Vitiligo immunopathogenesis: Insight of immune components and prospects of emerging immunotherapies.

It has been suggested that NLRP1 is involved in susceptibility to a wide range of autoimmune diseases including generalized vitiligo (GV). Genetic polymorphisms in the gene encoding NLRP1 (previously known as NALP1) have previously been shown to be associated with GV and there is speculation about their involvement in the regulation of NLRP1 expression. To explore NLRP1 polymorphisms and investigate their association with NLRP1 mRNA expression and disease activity in patients with GV. Polymerase chain reaction (PCR)-restriction fragment length polymorphism and TaqMan single nucleotide polymorphism (SNP) genotyping techniques were used to genotype NLRP1 A/G (rs2670660), T/C (rs6502867) and A/T (rs12150220) polymorphisms in 537 patients with GV and 645 controls in Gujarat. NLRP1 mRNA levels were measured in the whole blood of 122 patients with GV and 175 controls using real-time PCR. The NLRP1 rs2670660 and rs6502867 polymorphisms were found to be in significant association with GV, minor alleles of these SNPs being prevalent in active cases of GV. The rs12150220 polymorphism was found have a marginal association with GV. The frequency of susceptible haplotype 'GCT' was significantly higher in patients with GV and increased the risk of vitiligo twofold. A significant increase in NLRP1 mRNA expression was observed in patients with GV and patients with active GV. NLRP1 mRNA expression was increased in patients with GV with the susceptible GG (rs2670660) and CC (rs6502867) genotypes. Patients with the susceptible GG (rs2670660) and CC (rs6502867) genotypes had early age of onset of GV. Moreover, patients in the age at onset group of 1-20years showed increased expression of NLRP1 mRNA compared with the older age groups. Female patients showed a significant increase in NLRP1 mRNA and early age at onset of GV compared with male patients. Our results suggest that NLRP1 rs2670660 and rs6502867 polymorphisms may be genetic risk factors for susceptibility to and progression of GV. The upregulation of NLRP1 mRNA in patients with susceptible genotypes advocates the crucial role of NLRP1 in GV.

Background: Long non-coding RNAs (LncRNAs) represent a subset of genetic material exceeding 200 base pairs that lack protein-coding capacity, yet possess the unique capability to modulate gene expression. This study was conducted with the purpose of identifying the expression levels of LncRNA SIRT-1, LncRNA MCH, as well as the serum levels of IL-17, IL-33, and IFNγ in individuals with vitiligo. Furthermore, the investigation aimed to explore the potential correlation between long non-coding RNA and the parameters of study. Methods: The investigation was carried out on a cohort consisting of 30 patients with Generalized Vitiligo (GV) - both treated and untreated, 30 patients with Segmented Vitiligo (SV) - also both treated and untreated, and 25 Healthy Controls (HC). Using ELISA, the serum levels of IL-17, IL-33, IFNγ, SIRT 1, and PMCH were measured. Additionally, a gene expression analysis of long non-coding RNA (LncRNA) SIRT-1 and LncRNA PMCH was conducted in patients with GV and SV in order to shed light on their potential implications in the pathogenesis of vitiligo. Results: LncRNA SIRT-1 expression was significantly higher in GV compared to SV (p=0.030, Mann-Whitney test), with mean expression levels of 2.851 (SE: 1.052) and 0.507 (SE: 0.134), respectively. In contrast, no significant difference in LncRNA MCH expression was observed between the two vitiligo types. Conclusion: After investigation of the association between lncRNA expression of the SIRT1 and MCH genes and their corresponding serum concentrations in vitiligo patients, this research elucidated the dysregulated manifestations of LncRNA SIRT-1 and LncRNA MCH in individuals diagnosed with vitiligo, indicating their potential contributions to the etiology of vitiligo. This mechanism could involve the down regulation of serum SIRT-1 and MCH, as well as the elevation of cytokines. `

Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of pigmentation. Among various hypotheses proposed for the pathogenesis of vitiligo, oxidative stress-induced immune response that ultimately leads to melanocyte death remains most widely accepted. Oxidative stress which causes elevated levels of reactive oxygen species (ROS) can lead to dysfunction of molecules and organelles, triggering further immune response, and ultimately melanocyte death. In recent years, a variety of cell death modes have been studied, including apoptosis, autophagy and autophagic cell death, ferroptosis, and other novel modes of death, which will be discussed in this review in detail. Oxidative stress is also strongly linked to these modes of death. Under oxidative stress, ROS could induce autophagy by activating the Nrf2 antioxidant pathway of melanocytes. However, persistent stimulation of ROS might eventually lead to excessive activation of Nrf2 antioxidant pathway, which in turn will inactivate autophagy. Moreover, ferroptosis may be triggered by oxidative-related transcriptional production, including ARE, the positive feedback loop related to p62, and the reduced activity and expression of GPX4. Therefore, it is reasonable to infer that these modes of death are involved in the oxidative stress response, and that oxidative stress also acts as an initiator for various modes of death through some complex mechanisms. In this study, we aim to summarize the role of oxidative stress in vitiligo and discuss the corresponding mechanisms of interaction between various modes of cell death and oxidative stress. These findings may provide new ideas for exploring the pathogenesis and potential therapeutic targets of vitiligo.

Vitiligo is a polygenic autoimmune disorder characterized by loss of pigmentation due to melanocyte destruction. Hydroxychloroquine (HCQ) is an effective immunosuppressant widely used in the treatment of autoimmune disorders. As generalized vitiligo (GV) is commonly considered to be a Tcell and autoantibody-induced immune disorder, the present study aimed to determine whether HCQ protects melanocytes from autoantibody‑induced disruption. Anti‑melanocyte antibodies were obtained from the serum of patients with progressive GV and the effects of HCQ on prevent the autoantibody‑induced disruption of melanocytes was observed. Cell‑based ELISA, indirect immunofluorescence and western blotting were used to analyze the autoantibody content of sera samples obtained from 32patients with progressive GV. The cytotoxicity of HCQ was detected by MTT assay, and 1µg/ml HCQ was applied to human primary melanocytes (HMCs) to examine whether it could exert protective effects against autoantibody‑induced immune injury. Flow cytometry was used to measure autoantibody binding to the surface of HMCs. Complement‑dependent cytotoxicity (CDC) and antibody‑dependent cell‑mediated cytotoxicity (ADCC) were monitored by MTT and lactate dehydrogenase‑releasing assays. The concentration of autoantibodies in sera samples taken from GV patients was significantly higher than in controls, particularly in patients who had >10% of their body surface affected by vitiligo. The majority of the autoantibodies presented in the HMCs and human keratinocytes (HKCs) and were predominantly localized to the cell surface and cytoplasm. The molecular weights of the autoantigens were identified as 30, 37‑39, 42, 53, 60‑75, 90, 100, 110, and 126kDa; the 30kDa protein was observed only in HMCs. The addition of HCQ at a concentration of 1µg/ml produced no significant cytotoxicity in HMCs and was demonstrated to reduce the binding of GV immunoglobulinG (IgG) to the surface of HMCs. HCQ also significantly decreased the effects of ADCC and CDC that were mediated by GV IgG. The present study provides evidence that HCQ dissociates autoantibody-antigen complexes on the surface of HMCs and reverses ADCC and CDC activity invitro. Thus, in addition to its effectiveness as an antimalarial therapeutic agent, HCQ may also be a promising potential treatment for patients with vitiligo.

Vitiligo – Study In view of familial occurence

Mechanisms of pyroptosis in vitiligo.

Vitiligo-Inducing Phenols Activate the Unfolded Protein Response in Melanocytes Resulting in Upregulation of IL6 and IL8

Background: Poly (ADP-ribose) polymerase-1 (PARP-1) is a co-activator of nuclear factor-κB (NF-κB) and is also strongly activated by DNA damage. PARP has also been found to be associated with several autoimmune disorders. Vitiligo is a polygenic, multifactorial, acquired skin disorder caused due to loss of epidermal melanocytes. Among others, genetic and immunological factors are associated with vitiligo pathogenesis. Aim: To investigate the association of PARP1 exon 17 (rs1136410; V762A) and promoter CA microsatellite repeat (rs1136410) polymorphisms, and NF-κB promoter -94 indelATTG (rs28362491) polymorphism with vitiligo pathogenesis in Gujarat population. Methods: Genotyping of PARP1 17T/C (rs5030870) polymorphism was done by PCR-RFLP.PARP1 CA microsatellite and NF-κB-94 indel (rs28362491) polymorphisms were genotyped by Real-Time PCR. Anti-PARP antibody levels were assessed by ELISA. Results: The results suggested no significant difference in allele and genotype frequencies of PARP1 17 T/C (p=0.5094 and p=0.4201, respectively), PARP1 CA microsatellite polymorphisms (p=0.9519 and p=0.9338, respectively) and NF-κB-94 ATTG indel polymorphism (p=0.1482 and p=0.3784, respectively) in patients as compared to controls. Conclusion: This study suggests no association of PARP1 17 T/C, PARP1 CA microsatellite and NF-κB-94 ATTG indel polymorphisms with vitiligo susceptibility in Gujarat population. Additionally, anti-PARP1 antibody levels were not significantly different among patients and controls. These findings suggest the need for additional studies to explore the role of PARP1 in vitiligo pathogenesis. Keywords: Vitiligo, poly (ADP-ribose) polymerase-1(PARP-1), nuclear factor-κB (NF-κB), polymorphisms, Autoimmunity

Vitiligo is an autoimmune disorder characterized by pigment loss, and current treatment options remain inadequate. This study aims to identify oxidative stress-related biomarkers and hub genes associated with vitiligo diagnosis through genomic analysis and to examine the role of immune cell infiltration in the pathogenesis of vitiligo. The mRNA expression profile dataset GSE75819 was retrieved from the GEO database. Differential expression of oxidative stress-related genes in vitiligo was analyzed using R software. Protein-protein interaction (PPI) analysis, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted on the differentially expressed genes (DEGs). Immune cell infiltration between vitiligo and normal control groups was assessed using the CIBERSORT algorithm. Additionally, two machine learning algorithms were employed to identify hub genes, perform enrichment analyses, and evaluate their correlation with immune infiltration. A total of 415 Oxidative Stress-DEGs were identified in vitiligo, including 317 up-regulated and 98 down-regulated genes. PPI analysis highlighted the significance of certain ribosomal protein genes. KEGG enrichment analysis suggested an association between vitiligo and various neurodegenerative conditions, particularly through pathways such as oxidative phosphorylation and ribosome biogenesis. GO enrichment analysis indicated that the hub genes were significantly enriched in mitochondrial-related activities. Significant differences in immune infiltration patterns were observed between vitiligo patients and normal controls. Machine learning algorithms identified oxidative stress-related key genes associated with vitiligo, notably the DCT gene, whose expression was strongly linked to the activity of specific immune cell subsets and melanin biosynthetic pathways. Oxidative stress-related DEGs, ribosomal proteins, immune infiltration, and hub genes related to melanin biosynthesis, particularly DCT, are closely associated with the pathogenesis of vitiligo. These findings enhance our understanding of vitiligo and may aid in identifying therapeutic targets for the disease.

Vitiligo is an acquired pigmentary disorder characterized by the development of depigmented lesions in a variable distribution, owing to the loss or destruction of functioning melanocytes (Guerra et al., 2010). Complex interactions between genetic, immunological, biochemical, and environmental factors are likely to be related to the development of vitiligo (Malhotra and Dytoc, 2013). Despite having identified multiple risk factors of vitiligo, the molecular mechanisms of its pathogenesis remain obscure.

Genetic susceptibility to vitiligo: Recent progress from genome-wide association studies

Background:Vitiligo is an acquired depigmenting skin disorder with multifactorial pathogenesis including genetic, autoimmune, and neuronal factors. Both humoral- and cell-mediated immunities are supposed to have a role in the pathogenesis of vitiligo. Patients with vitiligo have an increased concentration of circulating autoantibodies that are specific to melanocyte cytoplasm and surface antigens that related to the extent of the disease.Aims and Objectives:The aim of the present study was to evaluate the role of antimelanocyte antibodies (AMAs), complement 3 and 4 (C3 and C4), and antinuclear antibodies (ANAs) in the pathogenesis of vitiligo.Materials and Methods:This study included 49 patients with nonsegmental vitiligo and 36 healthy individuals as a control group. All participants were subjected to detailed history, general examination, and detailed dermatological examination of the skin, hair, nails, and oral mucosa. The severity of vitiligo was assessed according to the Vitiligo Area Scoring Index (VASI). AMA, C3 and C4, and ANA serum levels were measured for patients and controls.Results:ANA, AMA, and C4 levels were significantly higher in the sera of patients than in controls. ANA, AMA, and C4 serum levels showed significant positive correlations with VASI score.Conclusion:Our results support the role of AMA in the pathogenesis of nonsegmental vitiligo, correlating with the disease extent and severity. However, a longitudinal study in a large cohort of patients to evaluate the clinical and predictive value of AMA is warranted.

Background: Vitiligo is a chronic skin disorder characterized by the loss of pigment, resulting in white patches on the skin. This condition occurs due to the destruction or dysfunction of melanocytes, the cells responsible for producing melanin, pigment that gives skin its color. Purpose: To assess and compare the serum levels of interleukin-2 and vitamin D3 between patients with vitiligo and healthy individuals, in order to investigate their potential role in the pathogenesis of vitiligo. Method: Case-control study was conducted on 120 subjects, divided into two groups: the patient group included 60 individuals diagnosed with vitiligo, and the control group consisted of 60 healthy volunteers. Blood samples were collected from all participants after obtaining verbal consent. Serum level of interlukin-2 and vitamin D3 was measured using ELISA (Bet Lab/China). Results: In this study) I found that the mean level of interleukin-2 was significantly higher in vitiligo patient (0.66044±0.039136) compared to healthy controls (0.96919±0.125146) with a statistically significant difference (P- value =0.020) However the two clinical types of vitiligo the clinical types of vitiligo (localized and generalized), no statistically significant difference was observed. The mean level in localized vitiligo was (0.56941±0.032243) and in generalized vitiligo was (0.72113± 0.059873) (P-value =0.057), also This study, according linear scatter plot showed no statistically significant relationship between the duration of vitiligo and the level of IL-2. Vitamin D3 levels no statistically significantly between patients of vitiligo compared to controls, the mean levels (0.85717±0.041315) for patients with vitiligo, while the control (1.01195±0.115793), was (p-value= 0.211). Statistically significant difference was found between localized (075233±0.042477) and generalized (0.92706±0.060467) types of vitiligo (p-value =0.037). Conclusion: The study showed a significant increase in interleukin–2 levels among patients with vitiligo compared to healthy individuals, suggesting a possible role of this cytokine in the immunopathogenesis of the disease. However, IL-2 levels did not significantly differ between localized and generalized types of vitiligo, which may indicate that IL-2 is more related to disease onset rather than its clinical distribution.

Melanocytes are specialized neural crest-derived cells that are responsible for skin pigmentation. In vitiligo, loss of functioning epidermal melanocytes results in loss of pigment. Based on published studies, many transcription factors including microphtalmia-associated transcription factor, SRY (Sex Determining Region Y)-Box 10 are responsible for differentiation of melanocytes from neural crest cells as well as development of melanoblasts). However, the pathogenesis of loss of pigmentation in skin still unclear. We studied the expression of several melanocyte-related proteins and markers in vitiligo samples and comparing them to normally pigmented skin samples. This may provide a more insight into the pathogenesis of vitiligo which is a still controversy. We assessed the expression of six antibodies including S100, Melan-A (to detect fully formed, functioning melanocytes), CD117 (a specific relevant tyrosinase inducer), MITF and SOX-10 (important related transcription factors), and BCL-2 (stem cell markers) in 32 skin samples. We demonstrated significant decline in the expression of all examined immunomarkers in the skin of vitiligo when compared to normal pigmented skin. Our data may speculate that vitiligo pathogenesis does not involve only destruction of functioning active melanocytes, but also, other steps of cellular stimulation of induction of melanocytes and melanogensis are significantly affected as well.

Vitiligo is a multifactorial disorder related to both genetic and non-genetic factors. The pathogenesis of vitiligo is associated with the melanocytes destruction that may result from immune and inflammatory mediators. The autoimmune theory is the most important theory about the pathogenesis of vitiligo. The aims of the study are the evaluation and assessment of serum levels of IL17 in vitiligo patients to reveal their possible role in pathogenesis of vitiligo and to correlate their levels with the severity of the disease. Patients and Methods: In this study, thirty patients (15 male and 15 females) were included in the present study and 30 apparently healthy, age and sex matched individuals were included as a control group. Patients were recruited from the outpatient clinic of Benha University Hospitals from Dermatology, Venereology and Andrology Department. All patients were subjected to full history, full dermatological and general examination. Measurement of serum levels of IL-17 using the commercially available ELISA kit. Results: The present study revealed significant increase in serum levels of IL-17 in patients than controls. Conclusion: Vitiligo is associated with increased serum level in IL-17 indicating that IL-17 may play a significant role in the pathogenesis of vitiligo.