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Previous observational studies have suggested that gut microbiota might be associated with vitiligo. However, owing to the limitations in observational studies of reverse causality and confounders, it remains unclear that whether and how the causal relationships exist. The results suggested that pylum.Bacteroidetes, family.BacteroidalesS24.7, genus.LachnospiraceaeND3007, genus.Marvinbryantia are protective factors for vitiligo. Conversely, family.Lachnospiraceae, order.Burkholderiales, genus.Adlercreutzia, genus.Catenibacterium and genus.Lachnospira are risk factors for vitiligo. In addition, the causative connection between dietary factors and the gut microbiota associated with vitiligo was also investigated. The results revealed that 'alcohol intake versus 10 years pervious' results in a reduction in the abundance of genus.Lachnospiraceae ND3007 and family.BacteroidalesS24.7, bread intake leads to a reduction of genus.Marvinbryantia, 'average weekly red wine intake' is linked to a decrease in the abundance of order.Burkholderiales, tea intake is associated with an augmentation in the abundance of genus.Catenibacterium, salad/raw vegetable intake elevates the abundance of order.Burkholderiales. In summary, this Mendelian randomization study substantiates potential causal effects of gut microbiota on vitiligo. Modulating the gut microbiota through regulating dietary composition may be a novel strategy for preventing vitiligo., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although a large number of existing studies have confirmed that people with vitiligo are prone to mental disorders, these observational studies may be subject to confounding factors and reverse causality, so the true causal relationship is inconclusive. We conducted a bidirectional Mendelian randomization (MR) analysis to assess the causality between vitiligo and mental disorders, namely depression, anxiety, insomnia, schizophrenia, bipolar disorder, obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD). Summary statistics from large available genome-wide association study (GWAS) datasets for generalized vitiligo (n = 44 266), depression (n = 173 005), anxiety (n = 17 310), insomnia (n = 386 988), schizophrenia (n = 130 644), bipolar disorder (n = 413 466), OCD (n = 9725) and ADHD (n = 225 534) were utilized. Inverse-variance weighted (IVW), MR-Egger and weighted median were employed to estimate causal effects. Sensitivity analysis and MR Pleiotropy Residual Sum and Outliers (MR PRESSO) were conducted to assess heterogeneity and pleiotropy, ensuring the robustness of the results. Additionally, we corrected for estimating bias that might be brought on by sample overlap using MRlap. In our findings, none of the rigorous bidirectional MR analyses uncovered a significant causal association. Even after applying the MRlap correction, the effect sizes remained statistically nonsignificant, thereby reinforcing the conclusions drawn via IVW. In summary, our genetic-level investigation did not reveal a causal link between generalized vitiligo and mental disorders., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To conduct a clinical biochemical study that aids in investigation of some non-coding RNA expressions and polymorphisms (including long non-coding RNAs and miRNAs) namely, MALAT-1 and miR-9 in attempt to provide new diagnostic biomarkers in vitiligo patients for Egyptians. Twenty patients having vitiligo and other twenty apparently controls were included in this study. Serum and biopsy were taken where patients were classified into lesional and peri-lesional groups. Laboratory and pathological investigations were assessed. Serum miR-9 and long-non coding MALAT-1 were measured. Vitiligo patients had a mean age of 36.40±13.75. The mean serum miR-9 level in patients group (4.28 ± 1.70) was significantly higher than in the control (1.05 ± 0.12) (p = 0.001). The MALAT-1 level in vitiligo patients was (3.65 ± 1.30) significantly higher than control (1.45 ± 0.15) (p = 0.001). There was a positive association between the expression levels of MALAT-1and miR-9in serum and tissue as well where p-value <0.05. miR-9 as well as long non-coding MALAT-1 may be considered as biomarkers for vitiligo susceptibility which may provide a new direction for treatment., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Expression of microRNAs (miRNAs) is often dysregulated in several cancers, including non-melanoma skin cancer (NMSC). Individuals with vitiligo possess a deregulated miRnome along with a lower risk of developing NMSCs. We used data sets from our previously published studies on vitiligo epidermis to construct functional miRNA-mRNA networks to understand the molecular basis underlying the lower incidence of NMSC observed in individuals with vitiligo. miRTarBase database was used to fetch the experimentally validated targets of differentially expressed miRNAs and two protein-protein interaction (PPI) networks were constructed for the miRNA-mRNA interactions (230 downregulated targets of 5 upregulated miRNAs and 47 upregulated mRNAs targeted by 12 downregulated miRNAs). Pathway enrichment analysis identified RNA biogenesis and transport as well as cell adhesion to be perturbed in vitiligo. Further, oncogenic transcription factors (OTFs) that were upregulated in publicly available squamous cell carcinoma (SCC) or basal cell carcinoma (BCC) microarray data were compared with that of vitiligo to decode skin cancer-specific molecular signatures. We identified three significantly upregulated miRNAs, miR-31-5p, miR-31-3p and miR-194-3p in lesional epidermis that could negatively regulate seven oncogenic transcription factors, FOXC1, AR, SP1, YY1, GLI2, TP53 and RARA, known to be over-expressed in SCC or BCC. Taken together, our study identified a perturbed miRNA-regulated transcriptome, which potentially confers protection to vitiligo skin from an increased incidence of NMSC., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitiligo is a multifactorial skin disease with established role of genetics and autoimmunity in its pathogenesis. Vitamin D receptor (VDR) polymorphisms have been suggested to correlate with risk of vitiligo in some ethnic populations. On the other hand, cathelicidin, one of the innate immune system components, has a role in development of some chronic skin diseases and VDR regulates the expression of cathelicidin. We aimed to determine the plasma level of cathelicidin and its association with the VDR gene polymorphisms as well as plasma vitamin D level in patients with vitiligo. Ninety vitiligo patients and 90 non-vitiligo controls participated in this study. Blood levels of 25(OH) vitamin D and cathelicidin were determined with ELISA. Genotyping for VDR polymorphisms (ApaI, TaqI, FokI and BsmI) was done with RFLP-PCR method. Mean blood level of cathelicidin was significantly higher in vitiligo patients as compared to controls (P < .0001). Mean blood level of vitamin D was significantly lower in patients than controls (P = .01). Statistically significant differences were not observed for both genotype and allele frequencies of BsmI, ApaI and TaqI polymorphisms. There was a borderline increased risk of vitiligo in over-dominant model of FokI polymorphism with OR = 1.8 and P = .051. Our findings was suggestive of the potential role of cathelicidin in the pathogenesis of vitiligo; however, future evaluations are needed to determine its precise mechanism. Genetic study of VDR gene polymorphism was suggestive of increased risk of vitiligo in association with a FokI polymorphism in Iranian population., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aetiology of vitiligo has not been fully elucidated, and several hypotheses have been investigated; among them, the most explored assumes an autoimmune basis for the disease. Supporting this hypothesis is the frequent co-occurrence of autoimmune diseases with vitiligo. In addition, various genetic loci associated with vitiligo harbour key immune response genes. Our general hypothesis is that autoimmunity-associated genes participate in the control of vitiligo susceptibility. To investigate this hypothesis, we tested for association between vitiligo and genes CYP27B1, REL, TNFAIP3 and IL2/IL21, all previously related to autoimmune diseases associated with vitiligo. The study was performed using two independent population samples: a family-based discovery set (211 trios) and a replication set (131 cases/119 controls). Statistically significant association with vitiligo was detected between markers of the REL and IL2 gene in the family-based sample. Both association signals were concentrated among patients displaying autoimmune comorbidity and non-segmental vitiligo. Evidence for validation was detected for IL2 marker. Our findings suggest REL and IL2 as new vitiligo susceptibility genes and reinforce the hypothesis of a shared genetic mechanism controlling vitiligo and other autoimmune diseases., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitiligo is an acquired skin depigmentation disorder resulting from the selective loss of epidermal melanocytes, and previous studies have suggested that a T lymphocyte-mediated mechanism has a role in melanocyte loss. Although Fas-Fas ligand (FasL) interactions are important for T lymphocytes to mediate cytotoxicity, there are only few reports examining the involvement of the Fas-FasL pathway in vitiligo using in vivo mouse models. In addition, there have been no reports concerning Fas-mediated apoptosis in human melanocytes in vitro. In this study, we found that the Fas-mediated pathway is involved in cytotoxic T lymphocyte (CTL)-dependent vitiligo in a mouse model and FasL-induced apoptosis of human melanocytes. Tumor necrosis factor (TNF)-α and interferon (IFN)-γ, the expression levels of which have been reported to be elevated in lesional skin of patients with vitiligo, synergistically upregulated Fas expression on human melanocytes but inhibited the Fas-mediated apoptosis. Treatment with TNF-α and IFN-γ synergistically upregulated the expression of the anti-apoptotic genes, c-IAP2, c-FLIP and MCL1. A siRNA knock-down study showed that c-FLIP and MCL1, but not c-IAP2, were involved in inducing synergistic inhibitory effects on Fas-mediated apoptosis. Furthermore, we found that FasL and TNF-related apoptosis-inducing ligand (TRAIL) synergistically induced apoptosis on human melanocytes. In conclusion, our results suggest that the Fas-FasL pathway is involved in CTL-dependent vitiligo and the elevated expression levels of TNF-α and IFN-γ in lesional skin may act synergistically on melanocytes to suppress Fas-mediated apoptosis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane receptor primarily expressed on melanocytes and melanoma cells. Single nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause red hair, fair skin and are associated with melanoma and keratinocyte-derived skin cancer development. Activation of wild-type (WT) MC1R in skin assists cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral humans migrated out of Africa, the evolutionary advantage of MC1R variants may have related to improved cutaneous vitamin D synthesis and higher birthweight reported with certain MC1R variants. Reduced photoprotection secondary to MC1R dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA repair, effects on cell proliferation and possibly immunological parameters), leading to clonal expansion of mutated cells within skin and subsequent carcinogenesis. Recent investigations suggest an association between MC1R genotype and vitiligo, with preliminary evidence that a MC1R agonist, [Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future development of compounds to correct defective MC1R responses secondary to MC1R variants could result in photoprotective benefits for fair-skinned individuals and reduce their skin cancer risk., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Understanding the cellular and molecular mechanisms leading to melanocyte loss in vitiligo is a mandatory step in improving the overall management of vitiligo patients. Until now, the study of vitiligo was characterised by a fragmented approach, and it is very hard to share and compare the data obtained by the different teams. The scenario mirrors the pathogenic puzzle, but it delays a true productive focus on the disease. The in vitro research is based on different models, ranging from monolayer cell culture of epidermal and dermal cells or 3D reconstructed skin to histological data, gene expression, computer simulation profile. For each model, several different (biochemical, phenotypic, immunological) aspects have been considered, increasing the mass of data difficult to be merged. Our purpose was to provide a practical synopsis of consolidated and advanced possibilities in the study of vitiligo, showing how data have been poorly shared until now. Following a short overview of the background of the disease, the approaches, ranging from basic cell biology to molecular and 'omics' studies, are summarised. New fluorescent probes and techniques open new possibilities for functional studies. Next, intracellular and superficial markers of the melanocytes, the main involved cells, are listed. Moving the focus from the epidermal level to the systemic and subcellular ones, this review aims to propose innovative multidisciplinary options for the vitiligo understanding. This paper focuses on the major practical and theoretical questions to be solved. It may be the basis for a more coordinated and productive approach to the biological question., (© 2012 John Wiley & Sons A/S.)

Thymic stromal lymphopoietin (TSLP) induces naïve CD4+ T cells to produce Th2 cytokines. In addition, to low production of Th2 cytokines, strong Th1 response, which plays an important role in vitiligo development, has been induced by blockade of TSLP or TSLP receptor. This study examined whether a functional TSLP polymorphism was associated with vitiligo. One hundred and sixty Korean patients with vitiligo and 568 healthy Korean individuals were examined for the four SNPs of TSLP gene. Luciferase activity was measured for promoter assay. The genotype and allele frequencies of -847C>T polymorphism were lower in vitiligo patients compared with the controls, whereas those of wild type were higher (P = 0.004, P = 0.017 respectively). None the less, the promoter activity of -847C decreased significantly (P = 0.013) compared with -847T, expecting lower TSLP mRNA levels in the polymorphism. Collectively, C allele at the TSLP -847C>T polymorphism may increase susceptibility to generalized vitiligo through decreasing TSLP mRNA expression levels.

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.

Patients with vitiligo have low levels/activities of catalase in their lesional and non-lesional epidermis as well as in their epidermal melanocytes under in vitro conditions while the levels of catalase mRNA are unaltered. This defect leads to a build-up of hydrogen peroxide (H(2)O(2)) in the 10(-3) m range in the epidermis of these patients. In this context, it was realized that 10(-3) m H(2)O(2) deactivates catalase. Along this line, it was also suspected that catalase in patients with vitiligo possesses a special sensitivity to this reactive oxygen species (ROS), and indeed several heterozygous single nucleotide polymorphisms (SNPs) have been documented in the cat gene of these patients. Based on the 3D structure of human catalase monomer, we have modelled the influence of three selected SNPs on the enzyme active site, on the NADPH- as well as the tetramerization-binding domains. Our results show that these SNPs severely alter catalase structurally, which in turn should make the enzyme more susceptible to ROS compared with wild-type enzyme. Taken together, the work presented herein together with the earlier results on SNPs in the cat gene suggests a genetic predisposition for an altered catalase in patients with vitiligo.

The pathobiology of vitiligo has been hotly disputed for as long as one remembers, and has been a magnet for endless speculation. Evidently, the different schools of thought--ranging, e.g. from the concept that vitiligo essentially is a free-radical disorder to that of vitiligo being a primary autoimmune disease--imply very different consequences for the best therapeutic strategies that one should adopt. As a more effective therapy for this common, often disfiguring pigmentary disorder is direly needed, we must strive harder to settle the pathogenesis debate definitively--on the basis of sound experimental evidence, rather than by a war of dogmatic theories. Recognizing, however, that it is theories which tend to guide our experimental designs and choice of study parameters, the various pathogenesis theories on the market deserve to be critically, yet unemotionally re-evaluated. This Controversies feature invites you to do so, and to ask yourself: is there something important or worthwhile exploring in other pathogenesis scenarios than those already favoured by you that may help you improve your own study design, next time you have a fresh look at vitiligo? Vitiligo provides a superb model for the study of many fundamental problems in skin biology and pathology. Therefore, even if it later turns out that, as far as your own vitiligo pathogenesis concept is concerned, you have barked-up the wrong tree most of the time, chances are that you shall anyway have generated priceless new insights into skin function along the way.

Background: Vitiligo is a skin disorder affected by genetic, environmental, local and endocrine factors. Endothelin-1, which is expressed by keratinocytes, has paracrine effects on melanocytes, influencing their homeostasis, proliferation and pigmentation. It is thought to play a role in the skin response to 311-nm, narrow-band ultraviolet irradiation., Objective: To investigate the association of endothelin-1 gene (EDN1) polymorphisms with vitiligo in a Korean population., Methods: To evaluate the expression of endothelin-1 in cultured human keratinocytes after irradiation with narrow-band ultraviolet B (NBUVB), we performed RT-PCR and ELISA. In addition, we genotyped 312 vitiligo patients and 313 matched-healthy controls, and compared the genotype, allele and haplotype frequencies of EDN1 polymorphisms (intron 4 G/A, rs2071942 and exon 5 G/T, rs5370) between the two groups, using PCR-restriction fragment length polymorphism. The effects of sex, onset age, the presence of autoimmune diseases, family history and clinical type were analysed statistically., Results: NBUVB induced the expression of endothelin-1 in cultured human keratinocytes. The genotype distributions and allele frequencies of EDN1 polymorphisms did not differ significantly between vitiligo patients and healthy controls. Moreover, the results were not related to sex, onset age, the presence of autoimmune diseases or family history. Interestingly, the haplotype frequencies of EDN1 polymorphisms differed significantly between vitiligo patients and healthy controls. When analysed according to clinical type, the haplotype frequencies in the focal and segmental clinical types differed significantly from healthy controls., Conclusion: This study suggests that EDN1 is related to the development of vitiligo in the Korean population.

Vitiligo is an acquired pigmentary disorder characterized by well-circumscribed depigmented patches. Autoimmune, self-destruction, neural, and genetic theories have been proposed for the pathogenesis of vitiligo. Reactive oxygen species play an important role in the physiology of cell damage, and catalase is known to regulate oxidative stress. Reduced catalase enzyme activity and accumulation of excessive hydrogen peroxide were observed in vitiligo. To examine whether catalase gene polymorphisms are associated with vitiligo patients in Korean population, we investigated two CAT gene polymorphisms including (T/C) BstX I (A/T) Hinf I in 118 vitiligo patients and 200 healthy volunteers. The CAT gene genotype distribution and allele frequency were not significantly different between vitiligo patients and healthy controls. But, the haplotype of two polymorphisms was associated with vitiligo. This study suggests possible association between the CAT gene and the vitiligo susceptibility.

Despite the lack of protective melanin and increased oxidative stress due to mM concentrations of epidermal H2O2 in vitiligo, there is no significantly increased risk for chronic actinic damage and non-melanoma skin cancer. Therefore the question arises, which protective mechanisms could be involved in the skin of these patients preventing the initiation of these cancers. Recently an overexpression of p53 has been shown in vitiligo. Unfortunately there was no further characterization of this elevated p53. Employing a functional colour yeast assay, the study presented herein demonstrates for the first time the overexpression of a functioning wild-type p53 protein in both depigmented and 'normal' pigmented epidermis of patients with vitiligo compared with healthy controls. Surprisingly long-term narrowband UVB (311 nm) treatment does not alter this expression. Moreover, MDM-2, PCNA and p21 protein expression remain unchanged compared with healthy controls. This increased epidermal p53 in vitiligo coincides with decreased thioredoxin reductase (TR) protein levels in both depigmented and pigmented skin whereas mRNA expression is unaffected. Because TR is one transcriptional target of p53, these results support a wild-type functionality, which was further supported by the specific p53 FASAY yeast test. To our knowledge this is the first example of persistent elevated functioning wild-type p53 in humans. Based on our results we hypothesize that the low incidence for actinic damage, basal cell and squamous cell carcinoma as documented in vitiligo could well reside in a protective function of up-regulated wild-type p53.

Vitiligo is an acquired melanin pigmentary disorder manifesting itself by expanding depigmented lesions of the skin. To date, the etiopathomechanism of vitiligo has not been convincingly elucidated and a number of seemingly mutually opposed hypotheses with equal likelihood still coexist. Concurrent theories on vitiligo etiology, together with supportive evidence, are reviewed here. Due to the observed variation in clinical manifestations of the disease, it seems likely that the etiology of vitiligo may differ among patients. Therefore several theories on vitiligo etiopathogenesis have been combined to formulate a convergence theory for vitiligo, also presented in this article. This theory states that stress, accumulation of toxic compounds, infection, autoimmunity, mutations, altered cellular environment and impaired melanocyte migration and/or proliferation can all contribute to vitiligo etiopathogenesis in varying proportions.