalinska A, van den Wijngaard RM, Nickoloff BJ, Das PK. Autoimmune aspects of depigmentation in vitiligo. J Investig Dermatol Symp Proc. 2004;9:68-72. Recently, data that may confirm this hypothesis were found, an immunohistochemistry study demonstrated an increased population of CD11c+ myeloid dendritic dermal cells and CD207+ Langerhans cells in the lesional border of vitiligo patches.9191 Wang CQ, Cruz-Inigo AE, Fuentes-Duculan J, Moussai D, Gulati N, Sullivan-Whalen M, et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS One. 2011;6:e18907.

Interestingly, melanocyte-specific cytotoxic T lymphocytes were associated with disease activity.9292 Lang KS, Caroli CC, Muhm A, Wernet D, Moris A, Schittek B, et al. HLA-A2 restricted, melanocyte-specific CD8(+) T lymphocytes detected in vitiligo patients are related to disease activity and are predominantly directed against MelanA/MART1. J Invest Dermatol. 2001;116:891-7. More recently, an in vitro study showed that cytotoxic T lymphocytes infiltrated in common vitiligo perilesional area destroyed neighboring melanocytes.9393 van den Boorn JG, Konijnenberg D, Dellemijn TA, van der Veen JP, Bos JD, Melief CJ, et al. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. J Invest Dermatol. 2009;129:2220-32.

Melanocytes and melanoma cells share differentiation antigens, and based on the number of cases observed in humans and mice, the spontaneous development of vitiligo in patients with melanoma has been considered as a sign of good prognosis for this tumor.9494 Nordlund JJ, Kirkwood JM, Forget BM, Milton G, Albert DM, Lerner AB. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983;9:689-96.

95 Lengagne R, Le Gal FA, Garcette M, Fiette L, Ave P, Kato M, et al. Spontaneous vitiligo in an animal model for human melanoma: role of tumor-specific CD8+ T cells. Cancer Res. 2004;64:1496-501.
-9696 Uchi H, Stan R, Turk MJ, Engelhorn ME, Rizzuto GA, Goldberg SM, et al. Unraveling the complex relationship between cancer immunity and autoimmunity: lessons from melanoma and vitiligo. Adv Immunol. 2006;90:215-41. In this regard, various studies about vitiligo's immunology are derived from the study of melanoma and melanoma vaccines; for example, immunotherapy against antigens such as gp100 and tyrosinase may lead to cytotoxic T lymphocytes infiltration both in the specific melanoma area as in vitiligo lesions.9797 Jacobs JF, Aarntzen EH, Sibelt LA, Blokx WA, Boullart AC, Gerritsen MJ, et al. Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients. Cancer Immunol Immunother. 2009;58:145-51.

98 Wankowicz-Kalinska A, Le Poole C, Wijngaard R, Storkus WJ, Das PK. Melanocyte-specific immune response in melanoma and vitiligo: two faces of the same coin? Pigment Cell Res. 2003;16:254-60.
-9999 Das PK, van den Wijngaard RM, Wankowicz-Kalinska A, Le Poole IC. A symbiotic concept of autoimmunity and tumour immunity: lessons from vitiligo. Trends Immunol. 2001;22:130-6.

Mice with surgically excised melanoma tumors generated cytotoxic T lymphocyte memory response against melanocytes, these mice that lacked regulatory T cells (TREGs) developed vitiligo, suggesting that TREGs would prevent autoimmunity against melanocytes.100100 Zhang P, Cote AL, de Vries VC, Usherwood EJ, Turk MJ. Induction of postsurgical tumor immunity and T-cell memory by a poorly immunogenic tumor. Cancer Res. 2007;67:6468-76. New data on patients with vitiligo corroborate these results, with the detection of reduced levels of chemokine CCL22, which increases TREGs (Regulatory T cells) migration toward the injured skin, leading to an inadequate number of TREGs in patients with vitiligo, insufficient to suppress a cytotoxic reaction in the skin of affected individuals.101101 Klarquist J, Denman CJ, Hernandez C, Wainwright DA, Strickland FM, Overbeck A, et al. Reduced skin homing by functional Treg in vitiligo. Pigment Cell Melanoma Res. 2010;23:276-86 In this same line of research, flow cytometry analysis revealed an increase in circulating CD8+ and a decrease in TREGs in patients with generalized vitiligo, in addition, expressive increases in these two cell types were identified in the perilesional skin of patients. However, regulatory T cells from peripheral blood had decreased ability of suppressing CD8+ T lymphocytes, suggesting that TREGs' malfunction and an increase in lymphocytes contributed to the destruction of melanocytes in the affected individuals.102102 Lili Y, Yi W, Ji Y, Yue S, Weimin S, Ming L. Global activation of CD8+ cytotoxic T lymphocytes correlates with an impairment in regulatory T cells in patients with generalized vitiligo. PLoS One. 2012;7:e37513. In contrast with some results of the latter article, another study did not find increase in TREGs or CD8+ T lymphocytes in the peripheral blood of patients with generalized vitiligo compared with controls, however, these cells were not assessed in vitiligo perilesional skin areas in this particular study.103103 Zhou L, Li K, Shi YL, Hamzavi I, Gao TW, Henderson M, et al. Systemic analyses of immunophenotypes of peripheral T cells in non-segmental vitiligo: implication of defective natural killer T cells. Pigment Cell Melanoma Res. 2012;25:602-11. Nevertheless, a relevant fact detected in by the authors was the decrease of invariant natural killer T cells (i NKT) in peripheral blood, these are regulatory cells, responsible for the Th1/Th2 immune response balance that are often diminished in other autoimmune diseases such as lupus erythematosus and rheumatoid arthritis, suggesting a protective effect on their part.103103 Zhou L, Li K, Shi YL, Hamzavi I, Gao TW, Henderson M, et al. Systemic analyses of immunophenotypes of peripheral T cells in non-segmental vitiligo: implication of defective natural killer T cells. Pigment Cell Melanoma Res. 2012;25:602-11.

The mechanism of self-tolerance loss, which magnifies the autoreactive cytotoxic lymphocytes actions in the destruction of melanocytes, is still unknown; a recent study showed evidence of functional defects in peripheral regulatory T cells (TREGs) in half of the patients tested with unstable vitiligo.104104 Ben Ahmed M, Zaraa I, Rekik R, Elbeldi-Ferchiou A, Kourda N, Belhadj Hmida N, et al. Functional defects of peripheral regulatory T lymphocytes in patients with progressive vitiligo. Pigment Cell Melanoma Res. 2012;25:99-109.

It has also been found in segmental vitiligo, whose pathogenesis was primarily linked to sympathetic nerves dysfunction, evidence that immune-mediated cellular responses including CD8+ T lymphocytes is involved in the early stages of this type of disease, moreover, in the same study flow cytometry detected a high expression level of IFN-γ in injured skin.105105 van Geel NA, Mollet IG, De Schepper S, Tjin EP, Vermaelen K, Clark RA, et al. First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi. Pigment Cell Melanoma Res. 2010;23:375-84.

A profile of Th-1 cytokines, Interferon-g, TNF-a and recently IL-8, has been well described in vitiligo skin areas both segmental and non-segmental.105105 van Geel NA, Mollet IG, De Schepper S, Tjin EP, Vermaelen K, Clark RA, et al. First histopathological and immunophenotypic analysis of early dynamic events in a patient with segmental vitiligo associated with halo nevi. Pigment Cell Melanoma Res. 2010;23:375-84.

106 Toosi S, Orlow SJ, Manga P. Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8. J Invest Dermatol. 2012;132:2601-9.

107 Wankowicz-Kalinska A, van den Wijngaard RM, Tigges BJ, Westerhof W, Ogg GS, Cerundolo V, et al. Immunopolarization of CD4+ and CD8+ T cells to Type-1-like is associated with melanocyte loss in human vitiligo. Lab Invest. 2003;83:683-95.

108 Birol A, Kisa U, Kurtipek GS, Kara F, Kocak M, Erkek E, et al. Increased tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha (IL1-alpha) levels in the lesional skin of patients with nonsegmental vitiligo. Int J Dermatol. 2006;45:992-3.
-109109 Moretti S, Spallanzani A, Amato L, Hautmann G, Gallerani I, Fabiani M, et al. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res. 2002;15:87-92. Besides Th-1 response, many evidences of Th-17 influence have been reported in vitiligo, with IL17+ lymphocytes infiltration in dermal areas on the border of vitiligo lesions being demonstrated by immunohistochemistry and immunofluorescence; in addition, an increased expression of IL-17A and IL-1 b was also found on the edges of lesions.9191 Wang CQ, Cruz-Inigo AE, Fuentes-Duculan J, Moussai D, Gulati N, Sullivan-Whalen M, et al. Th17 cells and activated dendritic cells are increased in vitiligo lesions. PLoS One. 2011;6:e18907. An increase of IL-17 in the serum of patients affected by vitiligo was recently described.110110 Khan R, Gupta S, Sharma A. Circulatory levels of T-cell cytokines (interleukin [IL]2, IL-4, IL-17, and transforming growth factor-beta) in patients with vitiligo. J Am Acad Dermatol. 2012;66:510-1.

ADHESION DEFECT THEORY

It has been suggested that adhesion defects are involved in the disappearance of melanocytes in vitiligo lesions.6363 Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A, et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol. 2012;21:411-6. The main clinical sign reinforcing this theory is the occurrence of koebnerization or Köebner phenomenon (appearance of vitiligo after an acute or chronic trauma), which may be present in up to 31% of Caucasian patients with common vitiligo.111111 Njoo MD, Das PK, Bos JD, Westerhof W. Association of the Kobner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol. 1999;135:407-13.

In one of the earliest studies that attempted to identify adhesion defects in the genesis of vitiligo, an immunohistochemical analysis was performed and demonstrated that tenascin protein, which can interfere with melanocyte adhesion, was over-expressed in damaged skin compared to the healthy skin of the same patients.112112 Lightner VA, Erickson HP. Binding of hexabrachion (tenascin) to the extracellular matrix and substratum and its effect on cell adhesion. J Cell Sci. 1990;95(Pt 2):263-77.,113113 Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK. Tenascin is overexpressed in vitiligo lesional skin and inhibits melanocyte adhesion. Br J Dermatol. 1997;137:171-8.

Experimental study with patients of the generalized subgroup (which included common, acrofacial and universal types) demonstrated that these patients presented melanocyte detachment after mechanical rubbing of the unaffected skin.114114 Gauthier Y, Cario-Andre M, Lepreux S, Pain C, Taieb A. Melanocyte detachment after skin friction in non lesional skin of patients with generalized vitiligo. Br J Dermatol. 2003;148:95-101. This observation led to the proposal of a new theory that non-segmental vitiligo is a melanocytorrhagic primary disorder, i.e., there would probably occur an acute loss of melanocytes (because most patients have a sudden onset of lesions), with an altered response of melanocytes to friction and possibly other types of stress, which would induce cell detachment and subsequent transepidermal loss. In this context, the authors of this theory speculated that an autoimmune phenomenon might be triggered by antigen release and recognition of affected melanocytes by dendritic cells or memory T cells during trans-epidermal migration, thereby exacerbating the detachment and loss of more melanocytes.3030 Gauthier Y, Cario Andre M, Taieb A. A critical appraisal of vitiligo etiologic theories. Is melanocyte loss a melanocytorrhagy? Pigment Cell Res. 2003;16:322-32.

Alterations in the main protein that adheres melanocytes to the epidermis basal layer, DDR1 (Discoidin Domain Receptor-1) have been implicated as one of the aggravating factors in the loss of melanocytes. Initially, genetic association studies have found evidence of a connection between non-segmental vitiligo and DDR1 gene alleles, which was more evident in vitiligo patients with the onset of disease before 25 years of age.6161 Silva de Castro CC, do Nascimento LM, Walker G, Werneck RI, Nogoceke E, Mira MT. Genetic variants of the DDR1 gene are associated with vitiligo in two independent Brazilian population samples. J Invest Dermatol. 2010;130:1813-8.,6262 Kim HJ, Uhm YK, Yun JY, Im SH, Yim SV, Chung JH, et al. Association between polymorphisms of discoidin domain receptor tyrosine kinase 1 (DDR1) and non-segmental vitiligo in the Korean population. Eur J Dermatol. 2010;20:231-2.

Functional studies attempting to explain the involvement of DDR1 and CCN3 protein (which controls the adhesion of DDR1 to epidermis basal layer115115 Fukunaga-Kalabis M, Martinez G, Liu ZJ, Kalabis J, Mrass P, Weninger W, et al. CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. J Cell Biol. 2006;175:563-9. observed that perilesional melanocytes did not express CCN3, moreover, the silencing of CCN3 in melanocytes induced a significant inhibition of their adhesion to collagen IV.6363 Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A, et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol. 2012;21:411-6. In this same study, it was demonstrated that the expression of DDR1 in lesional skin was decreased compared to perilesional skin in most patients, and collagen IV expression was diminished in all affected individuals.6363 Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I, Bibeyran A, et al. Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Exp Dermatol. 2012;21:411-6. In this same research line, a recent study confirmed the decreased expression of DDR1 in all lesional epidermis, whereas epidermal expression of DDR1 was secondary only to expression in keratinocytes and not in epidermis basal layer, where melanocytes are located. This study hypothesized that the vitiligo is a condition in which all the epidermis is affected and not only melanocytes.6464 Reichert-Faria A, Jung JE, Neto VM, de Castro CC, Mira MT, Noronha L. Reduced immunohistochemical expression of Discoidin Domain Receptor 1 (DDR1) in vitiligo skin. J Eur Acad Dermatol Venereol. 2013;27:1057-9.

VITILIGO'S BIOCHEMICAL THEORY

The hypothesis that vitiligo could be caused by a metabolic pathway dysfunction, not necessarily related to melanocytes, which would lead to the production of toxic metabolites such as catecholamines, oquinones and reactive oxygen species, has been widely investigated.3131 Dell'anna ML, Picardo M. A review and a new hypothesis for non-immunological pathogenetic mechanisms in vitiligo. Pigment Cell Res. 2006;19:406-11.,7070 Schallreuter KU, Bahadoran P, Picardo M, Slominski A, Elassiuty YE, Kemp EH, et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Exp Dermatol. 2008;17:139-40; discussion 41-60.

The involvement of oxidative stress damage to melanocytes is supported by evidence suggesting an imbalance between the oxidant/antioxidant systems in the epidermis of patients with vitiligo. It has been demonstrated that melanocytes on the lesion borders of vitiligo patients showed increased sensitivity to oxidative stress when in culture.116116 Jimbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol. 2001;144:55-65. Schallreuter et al. observed in vivo that patients with vitiligo can accumulate a concentration of H2O2 over 10-3 M in their epidermis.117117 Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ, et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Investig Dermatol Symp Proc. 1999;4:91-6. Different possible sources of endogenous production of H2O2 in the epidermis of vitiligo patients have been described, including an increase in monoamine oxidase A (MAO-A), increased activity of NADPH-oxidase and imbalance in (6R)-L-erythro 5,6,7,8-tetrahydrobiopterin (6-BH4) synthesis/recycling/regulation.117117 Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ, et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Investig Dermatol Symp Proc. 1999;4:91-6.

118 Hasse S, Gibbons NC, Rokos H, Marles LK, Schallreuter KU. Perturbed 6-tetrahydrobiopterin recycling via decreased dihydropteridine reductase in vitiligo: more evidence for H2O2 stress. J Invest Dermatol. 2004;122:307-13.

119 Schallreuter KU, Wood JM, Pittelkow MR, Buttner G, Swanson N, Korner C, et al. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res. 1996;288:14-8.
-120120 Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, et al. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science. 1994;263:1444-6. One of the likely consequences of increased 6-BH4 production observed in the epidermis of affected patients is the inhibition of phenylalanine hydroxylase enzyme, responsible for producing L-tyrosine from L-phenylalanine, leading to low levels of tyrosine and therefore, a defect in melanin synthesis.121121 Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ, et al. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta. 1994;1226:181-92.

Patients with vitiligo have a low level/activity of enzymatic and non-enzymatic antioxidants such as catalase, glutathione peroxidase and vitamin E, possibly increasing H2O2 toxicity.122122 Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, et al. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol. 1997;109:310-3.

123 Sravani PV, Babu NK, Gopal KV, Rao GR, Rao AR, Moorthy B, et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Indian J Dermatol Venereol Leprol. 2009;75:268-71.
-124124 Passi S, Grandinetti M, Maggio F, Stancato A, De Luca C. Epidermal oxidative stress in vitiligo. Pigment Cell Res. 1998;11:81-5. The results obtained for the levels of superoxide dismutase antioxidant were conflicting amongst studies.122122 Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S, et al. Increased sensitivity to peroxidative agents as a possible pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol. 1997;109:310-3.,123123 Sravani PV, Babu NK, Gopal KV, Rao GR, Rao AR, Moorthy B, et al. Determination of oxidative stress in vitiligo by measuring superoxide dismutase and catalase levels in vitiliginous and non-vitiliginous skin. Indian J Dermatol Venereol Leprol. 2009;75:268-71.,125125 Picardo M, Passi S, Morrone A, Grandinetti M, Di Carlo A, Ippolito F. Antioxidant status in the blood of patients with active vitiligo. Pigment Cell Res. 1994;7:110-5.,126126 Yildirim M, Baysal V, Inaloz HS, Kesici D, Delibas N. The role of oxidants and antioxidants in generalized vitiligo. J Dermatol. 2003;30:104-8. Further evidence on the involvement of oxidative stress in the disease pathogenesis is the suspension of the depigmentation process and skin color recovering with the removal of epidermal H2O2 by Narrow-Band-UVB 311nm activated pseudocatalase.117117 Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin DJ, et al. In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Investig Dermatol Symp Proc. 1999;4:91-6.

Studies have reported the involvement of the adrenergic and cholinergic systems in vitiligo pathogenesis.127127 Iyengar B. Modulation of melanocytic activity by acetylcholine. Acta Anat (Basel). 1989;136:139-41. Acetylcholinesterase (AChE) is an important enzyme in promoting and maintaining oxidative stress, being inactivated by oxidation of Trp,432 Trp,435Met436 residues by H2O2. Interestingly, AChE activity is low in vitiligo skin lesions during depigmentation, but it returns to normal when the damaged skin starts repigmentation.128128 Schallreuter KU, Elwary SM, Gibbons NC, Rokos H, Wood JM. Activation/deactivation of acetylcholinesterase by H2O2: more evidence for oxidative stress in vitiligo. Biochem Biophys Res Commun. 2004;315:502-8.Picardo et al. showed that abnormal catecholamine release by autonomic nerve terminations could result in excessive production of toxic radicals in the melanocyte microenvironment.125125 Picardo M, Passi S, Morrone A, Grandinetti M, Di Carlo A, Ippolito F. Antioxidant status in the blood of patients with active vitiligo. Pigment Cell Res. 1994;7:110-5. Furthermore, high levels of catecholamine metabolites in the urine of patients with vitiligo during the active phase of disease have been reported, when compared with age-matched controls.129129 Morrone A, Picardo M, de Luca C, Terminali O, Passi S, Ippolito F. Catecholamines and vitiligo. Pigment Cell Res. 1992;5:65-9.,130130 Cucchi ML, Frattini P, Santagostino G, Preda S, Orecchia G. Catecholamines increase in the urine of non-segmental vitiligo especially during its active phase. Pigment Cell Res. 2003;16:111-6.

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  • Financial Support: None
  • *
    Work performed at Santa Casa de Misericórdia de Curitiba Hospital - Paraná Pontifical Catholic University (PUCPR) - Curitiba (PR), Brazil.
  • How to cite this article: Tarlé RG, Nascimento LM, Mira MT, Silva de Castro CC. Vitiligo - Part 1 - review. An Bras Dermatol. 2014;89(3):461-70.

Publication Dates

  • Publication in this collection
    May-Jun 2014

History

  • Received
    25 Feb 2013
  • Accepted
    25 May 2013
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