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1.  IFN-gamma, IL-21 and IL-10 co-expression in evolving autoimmune vitiligo lesions of Smyth line chickens 
The Smyth line (SL) of chicken is an excellent animal model for human autoimmune vitiligo. In SL vitiligo (SLV) post-natal loss of melanocytes in feathers appears to be due to cell-mediated immunity. In this study, leukocyte-infiltration and associated expression (RNA) of immune function-related cytokines in growing feathers were investigated throughout SLV-development and -progression. Both leukocyte infiltration and cytokine expression levels started to increase near visible SLV onset (early SLV), reached peak levels during active SLV, and decreased to near pre-vitiligo levels after complete loss of melanocytes. Specifically, significant increases were noticed in relative proportions of T cells, B cells, and MHC II-expressing cells during active SLV. Levels of T cell infiltration were higher than those of B cells, with more CD8+ than CD4+ cells throughout SLV. Elevated leukocyte infiltration in early and active SLV was accompanied by increased levels of cytokine expression, especially in interferon-gamma, interleukin (IL)-10 and IL-21. Low expression of IL-4 and IL-17 did not suggest important roles of Th2 and Th17 cells in SLV pathogenesis. Taken together, SLV appears to be a Th1 polarized autoimmune disease, whereby interferon-gamma expression is strongly associated with parallel increases in IL-10 and IL-21, particularly during early and active stages of SLV.
doi:10.1038/jid.2011.377
PMCID: PMC3278581  PMID: 22113479
2.  Genome resequencing and bioinformatic analysis of SNP containing candidate genes in the autoimmune vitiligo Smyth line chicken model 
BMC Genomics  2014;15(1):707.
Background
The Smyth line (SL) chicken is the only animal model for autoimmune vitiligo that spontaneously displays all clinical and biological manifestations of the human disorder. To understand the genetic components underlying the susceptibility to develop SL vitiligo (SLV), whole genome resequencing analysis was performed in SLV chickens compared with non-vitiliginous parental Brown line (BL) chickens, which maintain a very low incidence rate of vitiligo.
Results
Illumina sequencing technology and reference based assembly on Red Jungle Fowl genome sequences were used. Results of genome resequencing of pooled DNA of each 10 BL and SL chickens reached 5.1x and 7.0x coverage, respectively. The total number of SNPs was 4.8 and 5.5 million in BL and SL genome, respectively. Through a series of filtering processes, a total of ~1 million unique SNPs were found in the SL alone. Eventually of the 156 reliable marker SNPs, which can induce non-synonymous-, frameshift-, nonsense-, and no-start mutations in amino acid sequences in proteins, 139 genes were chosen for further analysis. Of these, 14 randomly chosen SNPs were examined for SNP verification by PCR and Sanger sequencing to detect SNP positions in 20 BL and 70 SL chickens. The results of the analysis of the 14 SNPs clearly showed differential frequencies of nucleotide bases in the SNP positions between BL and SL chickens. Bioinformatic analysis showed that the 156 most reliable marker SNPs included genes involved in dermatological diseases/conditions such as ADAMTS13, ASPM, ATP6V0A2, BRCA2, COL12A1, GRM5, LRP2, OBSCN, PLAU, RNF168, STAB2, and XIRP1. Intermolecular gene network analysis revealed that candidate genes identified in SLV play a role in networks centered on protein kinases (MAPK, ERK1/2, PKC, PRKDC), phosphatase (PPP1CA), ubiquitinylation (UBC) and amyloid production (APP).
Conclusions
Various potential genetic markers showing amino acid changes and potential roles in vitiligo development were identified in the SLV chicken through genome resequencing. The genetic markers and bioinformatic interpretations of amino acid mutations found in SLV chickens may provide insight into the genetic component responsible for the onset and the progression of autoimmune vitiligo and serve as valuable markers to develop diagnostic tools to detect vitiligo susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-707) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-707
PMCID: PMC4152579  PMID: 25151476
3.  Transcriptome Analysis Reveals Markers of Aberrantly Activated Innate Immunity in Vitiligo Lesional and Non-Lesional Skin 
PLoS ONE  2012;7(12):e51040.
Background
Vitiligo is characterized by the death of melanocytes in the skin. This is associated with the presence of T cell infiltrates in the lesional borders. However, at present, there is no detailed and systematic characterization on whether additional cellular or molecular changes are present inside vitiligo lesions. Further, it is unknown if the normal appearing non-lesional skin of vitiligo patients is in fact normal. The purpose of this study is to systematically characterize the molecular and cellular characteristics of the lesional and non-lesional skin of vitiligo patients.
Methods and Materials
Paired lesional and non-lesional skin biopsies from twenty-three vitiligo patients and normal skin biopsies from sixteen healthy volunteers were obtained with informed consent. The following aspects were analyzed: (1) transcriptome changes present in vitiligo skin using DNA microarrays and qRT-PCR; (2) abnormal cellular infiltrates in vitiligo skin explant cultures using flow cytometry; and (3) distribution of the abnormal cellular infiltrates in vitiligo skin using immunofluorescence microscopy.
Results
Compared with normal skin, vitiligo lesional skin contained 17 genes (mostly melanocyte-specific genes) whose expression was decreased or absent. In contrast, the relative expression of 13 genes was up-regulated. The up-regulated genes point to aberrant activity of the innate immune system, especially natural killer cells in vitiligo. Strikingly, the markers of heightened innate immune responses were also found to be up-regulated in the non-lesional skin of vitiligo patients.
Conclusions and Clinical Implications
As the first systematic transcriptome characterization of the skin in vitiligo patients, this study revealed previously unknown molecular markers that strongly suggest aberrant innate immune activation in the microenvironment of vitiligo skin. Since these changes involve both lesional and non-lesional skin, our results suggest that therapies targeting the entire skin surface may improve treatment outcomes. Finally, this study revealed novel mediators that may facilitate future development of vitiligo therapies.
doi:10.1371/journal.pone.0051040
PMCID: PMC3519491  PMID: 23251420
4.  Analysis of Oxidative Stress Status, Catalase and Catechol-O-Methyltransferase Polymorphisms in Egyptian Vitiligo Patients 
PLoS ONE  2014;9(6):e99286.
Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population.
doi:10.1371/journal.pone.0099286
PMCID: PMC4051781  PMID: 24915010
5.  Vitiligo inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8 
Vitiligo is characterized by depigmented skin patches due to loss of epidermal melanocytes. Oxidative stress may play a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box binding protein 1 (XBP1), are increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators interleukin-6 (IL6) and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while over-expression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.
doi:10.1038/jid.2012.181
PMCID: PMC3443495  PMID: 22696056
6.  HSP70i Accelerates Depigmentation in a Mouse Model of Autoimmune Vitiligo 
Vitiligo is a T-cell-mediated autoimmune disease of the skin. Progressive depigmentation accelerates in response to stress. Personal trauma, contact with bleaching phenols, overexposure to UV, and mechanical injury can lead to progressive loss of melanocytes. This study was focused on the role of stress protein heat shock protein (HSP)70 for translating stress into an autoimmune disease to melanocytes. Intracellular HSP70 can act as a cytoprotectant, preventing apoptosis in cells under stress. Isoform HSP70i can be secreted by live cells, and in prior in vitro studies, HSP70 has been shown to activate dendritic cells and elicit an immune response to chaperoned proteins and peptides. Here, the role of HSP70 in precipitating and perpetuating vitiligo was assessed in vivo in a mouse model of autoimmune vitiligo. In this model, depigmentation was introduced by gene gun vaccination with eukaryotic expression plasmids encoding melanocyte differentiation antigens. Inclusion of human and mouse-derived inducible HSP70 in the vaccination protocol significantly increased and accelerated depigmentation in this model, accompanied by the induction of prolonged humoral responses to HSP70. Cytotoxicity toward targets loaded with a K(b)-restricted tyrosinase-related protein 2-derived peptide correlated with depigmentation. The data presented strongly support a role for HSP70i in progressive depigmentation in vivo.
doi:10.1038/jid.2008.45
PMCID: PMC3778919  PMID: 18337834
7.  Two Cases of Vitiligo Developed on the Persisting Dermal Melanocytosis: Is There a Difference between Epidermal Melanocytes and Dermal Melanocytes? 
Annals of Dermatology  2013;25(2):226-228.
Vitiligo is one of the most common pigmentary skin disorders; it is characterized by circumscribed depigmented macules due to the destruction of melanocytes. Although the etiology of vitiligo has not been fully elucidated, multiple factors including autoimmune and oxidative stress have been implicated in the pathogenesis of vitiligo. In contrast, dermal melanocytosis is histologically characterized by the presence of dermal melanocytes. It has been described that there are ectopic dermal melanocytes, which have failed to reach their proper location. A literature search revealed very few reports of patients with vitiligo developing vitiligo within dermal melanocytosis. Here, we report two cases of patients with vitiligo that occurred at pre-existing sites of dermal pigmented lesions. The histopathology showed the loss of epidermal melanocytes in spite of the existence of melanocytes in the dermis. There was no significant infiltration of inflammatory cells in the dermis. These cases illustrate unknown environmental factors as well as heterogeneity.
doi:10.5021/ad.2013.25.2.226
PMCID: PMC3662919  PMID: 23717017
Dermal melanocytosis; Vitiligo
8.  Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo 
The New England journal of medicine  2010;362(18):1686-1697.
BACKGROUND
Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.
METHODS
To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.
RESULTS
We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P = 9.05×10−23) and class II molecules (P = 4.50×10−34), PTPN22 (P = 1.31×10−7), LPP (P = 1.01×10−11), IL2RA (P = 2.78×10−9), UBASH3A (P = 1.26×10−9), and C1QTNF6 (P = 2.21×10−16). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P = 7.07×10−15) and GZMB (P = 3.44×10−8), and in a locus containing TYR (P = 1.60×10−18), encoding tyrosinase.
CONCLUSIONS
We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.
doi:10.1056/NEJMoa0908547
PMCID: PMC2891985  PMID: 20410501
9.  CD8+ T cells from vitiligo perilesional margins induce autologous melanocyte apoptosis 
Molecular Medicine Reports  2012;7(1):237-241.
Cell-mediated autoimmunity has been suggested to be involved in the melanocyte apoptosis that occurs in vitiligo. We investigated the cytotoxicity to autologous melanocytes of CD8+ T cells from the perilesional margins and peripheral blood samples of vitiligo patients. CD8+ T cells isolated from skin biopsied from the edges of depigmented skin patches of vitiligo patients or from peripheral blood samples of the same donors were proliferated in culture medium. The primary cultures of CD8+ T cells and autologous melanocytes were mixed at ratios of 1:1, 1:2 or 1:5 and incubated for 3 days. The apoptosis of the melanocytes was analyzed by flow cytometry. Secreted cytokines in selected samples were measured by cytokine arrays. The results show that the CD8+ T cells were successfully isolated from the vitiligo perilesional margins. This cell population showed a significantly higher percentage of CD69 expression (56.13±3.55 versus 29.93±2.35%, p<0.01) and CD137 expression (41.74±1.06 versus 25.97±1.63%, p<0.01) compared with CD8+ T cells in peripheral blood from the same donors. The co-culturing of CD8+ T cells from lesional skin with autologous melanocytes induced apoptosis in the melanocytes (16.63±1.21, 16.71±0.63 and 18.32±1.60% for CD8+ T cells and autologous melanocytes at ratios of 1:1, 1:2 and 1:5, respectively). IL-6 levels were much higher in the co-culture (3.01-fold higher than in a melanocyte monoculture and 17.32-fold higher than in a CD8+ T-cell monoculture). The CD8+ T cells were also demonstrated to secrete more IL-13. Taken together, our data demonstrate that the infiltration of active CD8+ T cells takes place in the vitiligo perilesional margins. Those CD8+ T cells present significantly higher activation levels and higher cytotoxicity to autologous melanocytes than their counterparts from peripheral blood samples. These data suggest that CD8+ T cells are likely to be involved in the pathogenesis of vitiligo.
doi:10.3892/mmr.2012.1117
PMCID: PMC3572717  PMID: 23042234
CD8+ T cells; melanocytes; vitiligo; cytokine
10.  4-Tertiary Butyl Phenol Exposure Sensitizes Human Melanocytes to Dendritic Cell-Mediated Killing: Relevance to Vitiligo 
The trigger initiating an autoimmune response against melanocytes in vitiligo remains unclear. Patients frequently experience stress to the skin prior to depigmentation. 4-tertiary butyl phenol (4-TBP) was used as a model compound to study the effects of stress on melanocytes. Heat shock protein (HSP)70 generated and secreted in response to 4-TBP was quantified. The protective potential of stress proteins generated following 4-TBP exposure was examined. It was studied whether HSP70 favors dendritic cell (DC) effector functions as well. Melanocytes were more sensitive to 4-TBP than fibroblasts, and HSP70 generated in response to 4-TBP exposure was partially released into the medium by immortalized vitiligo melanocyte cell line PIG3V. Stress protein HSP70 in turn induced membrane tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and activation of DC effector functions towards stressed melanocytes. Melanocytes exposed to 4-TBP demonstrated elevated TRAIL death receptor expression. DC effector functions were partially inhibited by blocking antibodies to TRAIL. TRAIL expression and infiltration by CD11c + cells was abundant in perilesional vitiligo skin. Stressed melanocytes may mediate DC activation through release of HSP70, and DC effector functions appear to play a previously unappreciated role in progressive vitiligo.
doi:10.1111/j.0022-202X.2005.23653.x
PMCID: PMC1747533  PMID: 15816839
autoimmune diseases; skin pigmentation; TNF-related apoptosis-inducing ligand; DC, dendritic cell; FACS, fluorescence activated cell sorting; FaSL, Fas ligand; HSP, heat shock protein; IFN, interferon; IL, interleukin; JAM, just another method; 4-TBP, 4-tertiary butyl phenol; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand
11.  Mutant HSP70 Reverses Autoimmune Depigmentation in Vitiligo 
Science translational medicine  2013;5(174):174ra28.
Vitiligo is an autoimmune disease characterized by destruction of melanocytes, leaving 0.5% of the population with progressive depigmentation. Current treatments offer limited efficacy. We report that modified inducible heat shock protein 70 (HSP70i) prevents T cell–mediated depigmentation. HSP70i is the molecular link between stress and the resultant immune response. We previously showed that HSP70i induces an inflammatory dendritic cell (DC) phenotype and is necessary for depigmentation in vitiligo mouse models. Here, we observed a similar DC inflammatory phenotype in vitiligo patients. In a mouse model of depigmentation, DNA vaccination with a melanocyte antigen and the carboxyl terminus of HSP70i was sufficient to drive autoimmunity. Mutational analysis of the HSP70i substrate-binding domain established the peptide QPGVLIQVYEG as invaluable for DC activation, and mutant HSP70i could not induce depigmentation. Moreover, mutant HSP70iQ435A bound human DCs and reduced their activation, as well as induced a shift from inflammatory to tolerogenic DCs in mice. HSP70iQ435A-encoding DNA applied months before spontaneous depigmentation prevented vitiligo in mice expressing a transgenic, melanocyte-reactive T cell receptor. Furthermore, use of HSP70iQ435A therapeutically in a different, rapidly depigmenting model after loss of differentiated melanocytes resulted in 76% recovery of pigmentation. Treatment also prevented relevant T cells from populating mouse skin. In addition, ex vivo treatment of human skin averted the disease-related shift from quiescent to effector T cell phenotype. Thus, HSP70iQ435A DNA delivery may offer potent treatment opportunities for vitiligo.
doi:10.1126/scitranslmed.3005127
PMCID: PMC3912753  PMID: 23447019
12.  Serum concentration of IL-6, IL-2, TNF-α, and IFNγ in Vitiligo patients 
Indian Journal of Dermatology  2012;57(1):12-14.
Background:
Vitiligo is an acquired depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. Although the etiology of vitiligo is unknown, over the last few years, substantial data from clinical research has greatly supported the ‘Autoimmune theory’ and this is supported by the frequent association of vitiligo with disorders that have an autoimmune origin, including Hashimoto's thyroiditis, Graves disease, type 1 insulin-dependent diabetes mellitus, and Addison's disease. As cytokines are important mediators of immunity, there is evidence to suggest that they play a major role in the pathogenesis of autoimmune diseases.
Aim:
Keeping this in view we have assayed sera for cytokine IL-6, IL-2, Tumor necrosis factor (TNF)-α, and IFNγ in 80 cases of vitiligo and compared it with healthy subjects, in order to find out whether they play a role in the pathogenesis of vitiligo or not.
Materials and Methods:
Serum IL-6, IL-2, TNF-α, and IFNγ were done by the indirect enzyme linked immunosorbent assay (ELISA).
Results:
The mean serum IL-6 and IL-2 levels in the patient group were significantly higher when compared with those of the normal controls. The mean serum IFNγ level in patients with vitiligo was significantly lower than that in the control group. There was no significant difference in the serum level of TNF-α between vitiligo and healthy controls.
Conclusion:
An increase in the production of proinflammatory cytokines such as IL-6 and IL-2 in vitiligo patients may play an important role in melanocytic cytotoxicity. Thus, we speculate that the cytokine production of epidermal microenvironment may be involved in vitiligo.
doi:10.4103/0019-5154.92668
PMCID: PMC3312648  PMID: 22470201
Cytokines; IFN-gamma; IL-2; IL-6; TNF-alpha; vitiligo
13.  Therapeutic implications of autoimmune vitiligo T cells 
Autoimmunity reviews  2006;5(7):486-492.
Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can re-direct the immune response towards the tumor.
doi:10.1016/j.autrev.2006.03.012
PMCID: PMC3462656  PMID: 16920575
Melanocytes; T cells; T cell avidity; T cell receptors; Melanosomes; Antigen presentation
14.  Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro 
Wang, Q | Jiang, M | Wu, J | Ma, Y | Li, T | Chen, Q | Zhang, X | Xiang, L
Cell Death & Disease  2014;5(1):e1022-.
The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.
doi:10.1038/cddis.2013.539
PMCID: PMC4040706  PMID: 24457966
stress; RNASET2; melanocyte; apoptosis; TRAF2
15.  Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo 
PLoS ONE  2012;7(12):e52298.
Abstract
Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates the crucial role of TNF-α in autoimmune pathogenesis of vitiligo.
doi:10.1371/journal.pone.0052298
PMCID: PMC3527546  PMID: 23284977
16.  Protein tyrosine phosphatase PTPN22 +1858C/T polymorphism is associated with active vitiligo 
Vitiligo is characterized by a skin depigmentation disorder resulting from an autoimmune response targeting melanocytes. Within the genetic factors involved in the development of the vitiligo immune response, various genes in the major histocompatibility complex (MHC) and non-MHC loci have been considered to be risk factors. The PTPN22 gene encodes for a lymphoid protein tyrosine phosphatase, a regulator of the activation and development of T-cells. The +1858C/T polymorphism has been associated to autoimmune disease susceptibility in different populations and could be implicated in the onset of vitiligo. To assess the possible association between the presence of PTPN22 +1858C/T and vitiligo, 187 patients with vitiligo and 223 control subjects were analyzed in the study. Genomic DNA was isolated using the salting-out method and samples were subjected to polymerase chain reaction-restriction fragment length polymorphism in order to detect the PTPN22 +1858C/T polymorphism. Causal associations were determined by χ2 test and their respective odds ratio (OR) was assessed in a 2×2 contingency table. The results showed an association between active vitiligo and the allele T load [P=0.0418; OR, 2.5706; 95% confidence interval (CI), 1.0040–6.5816], and active vitiligo-CT genotype (P=0.0389, OR, 2.6548; 95% CI, 1.0191–6.9156). In conclusion, the present data indicates a possible association between the PTPN22 +1858C/T genotype and a significant susceptibility of developing an active form of vitiligo.
doi:10.3892/etm.2014.1975
PMCID: PMC4186394  PMID: 25289035
vitiligo; PTPN22 +1858C/T; lymphoid protein tyrosine phosphatase; autoimmune diseases; polymerase chain reaction-restriction fragment length polymorphism; Mexican population; polymorphism
17.  Transfer of efficient anti-melanocyte T cells from vitiligo donors to melanoma patients as a novel immunotherapeutical strategy 
Background
Vitiligo is a relatively common progressive depigmentary condition that is believed to be due to the autoimmune-mediated loss of epidermal melanocytes. High frequencies of self-reactive T lymphocytes directed toward melanocyte differentiation antigens are found in vitiligo patients and might be directly responsible for the pathogenesis of the disease. An interesting aspect of vitiligo is its relation to melanoma: cytotoxic T lymphocytes directed to self antigens shared by normal melanocytes and melanoma cells are found in both conditions, but the resulting immune reactions are completely different. From this standpoint, the selective destruction of pigment cells that occurs in cases of vitiligo is the therapeutic goal sought in melanoma research.
Presentation of the hypothesis
Our working hypothesis is that vitiligo patients might represent a unique source of therapeutic cells to be used in allo-transfer for HLA-matched melanoma patients. The adoptive transfer of ex-vivo generated autologous tumor-specific T cells is a therapy that has met with only limited success, essentially because of inability to isolate therapeutically valuable T cells from the majority of tumor patients. Ideally, model systems where strong and efficient responses against the same (tumor) antigens are achieved would represent a better source of therapeutic cells. We believe it is possible to identify one such model in the melanoma-vitiligo dichotomy: T lymphocytes specific for different melanocyte differentiation antigens are found in vitiligo and represent the effective anti-melanocyte reactivity that is often ineffective in melanoma.
Testing the hypothesis
Melanocyte-specific T cell clones can be isolated from the peripheral blood of vitiligo patients and tested for their capacity to efficiently expand in vitro without loosing their cytotoxic activity and to migrate to the skin. Cytotoxicity against melanoma patients' non-tumor cells can also be tested. In addition, it would be interesting to attempt an in vivo animal model. If the results obtained from these validation steps will be satisfactory, it might be possible to plan the clinical grade preparation of relevant clones for transfer.
Implications of the hypothesis
When translated into a clinical trial, the possibility of in vitro selecting few effective tumor-specific T cell clones for infusion, inherent with this approach, could enhance the therapeutic graft-versus-tumor effect while possibly decreasing the risk of graft-versus-host disease.
doi:10.1186/1740-2557-2-7
PMCID: PMC1215509  PMID: 16135249
18.  Avian models with spontaneous autoimmune diseases 
Advances in immunology  2006;92:71-117.
Autoimmune diseases in human patients only become clinically manifest when the disease process has developed to a stage where functional compensation by the afflicted organ or system is not possible any more. In order to understand the initial etiologic and pathogenic events that are generally not yet accessible in humans, appropriate animal models are required. In this respect, spontaneously developing models - albeit rare – reflect the situation in humans much more closely than experimentally induced models, including knockout and transgenic mice. The present review describes three spontaneous chicken models for human autoimmune diseases, the Obese strain (OS) with a Hashimoto-like autoimmune thyroiditis, the University of California at Davis lines 200 and 206 (UCD-200 and 206) with a scleroderma-like disease and the amelanotic Smyth line with a vitiligo-like syndrome (SLV). Special emphasis is given to the new opportunities to unravel the genetic basis of these diseases in view of the recently completed sequencing of the chicken genome.
doi:10.1016/S0065-2776(06)92002-1
PMCID: PMC3292797  PMID: 17145302
19.  Innate immune mechanisms in vitiligo: Danger from within 
Current opinion in immunology  2013;25(6):676-682.
Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. While adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.
doi:10.1016/j.coi.2013.10.010
PMCID: PMC3935321  PMID: 24238922
20.  Concise review of recent studies in vitiligo 
Qatar Medical Journal  2013;2013(2):1-19.
Vitiligo is an acquired pigmentry disorder of the skin and mucous membranes which manifests as white macules and patches due to selective loss of melanocytes. Etiological hypotheses of vitiligo include genetic, immunological, neurohormonal, cytotoxic, biochemical, oxidative stress and newer theories of melanocytorrhagy and decreased melanocytes survival. There are several types of vitiligo which are usually diagnosed clinically and by using a Wood's lamp; also vitiligo may be associated with autoimmune diseases, audiological and ophthalmological findings or it can be a part of polyendocrinopathy syndromes. Several interventions are available for the treatment for vitiligo to stop disease progression and/or to attain repigmentation or even depigmentation. In this article, we will present an overall view of current standing of vitiligo research work especially in the etiological factors most notably the genetic components, also, types and associations and various and newer treatment modalities.
doi:10.5339/qmj.2013.10
PMCID: PMC4080492  PMID: 25003059
21.  GENETIC VARIATIONS IN NALP1 MRNA EXPRESSIONS IN HUMAN VITILIGO 
Indian Journal of Dermatology  2011;56(3):266-271.
Introduction:
Vitiligo is an acquired autoimmune disease of unknown etiology showing depigmentation of the skin due to the absence of melanocytes. Familial vitiligo suggests a genetic origin to this disease. Chromosome 17 was recently demonstrated to harbor the gene coding for NALP1.
Patients and Methods:
A total of 18 patients of vitiligo were selected on the basis of clinical history. Group 1 (N=8) showing segmental or localized vitiligo with one or two macules on the body. Group 2 (N=10) with generalized or whole body vitiligo. A control group of 10 healthy individuals were selected from our laboratory persons with no history or any infections or skin disease. NALP1 gene expression was studied using RT-PCR assay and the bands quantitated as intensity using volume as measurement and comparison of results was done using SPSS 16 version for statistical analysis. NALP1 gene expression was observed in vitiligo patients with different intensities.
Results:
Greater reduction in the intensity was seen in Group I, which was inversely proportional to the volume of the band. The intensity of the NALP1 and the GAPDH gene expression was more in Group 2 patients than that shown by Group 1.
Conclusion:
This study shows expression of NALP1 gene in patients as well as normals. NALP1 is widely expressed at low levels but is expressed at high levels in immune cells, particularly T cells and Langerhans cells, in which different patterns are seen that are consistent with the particular involvement of NALP1 in skin autoimmunity.
doi:10.4103/0019-5154.82478
PMCID: PMC3132901  PMID: 21772585
Gene expression; NALP1 gene and RT-PCR; vitiligo
22.  Frontiers and controversies in the pathobiology of vitiligo: separating the wheat from the chaff 
Experimental dermatology  2009;18(7):583-585.
The pathogenesis of vitiligo is complex and not well understood. Genes play a role in all aspects of vitiligo pathogenesis, and studies are ongoing to identify these genes and understand their biology. There is a body of interlocking, compelling evidence supporting an autoimmune basis for most or all cases of generalized vitiligo. The development of an autoimmune disease generally involves three components; the immune system, environmental triggers and other exogenous precipitating factors, and the target tissue. In vitiligo, precipitating factors could induce melanocyte damage in genetically susceptible individuals and consequent cell death, loss of tolerance, and induction of melanocyte-directed autoimmunity. Future research will more precisely define the multiple biological events that regulate development of vitiligo.
doi:10.1111/j.1600-0625.2008.00826.x
PMCID: PMC2745236  PMID: 19320739
autoimmunity; leukoderma; melanocytes; pigmentation
23.  Analysis of Inducible Nitric Oxide Synthase Gene Polymorphisms in Vitiligo in Han Chinese People 
PLoS ONE  2011;6(12):e27077.
Background
Vitiligo is a chronic depigmented skin disorder with regional melanocytes depletion. The pathogenesis was not completely clarified. Recently, more and more evidence suggested that polymorphisms of some genes are associated with vitiligo risk. Here, we want to examine the association between the inducible nitric oxide synthase (iNOS) gene polymorphisms and the risk of vitiligo in Chinese populations.
Methods and Principal Findings
In a hospital-based case-control study of 749 patients with vitiligo and 763 age- and sex-matched healthy controls, three polymorphisms of iNOS gene were genotyped by using the PCR-restriction fragment length polymorphism (PCR-RFLP) and mutagenically separated PCR (MS-PCR) methods, respectively. We found the iNOS-954 polymorphism was associated with a significantly higher risk of vitiligo (adjusted OR = 1.36, 95% CI = 1.02–1.81). Furthermore, this association is more pronounced in vulgaris vitiligo, active vitiligo and vitiligo without other autoimmune diseases in the stratification study. Analysis of haplotypes showed increased risk for the C-1173C-954CEx16+14 (OR = 1.44, 95% CI = 1.01–1.74). In addition, the serum iNOS activity is significantly associated with iNOS-954 combined genotype (GC+CC) and is much higher in vitiligo patients than in the controls (P<0.01). Logistic regression analysis of iNOS activity showed increased risk between higher activity and iNOS-954 G→C variant genotype carriers (Ptrend<0.001).
Conclusions and Significance
INOS gene polymorphisms may play an important role in the genetic susceptibility to the development of vitiligo.
doi:10.1371/journal.pone.0027077
PMCID: PMC3244382  PMID: 22205923
24.  Promoter polymorphism -119C/G in MYG1 (C12orf10) gene is related to vitiligo susceptibility and Arg4Gln affects mitochondrial entrance of Myg1 
BMC Medical Genetics  2010;11:56.
Background
MYG1 (Melanocyte proliferating gene 1, also C12orf10 in human) is a ubiquitous nucleo-mitochondrial protein, involved in early developmental processes and in adult stress/illness conditions. We recently showed that MYG1 mRNA expression is elevated in the skin of vitiligo patients. Our aim was to examine nine known polymorphisms in the MYG1 gene, to investigate their functionality, and to study their association with vitiligo susceptibility.
Methods
Nine single nucleotide polymorphisms (SNPs) in the MYG1 locus were investigated by SNPlex assay and/or sequencing in vitiligo patients (n = 124) and controls (n = 325). MYG1 expression in skin biopsies was detected by quantitative-real time PCR (Q-RT-PCR) and polymorphisms were further analysed using luciferase and YFP reporters in the cell culture.
Results
Control subjects with -119G promoter allele (rs1465073) exhibited significantly higher MYG1 mRNA levels than controls with -119C allele (P = 0.01). Higher activity of -119G promoter was confirmed by luciferase assay. Single marker association analysis showed that the -119G allele was more frequent in vitiligo patients (47.1%) compared to controls (39.3%, P < 0.05, OR 1.37, 95%CI 1.02-1.85). Analysis based on the stage of progression of the vitiligo revealed that the increased frequency of -119G allele occurred prevalently in the group of patients with active vitiligo (n = 86) compared to the control group (48.2% versus 39.3%, P < 0.05; OR 1.44, 95%CI 1.02-2.03). Additionally, we showed that glutamine in the fourth position (in Arg4Gln polymorphism) completely eliminated mitochondrial entrance of YFP-tagged Myg1 protein in cell culture. The analysis of available EST, cDNA and genomic DNA sequences revealed that Myg1 4Gln allele is remarkably present in human populations but is never detected in homozygous state according to the HapMap database.
Conclusions
Our study demonstrated that both MYG1 promoter polymorphism -119C/G and Arg4Gln polymorphism in the mitochondrial signal of Myg1 have a functional impact on the regulation of the MYG1 gene and promoter polymorphism (-119C/G) is related with suspectibility for actively progressing vitiligo.
doi:10.1186/1471-2350-11-56
PMCID: PMC2856544  PMID: 20377893
25.  SIRT1 regulates MAPK pathways in vitiligo skin: insight into the molecular pathways of cell survival 
Vitiligo is an acquired and progressive hypomelanotic disease that manifests as circumscribed depigmented patches on the skin. The aetiology of vitiligo remains unclear, but recent experimental data underline the interactions between melanocytes and other typical skin cells, particularly keratinocytes. Our previous results indicate that keratinocytes from perilesional skin show the features of damaged cells. Sirtuins (silent mating type information regulation 2 homolog) 1, well-known modulators of lifespan in many species, have a role in gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection and healthy ageing. In the literature there is no evidence for SIRT1 signalling in vitiligo and its possible involvement in disease progression. Here, biopsies were taken from the perilesional skin of 16 patients suffering from non-segmental vitiligo and SIRT1 signalling was investigated in these cells. For the first time, a new SIRT1/Akt, also known as Protein Kinase B (PKB)/mitogen-activated protein kinase (MAPK) signalling has been revealed in vitiligo. SIRT1 regulates MAPK pathway via Akt-apoptosis signal-regulating kinase-1 and down-regulates pro-apoptotic molecules, leading to decreased oxidative stress and apoptotic cell death in perilesional vitiligo keratinocytes. We therefore propose SIRT1 activation as a novel way of protecting perilesional vitiligo keratinocytes from damage.
doi:10.1111/jcmm.12206
PMCID: PMC3955157  PMID: 24410795
SIRT1; Akt; MAPK; vitiligo; oxidative stress

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