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doi: 10.1111/1346-8138.


Journal of Dermatology 2013; 40: 310–318


Modern vitiligo genetics sheds new light on an ancient disease
Richard A. SPRITZ
Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado, USA

Vitiligo is a complex disorder in which autoimmune destruction of melanocytes results in white patches of skin and overlying hair. Over the past several years, extensive genetic studies have outlined a biological framework of vitiligo pathobiology that underscores its relationship to other autoimmune diseases. This biological framework offers insight into both vitiligo pathogenesis and perhaps avenues towards more effective approaches to treatment and even disease prevention.

Key words:

autoimmune destruction, disease prevention, vitiligo, vitiligo genetics, vitiligo pathogenesis.

Vitiligo is a complex disorder in which white patches of skin and overlying hair result from autoimmune destruction of melanocytes within the lesions. Vitiligo appears to be of multifactorial causation, involving multiple underlying susceptibility genes and environmental triggers. Over the past several years there has been considerable progress in defining the genetic epidemiology and genetic pathogenesis of vitiligo, and its relationships to other autoimmune diseases. To date, almost all genetic studies have been of generalized or “non-segmental” vitiligo. Recently, advances by these genetic studies have outlined a biological framework that offers real insight into vitiligo pathogenesis and perhaps to more effective approaches to treatment and even disease prevention.

Human pigmentation diseases present the most visually striking of all disorders, and the phenotypes of oculocutaneous albinism, piebaldism and others have been known for thousands of years.1 Vitiligo itself has had a remarkable history of discovery and re-discovery of key observations overlooked or forgotten over the passage of time. Certainly, patients with various forms of patchy leukoderma were recognized during ancient times; however, vitiligo per se was not described as a specific medical entity until the mid-18th century.2 The first clue to vitiligo pathogenesis came from the description and illustration of a patient with concomitant vitiligo, adrenal insufficiency and pernicious anemia,3 highlighting a link between these three autoimmune diseases. Similar patients with multiple autoimmune diseases were later reported

by Schmidt4 and codified by Neufeld and Blizzard.5 Further evidence of immune or inflammatory influences in vitiligo came from the recognition that new lesions often occur at sites of € bner skin injury,6 a phenomenon first described in 1872 by Ko in the context of psoriasis and which came to bear his name.7 Perhaps the most important observation regarding vitiligo pathogenesis also came from Kaposi, who illustrated histological lack of cells containing pigment granules within vitiligo skin lesions,8 later re-described by Hu et al.9 and yet again by Breathnach et al.10 Probably the landmark early study of vitiligo was that of Lerner,11 who reported on clinical, epidemiological and genetic characteristics of 200 cases, thereby delineating many important clinical and epidemiological aspects of the disease, establishing the clinical terminology and classification scheme that is basically still in use today. This study provided an analytic framework that was adopted by many subsequent epidemiological surveys of vitiligo patients around the world,12–21 providing key information in formulating the genetic underpinnings of the disorder.

The earliest formal considerations of the genetic basis of vitiligo appear to have been by Stuttgen,22 Teindel23 and later by Lerner,11 all of whom noted familial aggregation of cases not clearly consistent with Mendelian single-gene inheritance. Stuttgen,22 in particular, was remarkable in suggesting the simultaneous involvement of both recessive and dominant contributory influences, predating the modern genetic concept of “complex inheritance” by decades. Subsequently, Das et al.,24,25 Bhatia et al.26 and Majumder et al.27 likewise all

Correspondence: Richard A. Spritz, M.D., Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045, USA. Email richard.spritz@ucdenver.edu Received 19 February 2013; accepted 20 February 2013.


© 2013 Japanese Dermatological Association

59 Tripathi et al.44.72 a locus that had been previously associated with several other autoimmune diseases. The first such study reported genetic association of vitiligo with single nucleotide polymorphisms (SNP) within CTLA4.2. by contrast. including with vitiligo. The first detection of novel vitiligo loci by genome-wide study came from linkage analysis of families with systemic lupus erythematosus (SLE) that included at least one case of vitiligo.64.25. 13.07). as well as other autoimmune diseases.30. supporting roles for both genetic and non-genetic factors in disease pathogenesis. this approach is considered acceptable for confirmation of established genes. Arcos-Burgos et al.12 found that the concordance for vitiligo in monozygotic twins was 23%. Candidate gene association studies. multifactorial inheritance.28 and Nath et al. and thus are subject to the caveats appropriate to the identification of these genes in the first place.25. Genetic linkage studies The first vitiligo genetic linkage studies were of candidate genes. as the vast majority report false-positives resulting from chance fluctuation due to insufficient statistical power.65 encoding a key regulator of the innate immune response.70 studied XBP1 as a candidate gene within the 22q12 linkage region.27.30 postulated multiple forms of vitiligo with different genetic underlying models.63 SLEV1 was subsequently confirmed by direct genome-wide study of Caucasian multiplex vitiligo families.332. 9. Genome-wide analysis of a unique Caucasian family with autosomal dominant vitiligo detected AIS1 on chromosome 1p31. including ABO and other blood groups.12. Comprehensive genome-wide linkage analyses of other multiplex vitiligo families also detected a number of other vitiligo susceptibility loci.15. 7. and the closely adjacent KIT gene would seem a better candidate for this linkage signal.46–55 While several of these studies reported weak associations. was negative.73 Even in that initial report. Ren et al.68 and on chromosomes 4. MOLECULAR GENETIC ERA Modern genetic studies of vitiligo have principally entailed five scientific approaches: genetic linkage analysis of families with multiple affected relatives (multiplex families). Close relatives of vitiligo patients have elevated risk of vitiligo. again with negative results. Gene expression studies are generally considered invalid as Candidate gene association studies The earliest candidate gene association studies of vitiligo were of loci that previously had been shown to be genetically linked and/or associated with other autoimmune diseases.33–35 Estimates of vitiligo heritability range from 46% in India to 16% in China. PDGFRA is not known to play a role in pigment cell biology. However.Vitiligo genetics and pathogenesis noted frequent familial clustering of vitiligo cases in a non-Mendelian pattern. whereas most other investigators favored polygenic. additional families with dominant vitiligo and FOXD3 mutations have not been described. Xu et al. CTLA4 was © 2013 Japanese Dermatological Association 311 . Though candidate gene association studies are not considered a valid approach to primary discovery of disease genes. Majumder et al. are largely discounted by modern geneticists as an approach to gene discovery.26.33 and Alkhateeb et al. detecting linkage of vitiligo with microsatellite polymorphic markers in HLA gene regions in families from several different populations. 11.45 Essentially.31–33 which is now generally accepted. thus far. 19 and 21 in Caucasians. Genetics researchers give highest credence to disease gene discoveries derived from genomewide linkage and GWAS. as these approaches are relatively free of biases and are robust to several important sources of potential error.61. finding more variation in familial vitiligo cases than controls. A linkage study of the HLA region in a large family with polyglandular autoimmune disease type II (Schmidt syndrome). candidate gene association studies comparing relatively small numbers of vitiligo patients (cases) to unaffected controls.60 tested linkage of vitiligo to MITF.43 and a number of other serum proteins.66 and the corresponding gene was subsequently identified as FOXD3.67 encoding a developmental regulator of melanoblast differentiation.71 studied PDGFRA as a candidate gene within the 4q12-q21 linkage region. with relative risks for first-degree relatives estimated at approximately 6–18-fold elevated. the results were inconsistent. Subsequently.15.36–42 blood group secretor status. PRE-MOLECULAR GENETIC STUDIES The earliest attempts to identify specific genes that may contribute to vitiligo were genetic association studies of vitiligo using a variety of protein polymorphic markers. though this assignment has not yet been confirmed. detecting the SLEV1 locus on chromosome 17p13. DNA sequencing studies and gene expression studies. partly because of inadequate study designs and partly because of likely genetic heterogeneity among the many different populations analyzed.69 some of which may correspond to genes detected in subsequent GWAS. on chromosomes 1. HLA) types and vitiligo. genomewide association studies (GWAS) comparing far larger numbers of cases to controls.58 DNA sequencing studies largely involve candidate genes previously identified by other means. Nevertheless.61. there were a number of case–control genetic association studies of histocompatibility antigen (human leukocyte antigen. population stratification and the impossibility of adequate correction for multiple testing given publication bias of positive results. all of these studies proved negative. a means of disease gene discovery as they cannot distinguish between primary causal differences versus secondary changes that are the result of pathway dysregulation or disease. 6 and 22 in Chinese.12.64 and the corresponding causal gene was eventually identified as NLRP1. but can be useful as a means of confirming the biological relevance of previous genetic findings.29 suggested a multilocus recessive model. meta-analysis of data from 11 of these studies56 subsequently identified association of vitiligo with HLA-A2 (odds ratio. The first positive results came from targeted linkage analysis of the major histocompatibility complex (MHC) on chromosome 6p. 2.

3 22q12. T cells. melanoblast differentiation Lymphoid transcriptional co-repressor. interacts with CTLA-4 Transcriptional co-activator? Positive regulator of immunoreceptor signaling Cytokine regulator of skin dendritic (Langerhans) cell maturation Presents peptide antigens Presents peptide antigens Presents peptide antigens B-cell transcriptional repressor Regulates differentiation and function of B cells.33 3q28 4p16.1 5q22. regulatory T-cells Apoptotic executioner protein T-cell regulator Melanin biosynthetic enzyme TYR regulation? T-cell transcriptional regulator B-cell.2 2q33.R.22 10p15.C A A C C C A A. 4 LNK adaptor Granzyme B Oculocutaneous albinism II Melanocortin-1 receptor NLR family.1 6p21. T cells.2 1p31.12 14q12 15q12-13.1 22q12.3 1p36.32 6q15 6q27 6q27 8q24.A. dendritic cells Regulates interleukin 2-mediated activation of T-cells. dendritic cells Regulate cellextracellular matrix i nteractions Regulates antigen receptor signaling in T cells.3 12q13. B cells.3 11q21 11q23. T-cell. Src-like adaptor isoform c Interleukin 2 receptor a-chain Caspase 7 CD44 antigen Tyrosinase None Ikaros zinc finger protein.3 Candidate gene PTPN22 FOXD3† RERE IFIH1 CTLA4‡ FOXP1 CD80 LPP CLNK TSLP§ HLA-A HLA-B-C HLA-DRB1-DQA1 BACH2 CCR6 SMOC2¶ TG/SLA IL2RA Gene desert CASP7 CD44 TYR Gene desert Gene desert IKZF4 SH2B3 GZMB OCA2 MC1R NLRP1 TICAM1†† UBASH3A XBP1§ C1QTNF6 Populations C C C C C C C A. apoptotic regulator Regulates innate antiviral immune responses Inhibits T cells via interaction with CD80 and CD86 Transcriptional regulator of B-cell.2 19p13.2 12q24.C C C C A C. basic leucine zipper Chemokine (C-C motif) receptor 6 SPARC-related modular calcium-binding protein Thyroglobulin. apoptosis Transcriptional regulator of MHC class II expression. Spritz Table 1.3 21q22.1 16q24.1 6p22.I C A.C Protein LYP protein tyrosine phosphatase Forkhead box D3 Atrophin-1-like protein isoform b Interferon-induced RNA helicase Cytotoxic T-lymphocyte-associated-4 Forkhead box P1 B-cell activation antigen B7-1 LIM domain containing preferred translocation Mast cell immunoreceptor signal transducer Thymic stromal lymphopoietin protein Leucocyte antigen A a-chain Leukocyte antigen B or C a-chain Major histocompatibility complex class II region BTB and CNC homology 1.2 3p13 3q13. Confirmed and suggestive vitiligo susceptibility loci identified by genome-wide association or linkage studies Chromosome 1p13. dendritic cells. plasma cells Innate immune response to light-induced apoptosis? 312 © 2013 Japanese Dermatological Association . pyrin domain containing 1 Toll-like receptor adaptor molecule 1 Ubiquitin associated and SH3 domain containing X-box binding protein 1 C1q and tumor necrosis factor related protein 6 Function Regulates T-cell signaling Transcriptional regulator of neural crest.1 10q25. subfamily 1A.23 2q24. monocyte development T-cell priming by B cells.C C C C C C C C A. T-cell developmental regulator Mediates CTL-induced target cell apoptosis.C C C A.C A. helper T-cell apoptosis Melanosomal membrane transporter /pump Regulates melanogenesis Regulates IL-1b innate immune response via NLRP1 inflammasome Mediates innate antiviral immune responses Regulates T-cell signaling.1 10q22.3 17p13.3 11p13 11q14.1 6p22.

FAS. IL2RB-C1QTNF6.2 Xp11.94 IL20. MC1R.87 GSTP1.81 Additional claimed candidate gene associations with vitiligo include AHR86.101 and one in Chinese. been detected in other GWAS. IL10. many based on little or no compelling biological rationale. XBP1).75 published a comprehensive review of 33 claimed vitiligo candidate genes (ACE. Birlea et al. two in Caucasians 81. because of complex patterns of long-range linkage disequilibrium across the MHC. Until recently. GZMB. Three large GWAS of vitiligo have been reported thus far.Vitiligo genetics and pathogenesis Table 1. the Indian–Pakistani GWAS reported association only with the MHC class II gene region. IKZF4. DDR1.100. IL2RA. finding support for only three (TSLP. ZMIZ1. particularly TYR. MBL2. (continued) Chromosome 22q13. and an intergenic interval at 11q23.1 between SLC29A3 and CDH23.81 A number of investigators reported association of vitiligo with loci in the MHC.103 These studies have detected 30 vitiligo susceptibility loci in Caucasians (Table 1): PTPN22. § XBP1. CD80. and FOXP3. and formal trans-ethnic analysis indicated that association signals in Caucasians and Indian–Pakistani patients in this genomic region likely share the same ancestral origin. Similarly. the HLA class I gene region.101 ‡ † only associated with vitiligo in patients who also had concomitant autoimmune diseases. a gene that also had been previously associated with a number of other autoimmune diseases. it has been difficult to assign genetic association to specific genes within the MHC.106 GWAS Genome-wide association studies are currently the “gold standard” of genetic studies of complex diseases. involved in T-cell tolerance Transcriptional regulator of regulatory T-cell function and development Found only in a single family with autosomal dominant vitiligo.96 Some of these claimed novel candidate gene associations may be valid. OCA2. vitiligo association with at least LPP. TGFBR2.80 most importantly by the first GWAS of vitiligo. VDR. IL24e and IL20RA.3 between DDX6 and CXCR5. C12orf10. CASP7.79. highly detailed candidate gene association studies.77 reported association of vitiligo with PTPN22. CTLA4. PTGS2. NFE2L2. Over the following years.104 The parallel studies of Chinese have detected nine vitiligo susceptibility loci (Table 1): LPP. GSTT1. FOXP3) in analysis of a genome-wide vitiligo GWAS dataset. KITLG. CAT. RERE. a gene desert at 11q21. The first vitiligo GWAS was an analysis of patients from a population isolate in Romania with a high prevalence of vitiligo and other autoimmunity. with apparent genetic association being secondary to epidemiological association of vitiligo with other autoimmune diseases for which CTLA4 is causal. though most are likely to represent false-positives. though other genes associated with vitiligo susceptibility or protection may be population-specific. GSTM1.74 Subsequently. CLEC11A. FOXP3.98 While association with SMOC2 has not © 2013 Japanese Dermatological Association 313 . FOXP1. CD4. IKZF4 and C1QTNF6 appears to be shared between the Caucasian and Chinese populations. FOXD3. driven by primary association with these other diseases. CLNK. OCA2 and MC1R.93 while candidate genes reported not to be associated include CD28.103 DNA sequencing studies Gene-specific DNA sequencing analyses are. TAP1-PSMB8.92 TLR2 and TLR4.75 XBP1 was identified as a positional candidate based on linkage in Chinese.88 IL4.66.105 and the claimed association of vitiligo with GCH1 mutations was quickly refuted. TOB2. COMT. an intergenic interval at 10q22. STAT4.95 and SMOC2. UBASH3A.78 This association was subsequently confirmed by other investigators. SH2B3. PDGFRA-KIT. TSLP.102 Thus. MHC class I (HLA-B-HLA-C).97 detecting association with SMOC2 located at distal chromosome 6q27.70 ¶ SMOC2 is located very close to CCR6 and may represent the same association signal.102 while a small gene-centric GWAS of vitiligo has been reported in Indian–Pakistani patients.89 IL19 and IL20RB.81. IL1RN. The first such study was of GCH1. TXNDC5. which was detected in GWAS of vitiligo in both Caucasians81 and Chinese.90 MTHFR.94 ICOS. TYR.99. TNF. MHC class II (c6orf10-BTNL2-DRB1-DQA1). CTLA4 (only in patients with other autoimmune diseases). typically comparing the frequency of either specific variants or of all observed variation in specific candidate genes in cases versus in controls. Canton et al. CCR6. ESR1. †† TICAM1 achieves highly suggestive association in analysis of GWAS data in Caucasians. XBP1. COX2. FBXO11. IL2RA.91 PRO2268.100. TSLP. as confirmed in subsequent studies.74–76 Association of CTLA4 with vitiligo may thus be secondary. 2 Forkhead box P3 Function Inhibitor of cell cycle progression. UVRAG.82–85 However.23 Candidate gene TOB2 FOXP3§ Populations C C Protein Transducer of ERBB2. TG/SLA. a large number of candidate gene studies of vitiligo were published. RNASET2FGFR1OP-CCR6. it is located very close to CCR6 in chromosome 6q27.101. CD44.90 INOS.99. LPP.99 and it may be that all of three reports represent the same association signal. AIRE. IL2RA. CCR6. BACH2. TICAM1. XBP1. EDN1. C1QTNF6. IKZF4. FOXP3 and TSLP are the only vitiligo candidate genes that achieve suggestive association in analysis of genome-wide association study data in Caucasians. HLA-A.67 CTLA4 is only associated with vitiligo in patients with other concomitant autoimmune diseases. in effect.74–76 This has been interpreted as perhaps indicating that there are multiple genetically distinct subtypes of vitiligo76 or that CTLA4 is not actually causal for vitiligo. IFIH1. most such studies have lacked sufficient statistical power or rigor to prove that observed DNA sequence variations are truly causal for the disease versus being rare non-causal polymorphisms.

Perhaps stimulated by IL-1b and facilitated by interaction of CD80 with CTLA4 and by the action of PTPN22. Recently. The activated T cells express IL-2. L155H-T246S-T782S-T878M-T995I-M1119V-M1184V-V1241LR1366C. perhaps consistent with implication of these pathways in vitiligo pathogenesis by previous genetic studies. and GZMB is introduced into the target melanocyte.115 which is not surprising given that a greatly reduced number of melanocytes within vitiligo lesions is the hallmark of the disease. OCA2 and the melanocortin-1 receptor (MC1R). “Circuit” of melanocyte damage. Jin et al. perhaps facilitating microinfection. the role of which in vitiligo pathogenesis remains uncertain. Skin is damaged by ultraviolet (UV) or other trauma. The first such study identified VIT1. while a less common but even higher risk haplotype contains nine non-synonymous substitutions. More recently. Gene expression studies A number of studies have compared expression of genes in normal versus vitiligo skin or melanocytes. but it is difficult to have confidence that any of the reported differences are in fact causal for vitiligo. melanocyte autoantigen presentation. though the mechanism by which this multi-variant granzyme B affects vitiligo susceptibility is not yet known. finding that the predominant HLA-A vitiligo-associated susceptibility allele is HLAA*02:01:01:01. either genome-wide or of selected candidate genes.111 sequenced GZMB and found that the causal allele involved a common multi-variant haplotype containing three non-synonymous substitutions in strong linkage disequilibrium. Other investigators have carried out differential expression studies of a very large number of candidate genes. L155HV1059M-M1184V. Ferrara et al.116 carried out transcriptome analyses of vitiligo patients and found evidence of upregulated innate immunity in non-lesional skin. or would even remain statistically 314 © 2013 Japanese Dermatological Association .104 sequenced both HLA-A and TYR in Caucasian vitiligo patients. Spritz DNA sequences of a number of additional vitiligo candidate genes have subsequently been compared in vitiligo cases versus controls. while finding that two common non-synonymous substitutions of TYR.109 None of these studies showed convincing significant differences in cases versus controls after appropriate correction for multiple testing.112 sequenced NLRP1 and found that the common high-risk haplotype contains three non-synonymous substitutions in strong linkage disequilibrium. HLA-A2 presents tyrosinase peptide as an autoimmune antigen. These authors showed that the common multi-variant high-risk haplotype results in 1. Langerhans cells take up peptide autoantigens presented by human leukocyte antigen (HLA) class I molecules expressed on the surface of nearby melanocytes.A. several vitiligo susceptibility genes detected by GWAS have been subjected to NextGeneration DNA resequencing to identify sequence variation that is apparently causal for disease. suggesting that these loci and variants act via a common pathway. which binds to the IL-2 receptor expressed on their surface.R. stimulating maturation to cytotoxic T cells that express granzyme B (GZMB). These include ASIP. the response of which is regulated by PTPN22. Yu et al. immune triggering and propagation. Figure 1. Levandowski et al. thereby activating caspases that cleave the interleukin (IL)-1b precursor to biologically active secreted IL1b. including peptides derived from tyrosinase (TYR). presenting a likely mechanism for disease pathogenesis associated with this haplotype. a gene downregulated in vitiligo melanocytes113 and later renamed FBXO11. stimulating nucleation of an NLRP1 inflammasome.108 MC1R. The TCR expressed by these autoreactive cytotoxic T cells binds its cognate autoantigen presented on the surface of target melanocytes by HLA class I molecules.8-fold elevation of processing of the inactive interleukin (IL)-1b precursor to biologically active IL-1b cytokine by the NLRP1 inflammasome. and these peptide autoantigens are then transferred to HLA class II molecules expressed on the Langerhans cell surface. Molecules displaying pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP) interact with NLRP1 in the cytoplasm of Langerhans cells. inducing apoptosis. whereas the TYR 192Y and 402Q substitutions likely reduce the amount of tyrosinase peptide available for presentation. S192Y and R402Q. T-cell programming and melanocyte target cell killing in vitiligo.107. Q55R-P94A-Y247H. mostly in relatively small numbers.114 Analyses comparing genes differentially expressed in vitiligo lesions versus in uninvolved skin principally detect genes that encode melanocyte components. appear to exert both individual and synergistic protective effects. A serious problem in such studies is the difficulty in distinguishing causal changes from those that result from the disease state or from melanocyte stress or senescence. these melanocyte-derived peptide autoantigens are then presented to immature T cells that express cognate T-cell receptors (TCR).107–109 MYG1/c12orf10110 and POMC.

autoantigen programming and target cell killing by immune effector cells thus incorporates many of the genes and proteins that modulate vitiligo susceptibility. Vol III. Abnormalities of pigmentation. Melanocyte-specific CTL then recognize the cognate melanocyte autoantigens presented on the melanocyte surface by HLA class I molecules. Within the dendritic cells.81. as well as cytolytic molecules such as granzyme B.101 This apparent genetically inverse relationship of melanocyte-specific genes to vitiligo versus melanoma led to the suggestion that vitiligo may represent a dysregulated normal process of immune surveillance against malignant melanoma.  ne ral. which then present these antigens to immature T cells.D. Oxford: Elsevier. R01AR056292 and P30AR057212 from the National Institutes of Health. melanocyte autoantigens are transferred from HLA class I molecules to HLA class II mol- ecules. Vienna 1879. J Invest Dermatol 1959. M. A likely common € bnerization. soit de naissance. Pathologie und Therapie der Hautkrankheiten. Korf B. with pathway for initial vitiligo triggering may be Ko various types of skin damage resulting in localized cell killing and perhaps localized microinfection. the same SNP having genetically opposite roles in vitiligo versus melanoma susceptibility. 33: 267–280.104 NLRP1112 and GZMB. Doniach D. 2 Le Cat C-N. Several of the genes identified as conferring vitiligo susceptibility. Vjschr Dermatol 1876. 1980. At the same time. Reprinted in Med Classics 1937. New Sydenham Society. IL-1b is a potent pro-inflammatory cytokine. Vitiligo. 12 Alkhateeb A. 1). and the target cells are ultimately lysed by granzyme B. Together. Spritz RA. CURRENT UNDERSTANDING To date. In: Pinchera A. eds. Most of these loci contain or are in close proximity to plausible biological candidate genes. 4 Schmidt M. Two such studies89. € bner H. New York: Academic Press.92 have correlated altered gene expression with genetic association of specific SNPs in the corresponding genes. Melanocyte peptide antigens are presented to skin-resident dendritic cells (principally Langerhans cells) by HLA class I molecules on the melanocyte surface.104 HLA-A. New Sydenham Society. soit accidentellement. 1765. have also emerged as genes involved in susceptibility to malignant melanoma. London 1874. Immature T cells then express and secrete IL-2. Hearing VJ. eds. 21: 212–221. Amsterdam. other pathways of inflammasome activation and innate immune induction are also possible. and perhaps not even substantially correct.].. Blizzard RM. A. Eine biglanduiare Erkrankung (Nebennieren und Schilddruse) bei Morbus Addisonii. this model nevertheless provides for the first time a conceptualization of vitiligo pathogenesis that encompasses advanced biological knowledge of the disease and that may highlight potential new avenues for therapy and even disease prevention in individuals with high genetic susceptibility. [N. In vitro studies on vitiligo. 6 Hebra F. On the constitutional and local effects of disease of the suprarenal capsules. 2:244–93. inducing their maturation to cytotoxic T-cells (cytotoxic T lymphocytes. which bind to NLRP1 and thereby induce assembly of the NLRP1 inflammasome.117 These genetic and functional studies have begun to provide a hypothetical framework for understanding the initial triggering. 357–365. Verh Dtsch Ges Pathol 1926. 47: 125–140. Pyeritz R. Traite de la couleur de la peau humaine en ge tamorphose d’une de celle des negres en particulier. Epidemiology of vitiligo and associated autoimmune diseases in © 2013 Japanese Dermatological Association 315 . 3 Addison T. NLRP1 inflammasome assembly activates caspases that cleave the IL-1b precursor to biologically active secreted IL-1b.111 yielding deeper insights into the roles played by these proteins in disease pathogenesis. Lesney PF. J Invest Dermatol 1966. particularly those expressed in melanocytes. 6th edn. physician to Guy’s Hospital. 11 Lerner . While certainly not complete in all details. 32: 285–310. 10 Breathnach AS. This “circuit” of melanocyte triggering. J Invest Dermatol 1959. Approximately 90% of these genes encode immunoregulatory proteins. perhaps facilitating presentation of autoantigens that trigger or provide specificity to the immune response. Bennett DC. approximately 36 loci with convincing or strongly suggestive evidence for a role in vitiligo susceptibility have been identified (Table 1). immune propagation. In: Rimoin D. Principles and Practice of Medical Genetics. these proteins constitute a dense immunoregulatory network that highlights systems and pathways that mediate vitiligo susceptibility. present those autoantigens to the immune system). 2013 (in press). 1855. Langerhans cells take up infectionderived molecules that display “pathogen-associated molecular patterns” (PAMP) and damage-derived molecules that display “damage-associated molecular patterns” (DAMP). et de la me des couleurs en l’autre. which binds to IL-2 receptor expressed on the cell surface. 5 Neufeld M. and thus provide at least some external validation that the candidate gene in question may be relevant to vitiligo pathogenesis. Zur Aetiologie der Psoriasis. 9 Hu F.P. Bor S. whereas approximately 10% encode melanocyte proteins that likely serve as autoantigens that both stimulate the melanocyte-specific immune response and act as targets for immune recognition and cell killing (or in the case of HLA class I and perhaps class II molecules. Fain PR. including the Exanthemata. Fosnaugh RP.101 Moreover. On Diseases of the Skin. CTL) that express T-cell receptor molecules specific to the cognate melanocyte autoantigen.Vitiligo genetics and pathogenesis significant could appropriate multiple-testing corrections be applied across the numerous such reports. Wyllie LM-A. REFERENCES 1 Spritz RA. 8 Kaposi M. ACKNOWLEDGMENTS This study was supported in part by grants R01AR045584.B. Symposium on Autoimmune Aspects of Endocrine Disorders. Thody A. Fenzi GF et al. In: A collection of the published writing of the late Thomas Addison. Tay W. 8: 7 Ko 559–561. DNA sequencing and functional analyses have identified apparent causal variation for TYR.. London 1868. trans and ed. Urban und Schwartzenberg. immune propagation and ultimate cytotoxicity of the anti-melanocyte immune response (Fig. Polyglandular autoimmune diseases. Kaposi M. Electron microscopy of peripheral nerve terminals and marginal melanocytes in vitiligo.

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