Vitiligo Autoimmunity Research Articles

LL37-DNA Complex Drives Vitiligo Progression Through TLR9-MyD88 Signaling Pathways.

Vitiligo is an autoimmune disorder characterized by chronic depigmentation and milk-white patches on the skin. Skin infiltration by autoreactive CD8+ T cells causes melanocyte destruction in vitiligo. Multiple risk factors, particularly immune-related inflammatory factors, are involved in the disappearance of melanocytes. LL37 is a classic damage-associated molecular pattern molecule that is involved in the development of various autoimmune diseases. An enhanced expression of LL37 in vitiligo is known; however, the exact role of LL37 in melanocyte loss has not yet been elucidated. In the present study, we detected increased LL37 expression in vitiligo serum and lesions. Furthermore, we confirmed that cultured keratinocytes released LL37 after treatment with H2O2. Moreover, the LL37-DNA complex enhanced the secretion of CXCL9, CXCL10, and CXCL16 from keratinocytes via the TLR9-MyD88 signaling pathway and facilitated the migration of CD8+ T cells. Altogether, our study demonstrates that LL37 released from keratinocytes binds to DNA and contributes to melanocyte destruction under oxidative stress-induced autoimmunity in vitiligo.

Differential expression of serum CXCL9 and CXCL10 levels in vitiligo patients and their correlation with disease severity and stability: A cross-sectional study.

Background Vitiligo is an acquired disorder of pigmentation with an elusive pathogenesis, though various theories have been proposed. The presence of peri-lesional autoreactive CD8+ T cell infiltrate suggests the involvement of abnormal immune responses and autoimmunity in vitiligo. Recent studies have identified the IFN-γ-CXCL9/CXCL-10 axis as a key component of the autoimmune response that perpetuates disease activity in vitiligo. Objectives The primary objective was to estimate serum CXCL9 and CXCL10 levels in vitiligo patients compared to age- and sex-matched controls. Additionally, the study aimed to find correlations between CXCL9 and CXCL10 levels and disease severity and stability. Secondary objectives included comparing levels in segmental/nonsegmental vitiligo and stable/progressive vitiligo and assessing the impact of age and gender. Methods A hospital-based cross-sectional study included 60 vitiligo patients and 30 age- and sex-matched controls. Serum levels of CXCL9 and CXCL10 were assessed using Enzyme-linked immunosorbent assay (ELISA). Cases were clinically evaluated for the type of vitiligo (segmental or non-segmental), disease severity (VASI score), and disease stability (VIDA score). Statistical analysis included t-tests, chi-square tests, and correlation coefficients. P value less than 0.5 was taken as significant. Results Serum CXCL9 and CXCL10, both, were significantly raised in vitiligo patients as compared to controls (p-value = 0.001* & 0.001* respectively) and correlated positively with both VASI score (p-value = 0.001* & 0.001* respectively) and with VIDA score (p-value = 0.032* & 0.001* respectively). Serum CXCL10 showed significant elevation in progressive vitiligo, and CXCL9 exhibited a non-significant trend. No significant difference was observed between segmental and non-segmental vitiligo. Both chemokines positively correlated with disease severity and stability, while age and gender did not significantly impact chemokine levels. Conclusion The expression of chemokines CXCL9 and CXCL10 is markedly increased and correlated positively with disease severity & instability, underscoring their mechanistic role in vitiligo pathogenesis. The values were also higher in the progressive group than in the stable group, inferring their conceivable potential as serum biomarkers. Both serum CXCL9 and CXCL10 were significantly elevated in vitiligo patients compared to controls and they can be used as potential serum biomarkers for assessing the disease activity. Limitations Small sample size of control population. The voluntary sampling technique led to an unequal number of patients in progressive and stable vitiligo groups, as well as in segmental and non-segmental groups. The current study did not include blister fluid analysis and the effect of therapy on the chemokine levels. Conclusion The expression of chemokines CXCL9 and CXCL10 is markedly increased and correlates positively with disease severity and instability, underscoring their mechanistic role in vitiligo pathogenesis. The values were also higher in the progressive group than in the stable group, inferring their conceivable potential as serum biomarkers. *represents statistically significant results.

Membranal Expression of Calreticulin Induced by Unfolded Protein Response in Melanocytes: A Mechanism Underlying Oxidative Stress–Induced Autoimmunity in Vitiligo

Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from endoplasmic reticulum to membrane in melanocytes under oxidative stress. To investigate the potential role of CRT in the pathogenesis of vitiligo, we analyzed the correlation between CRT and ROS in serum and lesions of vitiligo, detected CRT and protein kinase RNA-like ER kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway, then tested the chemotactic migration of CD8+ T cells or CD11c+ CD86+ cells. Initially, we verified the overexpression of CRT in perilesional epidermis that was positively correlated with the disease severity of vitiligo. Furthermore, the PERK branch of UPR was confirmed to be responsible for the overexpression and membranal translocation of CRT in melanocytes under oxidative stress. We also found that oxidative stress-induced membranal translocation of CRT promoted the activation and migration of CD8+ T cells in vitiligo. Additionally, dendritic cells from vitiligo patients were also prone to maturation with the co-incubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes via UPR and might play a role in oxidative stress-triggered CD8+ T cell response in vitiligo.

Identifying potential inhibitors of C-X-C motif chemokine ligand10 against vitiligo: structure-based virtual screening, molecular dynamics simulation, and principal component analysis

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW ≤ 500 Da), hydrogen bond donor (HBD ≤ 5), hydrogen bond acceptor (HBA ≤ 10), and lipophilicity (logP ≤ 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer’s Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry’s pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein. Communicated by Ramaswamy H. Sarma

Targeting the elevated IFN-γ in vitiligo patients by human anti- IFN-γ monoclonal antibody hampers direct cytotoxicity in melanocyte

BackgroundVitiligo is an autoimmune disease that progressively destroys melanocytes in the skin, resulting in patchy disfiguring depigmentation. The direct pathological effect of IFN-γ, CXCL10 to the melanocytes in vitiligo has been reported, but there are contradictory results to which cytokine exerts the critical cytotoxic effect on melanocytes. ObjectiveThe overarching goal was to study the direct toxicity of highly expressed cytokine in vitiligo skin lesions to melanocytes. MethodsWe obtained the interstitial fluid analyte from lesion and non-lesion skin of vitiligo patients and healthy control and sent for high sensitivity multiplex cytokine panel. We further performed functional study to identify the direct toxicity effect of the highly expressed cytokines. ResultsWe found a significant elevation of IFN-γ, CXCL9, CXCL10, CXCL11 in the vitiligo skin. Ex vivo melanocyte studies support the direct role of IFN-γ per se in melanocyte cell loss, increased oxidative stress and melanogenesis disruption. Interestingly, we found that IFN-γ regulated cell death through oxidative stress-related ferroptosis cell death, which may initiate autoimmunity in vitiligo. In contrast to blocking selected cell death pathway, our in vitro study supports the rescue effect of human anti-IFN-γ monoclonal antibody 2A6Q to IFN-γ induced cell death, oxidative stress, and loss of function in melanocytes by interrupting IFN-γ signaling, which may be a potential therapeutic option for vitiligo. ConclusionThis study further confirms the direct of toxicity effect of IFN-γ per se towards melanocyte in vitiligo skin and the potential utility of human anti-IFN-γ monoclonal antibody in treating vitiligo.

1298 Membranal expression of calreticulin induced by unfolded protein response in melanocytes: A mechanism underlying oxidative stress-induced autoimmunity in vitiligo

1298 Membranal expression of calreticulin induced by unfolded protein response in melanocytes: A mechanism underlying oxidative stress-induced autoimmunity in vitiligo

Thyroid Autoimmunity in Vitiligo: A Case-Control Study.

Introduction There is scanty evidence regarding the role of autoimmunity in vitiligo, especially in the Asian population. Moreover, the existing studies reported conflicting results. This prompted the investigators to identify the association of thyroid autoimmunity with vitiligo by employing a case-control design in this setting. Methodology The present study was a hospital-based case-control study conducted in one of the tertiary care hospitals of North India. We recruited 30 subjects aged 16-60 years with vitiligo attending the skin and venereal diseases outpatient department. The subjects attending the general medicine outpatient department without having a diagnosis of vitiligo were considered for the control group. Thyroid hormones (FT3 and FT4), thyroid-stimulating hormones, anti-thyroid peroxidase(anti-TPO) antibodies, and anti-thyroglobulin (anti-TG) antibodies were the primary investigations performed among the study subjects. Results The mean age of the study subjects was 31.3 (SD: 13.3) years. Both the case and control groups were comparable based on selected socio-demographic variables (p > 0.05). There was a statistically significant difference in terms of mean anti-TPO and anti-TG values between the case and control groups in which subjects with vitiligo reported significantly higher values (p < 0.05). Conclusion Our study reported a significant elevation in the mean values of the thyroid antibodies (anti-TG and anti-TPO antibodies) in vitiligo subjects compared to control subjects in this setting. Hence, screening for autoimmune thyroid diseases among patients with vitiligo is suggested for the early detection and the initiation of appropriate intervention.

Is the targeted approach for vitiligo satisfactory?

Vitiligo is also known as Safed Daagh, Safed Kodh, Phuleri and Savitra in vernacular. Vitiligo causes social and psychological distress, affecting 0.1 to 2 Percent global population. The pathology demonstrates depigmentation of the skin, with loss of melanocytes by autoreactive cytotoxic T cells. The vitiligo-infiltrating lymphocytes were T lymphocytes, and most were CD8+The elevated levels of H2O2 in the skin mediate the production of proinflammatory cytokines like IL-1β, IL6, and IL-8 indirectly by activating the calreticulin pathway. Autoimmunity in vitiligo is driven by the IFN-γ-CXCL10 cytokine (motif chemokine ligand) signaling pathway. No drug can stop the process of vitiligo. Most of the drugs are used in combination. Light therapy can help to restore some color. Topical steroids, calcineurin inhibitors, and narrow-band ultraviolet (UV)–B phototherapy are widely used. New depigmenting therapies are emerging such as helium-neon (He–Ne) lasers and prostaglandin E2 analogs. In cases of stable disease, surgical procedures such as skin grafting, blister grafting, orCellular suspension transplant are often tried. Ruxolitinib is the first medication that can restore pigment in patients with nonsegmental vitiligo. Tildrakizumab is also being evaluated in form of Topical Cream. Unfortunately, vitiligo is life long condition which is difficult to treat with satisfaction.

022 The role of ISG15-USP18 axis in oxidative stress-induced vitiligo

Vitiligo is a relatively common, acquired depigmenting disease caused by the loss of epidermal melanocytes. Oxidative stress is known to participate in the initiation of vitiligo by triggering autoimmunity. In this study, we tried to identify factors serving as a bridge between oxidative stress and autoimmunity in vitiligo. According to RNA sequencing analysis on H2O2-treated melanocytes, interferon-stimulated gene 15 (ISG15) among interferon signaling-related genes were particularly upregulated.

Immune Activities in Choroids of Visually Impaired Smyth Chickens With Autoimmune Vitiligo.

Vitiligo is a common dermatological disorder affecting 1–2% of the world’s population. It is characterized by postnatal, autoimmune destructions of melanocytes in the skin, resulting in patches of depigmentation. Autoimmunity in vitiligo may also affect melanocytes in non-integumental tissues, including the eyes where choroidal melanocytes are the target of the autoimmune response. The Smyth line (SL) of chicken is the only animal model that spontaneously and predictably develops all clinical and biological manifestations of autoimmune vitiligo. In SL vitiligo (SLV), destruction of epidermal melanocytes in growing feathers (GFs) involves a melanocyte-specific, Th1-mediated cellular immune response. Smyth chickens may also exhibit uveitis and vision impairment. Previous studies established a strong association between SLV and vision impairment, including similar pathology in affected eyes and GFs. To determine the presence, types, and activities of choroid infiltrating mononuclear cells, we collected eyes before, near onset, and during active SLV from sighted, partially blind, and blind SL chickens. All SL chickens with vision impairment had SLV. Immunohistochemistry and quantitative reverse transcriptase-PCR analyses revealed mononuclear cell and cytokine expression profiles in the autoimmune destruction of melanocytes in choroids that are identical to those described in GF, demonstrating the systemic nature of autoimmunity against melanocytes in SLV. In addition, we observed aberrant melanogenesis in SL eyes. The immunopathogenesis in SL vision impairment resembles human vitiligo-associated ocular diseases, especially Vogt–Koyanagi–Harada syndrome and sympathetic ophthalmia. Hence, the Smyth chicken autoimmune vitiligo model provides the opportunity to expand our understanding of spontaneous autoimmune pigmentation disorders and to develop effective treatment strategies.

Active vitiligo vulgaris following the administration of the Oxford–AstraZeneca (AZD1222) vaccine against SARS-CoV-2

Sir, There is significant uncertainty surrounding vaccines against COVID-19. Due to the critical need, these vaccines are being developed and approved at a uniquely fast pace [1]. Currently, the approved vaccines take their action by administering the host with sequences encoding the viral spike protein. This essentially means that these gene-therapy-based vaccines, whose long-term effects remain unknown, are going to be administered globally [2]. Therefore, despite their safety and efficacy demonstrated in respective clinical trials, it is reasonable to be cautious and adopt more intensive post-marketing vigilance [3]. A forty-nine-year-old diabetic male presented with asymptomatic, rapidly growing, leukodermal patches on the scalp (Fig. 1), which began to appear suddenly fourteen days following the administration of the first dose of the Oxford–AstraZeneca (AZD1222) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The patches were clinically consistent with vitiligo and were confirmed with their well-defined, ivory-white patches by Wood’s lamp examination (Fig. 2).There were no leucodermic patches anywhere else on the body, no family history of vitiligo, and no history of COVID-19 viral infection. After one week of reevaluation, the patch increased in size. The patient also presented with cellulitis on the right groin persistent for three days and was treated with an antibiotic with a follow-up. All baseline investigations, including a full blood count and renal and liver function tests, were normal. The patient is currently on follow-up. Cytokines play a role in regulating the immune response and the depigmentation process in vitiligo. There is an imbalance in cytokine levels in patients with vitiligo. IFN-g expression plays a role in the autoimmune process in vitiligo. The expression of the cytokine IFN-g is associated with melanocyte destruction in the active phase of vitiligo lesions [4]. IFN-g interacts with the viral receptor, resulting in the consequent reduction of several virus replicating, down-regulating genes and gene products [5]. Li et al. [6] demonstrated that IFNs are potential drug choices for SARS-CoV-2 infection. Here, we hypothesize that patients with non-segmental vitiligo (NSV), an autoimmune skin (and mucosal) disorder, may clear SARS-CoV-2 infection more efficiently and have a lower risk of COVID-19 development. Conversely, in the case of COVID-19 development, vitiligo autoimmunity may influence the cytokine storm-related disease burden. In addition, immune activation during SARS-CoV-2 infection or COVID-19 disease may increase vitiligo disease activity. Our hypothesis is based on the shift of the immune system in NSV toward adaptive type 1 (IFNg and CD8 T cells) and innate immune responses [7]. It is unclear whether the vitiligo in our patient was caused by vaccination, However, the temporal relationship between the vaccine and the development of the disease is interesting. We may, therefore, conclude that our patient had his latent vitiligo activated by the vaccine. Yet, further work is needed to demonstrate a causal relationship between vitiligo and COVID-19 vaccination. To the best of our knowledge, this is the first reported case of vitiligo associated with the administration of the Oxford–AstraZeneca (AZD1222) vaccine.

The genetics of pediatric cutaneous autoimmunity: The sister diseases vitiligo and alopecia areata

Autoimmunity, the reaction of the host against self, is a complex pattern of immunologic response that allows the immune system to react to “normal” tissue. Many such diseases exist in the skin, but in particular, two stand out as visible manifestations of autoimmune cutaneous attack. These are vitiligo, the immune attack on the melanocyte, and alopecia areata, the immune attack of the hair unit. These two illnesses include the prototypes of "simple" attacks on specific components of the skin. Other such illnesses are psoriasis—a complex series of immunologic responses resulting in a characteristic pattern of keratinocyte hyperproliferation—and lichen planus, which is similarly associated with a typical cutaneous skin disease pattern, but these will not be included in this review. In comparison, autoimmune polyendocrinopathies have defined pathways of disease based on single-gene mutations that can result in a variety of autoimmune skin features including vitiligo and alopecia areata. This contribution reviews known patterns of autoimmunity in childhood skin disease with a particular focus on single-gene disorders where they exist, and the more common multifactorial genes that contribute to this breach of the immune system's regulatory checks and balances. Genetic mechanisms that will be covered include innate and adaptive immunity, major histocompatibility complex II class associations, genetic polymorphisms, and major histocompatibility complex I class associations that bridge autoinflammatory and autoimmunity states, as well as alterations in oxidative metabolism promoting tissue destruction. End-organ tissue destruction appears to occur via interferon gamma and cytotoxic mediated activity and is a promising new therapeutic target. Janus kinase inhibitors also have the benefit clinically of both affecting the immune cascade at the cytotoxic T cell level and allowing triggering of melanocyte and hair follicular activity through the signal transducer and activator of transcription pathway, representing an attractive therapeutic with dial activity, among other cytokines implicated in end-organ destruction. Transplacental autoimmunity will not be covered herein. Greater insight into mechanisms of pediatric cutaneous autoimmunity in vitiligo and alopecia areata has yielded better therapeutic options and interventions. Understanding the basis of autoimmune triggering in our patients, that is, personalized medicine, may allow for targeted therapeutics with a goal of induction of remission, regeneration, or rejuvenation of the end-organ with the least toxic side effect profile.

Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8+ T cells activation via JAK-STAT pathway in vitiligo

Oxidative stress and effector memory CD8+ T cells have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on memory CD8+ T cells function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal H2O2 content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans-presentation by activating NF-κB signaling in keratinocytes. What's more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8+ TEMs activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8+ TEMs activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to the activation of CD8+ TEMs, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.

792 Oxidative stress-induced IL-15 trans-presentation in keratinocytes contributes to CD8+ T cells activation via JAK-STAT pathway in vitiligo

Oxidative stress and melanocyte-specific CD8+ T cell have been greatly implicated in vitiligo pathogenesis. However, the crosstalk between these two crucial pathogenic factors has been merely investigated. IL-15 has been regarded as an important cytokine exerting its facilitative effect on immune cell function in various autoimmune diseases. In the present study, we initially discovered that the IL-15 expression was significantly increased in vitiligo epidermis and highly associated with epidermal H2O2 content. In addition, epidermal IL-15 expression was mainly derived from keratinocytes. Then, we showed that oxidative stress promoted IL-15 and IL-15Rα expression as well as IL-15 trans-presentation by activating NF-κB signaling in keratinocyte. What’s more, the trans-presented IL-15, rather than the secreted one, was accounted for the potentiation of CD8+ T cells activation. We further investigated the mechanism underlying trans-presented IL-15 in potentiating CD8+ T cell activation and found that the blockage of IL-15-JAK-STAT signaling could be a potent therapeutic approach. Taken together, our results demonstrate that oxidative stress-induced IL-15 trans-presentation in keratinocyte contributes to the activation of CD8+ T cell, providing a novel mechanism by which oxidative stress initiates autoimmunity in vitiligo.

Oxidative Stress–Induced HMGB1 Release from Melanocytes: A Paracrine Mechanism Underlying the Cutaneous Inflammation in Vitiligo

Vitiligo is a cutaneous depigmentation disorder caused by the destruction of epidermal melanocytes. The generation and the skin infiltration of autoreactive CD8+ cytotoxic T cells triggered by oxidative stress play a critical role in vitiligo. High-mobility group protein B1 (HMGB1) is a classic damage-associated molecular pattern molecule with strong proinflammatory effects in inflammatory reactions. A previous study reported an enhanced expression of HMGB1 in vitiligo lesions, but the role of HMGB1 in cutaneous inflammation of vitiligo is still unknown. In the present study, we initially found that HMGB1 was released from the nucleus of melanocytes in vitiligo perilesional skin. Furthermore, cultured normal human melanocytes could release HMGB1 under treatment with hydrogen peroxide. Moreover, HMGB1 facilitated the secretion of CXCL16 and IL-8 from keratinocytes by binding to the receptor for advanced glycation end products and activating NF-κB and extracellular signal-regulated kinase signaling pathways. Subsequently, HMGB1 led to the formation of chemotaxis for the migration of CD8+ T cells from patients with vitiligo by increasing the release of CXCL16 from keratinocytes. Additionally, HMGB1 promoted the maturation of dendritic cells from patients with vitiligo. Altogether, our study demonstrates that HMGB1 released from melanocytes contributes to the formation of oxidative stress-induced autoimmunity in vitiligo.

Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease

Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, because topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.

Oxidized tyrosinase: A possible antigenic stimulus for non-segmental vitiligo autoantibodies

BackgroundVitiligo is a common pigmentary disorder, the precise etiology of which remains obscure. Tyrosinase, a key enzyme involved in melanin synthesis, has now been implicated as an autoantigen for vitiligo patients, but it is not clear how this prevalent protein becomes antigenic in vitiligo. ObjectiveTo investigate the status and contribution of oxidized tyrosinase in vitiligo and to explore whether oxidized tyrosinase has a role in disease progression. MethodsTyrosinase was modified by reactive-oxygen-species (ROS). Binding characteristics of antibodies in vitiligo patients (n=25) with varying disease duration (DD) and disease severity were screened against ROS-modified tyrosinase (ROS-tyrosinase) by immunoassays and their results were compared with healthy controls (n=23). ResultsThe ROS caused extensive alterations in conformation and function of tyrosinase. Protein-A purified IgGs from vitiligo patients (Vt-IgG) showed strong binding to ROS-tyrosinase in comparison with IgGs from healthy controls (p<0.001). Interestingly, not only was there an increased number of subjects positive for anti-ROS-tyrosinase-IgGs, but also the levels of these IgGs were significantly higher among vitiligo patients, whose DD were ≥10 years as compared to patients with short DD (<10 years). In addition, a significant correlation was observed between the levels of anti-ROS-tyrosinase-IgGs and the patients’ ages or with disease severity. Experimentally induced anti-ROS-tyrosinase-IgGs show reactivity with tyrosinase from vitiligo patients. Furthermore, vitiligo patients had lower levels of tyrosinase activity compared with healthy controls. Not only these, levels of carbonylation were also higher among vitiligo patients whose DD were ≥10 years as compared to patients with DD<10 years. ConclusionsThis is the first study to demonstrate the role of oxidized tyrosinase in vitiligo. Our novel results support an association between oxidized tyrosinase and vitiligo autoimmunity. The stronger antibodies response to oxidized tyrosinase in vitiligo patients with higher DD or with severe patients suggests that oxidized tyrosinase may be a useful biomarker in evaluating the progression of vitiligo and in elucidating the mechanisms of disease pathogenesis.

Anti-thyroid peroxidase antibody in vitiligo: a prevalence study.

Aim. The aim of the study was to study the relation of vitiligo with demographic data like age, sex, and duration and determine the prevalence of thyroid autoimmunity in vitiligo patients. Materials and Methods. This study was a cross sectional study consisting of 100 patients clinically diagnosed (old and new) as having vitiligo irrespective of age or sex. Patients with known thyroid disease on supplementation therapy, or who had undergone thyroid surgery, those on antithyroid medication, patients with other causes of leukoderma, and cases who do not provide informed consent were excluded from the study. Serum TSH and anti-TPO antibodies were measured in all the patients. Results. The prevalence of anti-TPO antibody positivity was found to be 28%. Conclusion. According to our study, none of our vitiligo patients had symptoms or signs of thyroid disease at the time of presentation but, on biochemical evaluation, anti-TPO antibodies were found in a considerable number of patients. Hence, we recommend screening of these patients with thyroid antibodies.

Mitochondrial DNA acquires immunogenicity on exposure to nitrosative stress in patients with vitiligo

Vitiligo is a common pigmentary skin disorder of unknown etiology. Many studies show the defective mitochondrial functionality in vitiligo patients, but the potential role of mitochondrial DNA (mtDNA) in the pathogenesis of vitiligo remains to be investigated. Recent evidences demonstrate that mitochondria possess their own nitric-oxide-synthase and can produce endogenous peroxynitrite (ONOO−). This study was undertaken to investigate the role of ONOO−-modified-mitochondrial-DNA (ONOO−-mtDNA) in vitiligo autoimmunity. Our data revealed that ONOO−-induced modifications in mtDNA caused structural alterations. Specificity of immunoglobulin G (IgG) from vitiligo patients (n=26) and controls (n=25) were analysed towards ONOO−-mtDNA. Vitligo-IgG samples (Vt-IgG) show preferential binding to ONOO−-mtDNA in comparison with native mtDNA (p<0.01). Anti-ONOO−-mtDNA–IgG show cross-reactivity with isolated DNA from vitiligo patients. Furthermore, levels of anti-ONOO−-mtDNA–IgG, inducible-nitric-oxide-synthase (iNOS), nitric oxide (NO) and nitrotyrosine were higher among vitiligo patients whose disease durations (DD) were ⩾5years as compared to patients with lower DD (DD<5years). In conclusion, this is the first study to demonstrate the role of ONOO−-modified mtDNA in vitiligo patients. Our data provide an important insight into the immunological mechanisms occur in vitiligo. The ONOO−-mtDNA may be useful in elucidating the mechanisms of disease pathogenesis.

Clinical patterns of vitiligo and its associated co morbidities: A prospective controlled cross-sectional study in South India

Aim:The purpose of this study is to assess the clinical patterns and associations of vitiligo, audiometric functions, and ocular involvement and to correlate the morphology, clinical behaviour and comorbidities associated with vitiligo.Settings and Design:For this prospective and cross-sectional study 80 self-reporting patients in the age group 7-75 years with vitiligo attending the outpatient department of Manipal hospital during the period August 2008 to February 2010 were selected and the data was analysed.Materials and Methods:The patients were subjected to detailed history, clinical examination and investigations [complete blood count (CBC), absolute eosinophil count (AEC), erythrocyte sedimentation rate (ESR), thyroid stimulating hormone (TSH), vitamin B12 estimation, fasting blood sugar (FBS), and post prandial blood sugar (PPBS),antibody titre estimations that is antithyroid peroxidase (ATPA), antithyroglobulin (ATA), antinuclear antibodies (ANA),urine analysis], audiometric evaluation and ophthalmic examination.Statistical Analysis Used:The Fisher exact test has been used to find the significance of study parameters on categorical scale between two or more groups.Results:In the present series of 80 cases, 41 (51.25%) were males and 39 (48.75%) were females. The male to female ratio was 1.05:1. In our study 20% cases gave definite family history of vitiligo and patients in the age group of 20 - 30 years were the most commonly affected. Generalized vitiligo (31.3%) was the most common type followed by segmental (30%), focal (18.8%), acrofacial (8.8%), and mucosal vitiligo (11.3%). In the present study there was a high incidence of autoantibodies (22.5%), vitamin B12 deficiency (30%), hypothyroidism (11.3%), elevated absolute eosinophil count (16.3%), hypoacusis (10%) and retinal changes (8.8%). This suggests multisystem autoimmunity in vitiligo.