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Vitiligo is an autoimmune skin disease that can be influenced by stress, including that resulting from sleep deprivation and sleep disturbances. Sleep is essential in the regulation of several hormonal, metabolic and autoimmune pathways that may have important roles in vitiligo. This study aimed to investigate the potential interplay between hormonal, metabolic, and autoimmune markers in vitiligo patients, and the possible influence of sleep quality in these vitiligo pathways. A cohort of 30 vitiligo patients and 26 healthy controls were assessed for various laboratory markers, including thyroid-stimulating hormone (TSH), parathyroid hormone (PTH), serum calcium, 1.25(OH)2D, 25(OH)D, anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG), and antinuclear antibodies (ANA). The study evaluated sleep quality using the Pittsburgh Sleep Quality Index (PSQI). Positive anti-TPO were found in the vitiligo group, but did not in the control group. Vitamin D 25(OH)D mean levels were clinically insufficient in both groups (< 30 mg/dL). Reactive ANA was analyzed with 2 variables related to vitiligo: phototherapy and skin activity. No statistical correlation was found in the chi-square test on this relationship. Descriptive findings have shown that the positivity to anti-TPO and anti-TG, associated or not with reactive ANA, was higher in vitiligo group. Great part (85.7%) of vitiligo group were "poor sleepers" (PSQI > 5), which has increased (88.2%) when considering only individuals with signs of vitiligo activity. Autoimmune hypothyroidism and positive anti-TPO are expected in vitiligo, although this marker is not usually measured in the first laboratory screening to this disease. Adequate vitamin D levels may be a key adjuvant in skin pigmentation, and be related to sleep quality and immune regulation, as this vitamin can be related to better sleep and immunomodulation in autoimmune diseases. Evaluating ANA before phototherapy can be controversial, but it should be considered in cases with a poor response to this treatment, or when there is a higher risk of other autoimmune diseases. Poor sleep predominated in the vitiligo group, based on PSQI scores that reported worse subjective sleep in these patients. Worse sleep predominated in individuals with signs of skin activity and reactive autoimmune markers. Screening these components could be important in the management of vitiligo, as maintaining body homeostasis can help to improve the disease course. Sleep should be considered as a potential modulator of several multidirectional vitiligo pathways., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: CD20 + T cells represent up to 5% of circulating T lymphocytes. These cells have been shown to produce higher levels of IL-17A and IFN-γ than those of CD20 -  T lymphocytes. Some reports described the role of CD20 + T cells in autoimmune disorders such as multiple sclerosis and rheumatoid arthritis possibly due to their ability to produce these inflammatory cytokines. This study is aimed at describing the behavior of CD20 + T lymphocytes in the most frequent autoimmune disorder, i.e., Hashimoto's thyroiditis (HT), presenting isolated or associated to further autoaggressive disorders in a frame of poly-autoimmunity., Methods: The study group encompasses 65 HT patients: 23 presenting in isolated form (IT) and 42 with an associated non-endocrine autoimmune disorder [16 with chronic atrophic gastritis (CAG), 15 with nonsegmental vitiligo (VIT), and 11 with celiac disease (CD)]. Twenty healthy donors act as control group (HD). Chronic use of interfering drugs, severe or chronic disorders, and pregnancy and lactation were used as exclusion criteria. Whole blood samples (100 µl) were stained with fluorescent-labeled antibodies (anti-CD45, anti-CD3, anti-CD19, anti-CD16, anti-CD56, anti-CD4, anti-CD8, anti-CD20). Red blood cells were then lysed by adding 1 ml of hypotonic buffer, and samples were acquired on a Flow Cytometer., Results: CD3 + CD8 + CD20 + T lymphocytes' percentages, were significantly higher in the whole group of autoimmune patients compared to healthy donors (p = 0.0145). Dividing HT patients based on the type of presentation of autoimmune thyroiditis, CAG group showed the highest percentage of these cells as compared to HD and CD (p = 0.0058). IT patients showed higher percentages of CD3 + CD8 + CD20 + cells than those of HD patients although not reaching statistical significance. However, dividing IT group based on thyroid function, hypothyroid patients showed higher CD8 + CD20 + cell percentages than those of HD and euthyroid patients (p = 0.0111). Moreover, in IT patients, these cells were negatively correlated with FT4 levels (p = 0.0171; r = -0.4921)., Conclusions: These preliminary findings indicate that CD8 + CD20 + T cells are activated in patients with autoimmune thyroiditis and may behave differently according to the presence of poly-autoimmunity and hypothyroidism., (© 2024. The Author(s).)

Vitiligo is characterized by depigmented skin lesions involving melanocyte defects and immune dysregulation. Haematological markers like neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been explored in various skin disorders. Given vitiligo's proposed pathogenesis, we hypothesized differences in NLR and PLR in vitiligo patients compared to controls. In a national retrospective cohort study (2005-2020) in Israel, blood count data from patients diagnosed with vitiligo (ICD-10 codes) were analysed, excluding patients with recent infections, surgeries, or malignancies. Controls matched for age and sex were selected. Sub-analyses examined age groups, treatment type, and matched controls. Children (n = 3,796) and adults (n = 38,608) with vitiligo showed significant differences in gender distribution, cell counts, and ratios. Vitiligo patients (n = 38,358) exhibited lower NLR, decreased neutrophils and platelets, and increased lymphocytes compared with controls. Non-systemically treated vitiligo patients (n = 33,871) displayed lower NLR and neutrophils compared with matched controls. Systemically treated vitiligo patients (n = 4,487) showed lower NLR, higher PLR, and reduced lymphocytes. Logistic regression identified associations between increased lymphocyte and platelet counts and being systemically treated. This study highlights significant haematological differences in vitiligo patients, emphasizing the potential utility of NLR as an accessible tool for vitiligo assessment. Further investigations are warranted to elucidate the roles of neutrophils and lymphocytes in vitiligo pathogenesis.

Melanoma is the most severe form of skin cancer with an incidence that is increasing all over the world. Melanoma cells derive from normal melanocytes and share different melanocyte-specific antigens, the same antigens against which an immune reaction develops in vitiligo, a skin disease characterized by autoimmune-mediated melanocyte destruction. The purpose of this review is to present the autoimmune-mediated melanocyte destruction associated with melanoma development, progression and treatment. Patients with vitiligo seem to have a lower chance of developing melanoma. On the other hand, patients with melanoma can develop depigmented lesions even at distant sites from the primary tumor, defined as melanoma-associated leukoderma (MAL). Drug-associated leukoderma (DAL) was also described in melanoma patients treated with immunotherapy or targeted therapy and it seems to be a favorable prognostic factor. Clinically, MAL and DAL can be diagnosed as vitiligo and there are few differences between these three entities. In this review, the incidence of DAL in melanoma patients treated with different therapies was researched in the literature and patient outcome was recorded, with studies showing a prolonged disease-free survival in melanoma patients with DAL, treated with immune checkpoint inhibitors. Further studies are however needed to understand the dynamics of autoimmune-mediated melanocyte destruction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ungureanu, Vasilovici, Halmágyi, Trufin, Apostu and Şenilă.)

A comprehensive analysis of spatial transcriptomics was carried out to better understand the progress of halo nevus. We found that halo nevus was characterized by overactive immune responses, triggered by chemokines and dendritic cells (DCs), T cells, and macrophages. Consequently, we observed abnormal cell death, such as apoptosis and disulfidptosis in halo nevus, some were closely related to immunity. Interestingly, we identified aberrant metabolites such as uridine diphosphate glucose (UDP-G) within the halo nevus. UDP-G, accompanied by the infiltration of DCs and T cells, exhibited correlations with certain forms of cell death. Subsequent experiments confirmed that UDP-G was increased in vitiligo serum and could activate DCs. We also confirmed that oxidative response is an inducer of UDP-G. In summary, the immune response in halo nevus, including DC activation, was accompanied by abnormal cell death and metabolites. Especially, melanocyte-derived UDP-G may play a crucial role in DC activation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells-derived exosomes (hUMSCs-Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti-oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D-Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D-Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8 + T cells infiltration, and expanded Treg cells in skin, and 3D-Exos exerted a better effect than 2D-Exos. Mechanistically, 3D-Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H 2 O 2 -induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR-132-3p and miR-125b-5p enriched in 3D-Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D-Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells-mediated immunosuppression and suppressing oxidative stress-induced melanocyte damage via the delivery of miR-132-3p and miR-125b-5p. The employment of 3D-Exos will be a promising treament for vitiligo., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Recent studies increasingly suggest that microbial infections and the immune responses they elicit play significant roles in the pathogenesis of chronic inflammatory skin diseases. This study uses Mendelian randomization (MR) and Bayesian weighted Mendelian randomization (BWMR) to explore the causal relationships between immune antibody responses and four common skin diseases: psoriasis, atopic dermatitis (AD), rosacea, and vitiligo., Methods: We utilized summary statistics from genome-wide association studies (GWAS) for antibody responses to 13 infectious pathogens and four skin diseases. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to assess causal relationships using multiple MR methods, including inverse variance weighted (IVW), MR Egger, and weighted median. BWMR was also employed to confirm findings and address potential pleiotropy., Results: The IVW analysis identified significant associations between specific antibody responses and the skin diseases studied. Key findings include protective associations of anti-Epstein-Barr virus (EBV) IgG seropositivity and Helicobacter pylori UREA antibody levels with psoriasis and AD. anti-chlamydia trachomatis IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoprotein E and I antibody levels were negatively associated with rosacea, while EBV Elevated levels of the early antigen (EA-D) antibody levels and HHV-6 IE1B antibody levels were positively associated with rosacea. H. pylori Catalase antibody levels were protectively associated with vitiligo, whereas anti-herpes simplex virus 2 (HSV-2) IgG seropositivity was positively associated with vitiligo. The BWMR analysis confirmed these associations., Conclusion: This study underscores the significant role of H. pylori and other pathogens in these skin diseases, suggesting both protective and exacerbating effects depending on the specific condition. Understanding these pathogen-immune interactions can lead to the development of more effective, personalized treatments and preventative strategies, ultimately improving patient outcomes and quality of life., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Background: Regulatory T cells (Tregs) play vital roles in controlling immune reactions and maintaining immune tolerance in the body. The targeted destruction of epidermal melanocytes by activated CD8 + T cells is a key event in the development of vitiligo. However, Tregs may exert immunosuppressive effects on CD8 + T cells, which could be beneficial in treating vitiligo., Methods: A comprehensive search of PubMed and Web of Science was conducted to gather information on Tregs and vitiligo., Results: In vitiligo, there is a decrease in Treg numbers and impaired Treg functions, along with potential damage to Treg-related signaling pathways. Increasing Treg numbers and enhancing Treg function could lead to immunosuppressive effects on CD8 + T cells. Recent research progress on Tregs in vitiligo has been summarized, highlighting various Treg-related therapies being investigated for clinical use. The current status of Treg-related therapeutic strategies and potential future directions for vitiligo treatment are also discussed., Conclusions: A deeper understanding of Tregs will be crucial for advancing Treg-related drug discovery and treatment development in vitiligo., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829., (© 2024. The Author(s).)

Calreticulin (CRT), a damage-associated molecular pattern molecule, is reported to translocate from the endoplasmic reticulum to the 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 endoplasmic reticulum kinase (PERK) expression in vitiligo lesions, and studied the production of CRT and mediators of unfolded protein response (UPR) pathway and 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. In addition, dendritic cells from patients with vitiligo were also prone to maturation with the coincubation of melanocytes harboring membranal CRT. CRT could be induced on the membrane of melanocytes through UPR and might play a role in oxidative stress-triggered CD8 + T-cell response in vitiligo., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Generalized vitiligo(GV) is a skin depigmenting condition due to loss of melanocytes. Regulatory T cells(Tregs), responsible for peripheral tolerance, show altered numbers and functions in GV patients, likely influenced by the aging process. Therefore, the present study was focused on measuring the relative telomere length of Tregs in 96 GV patients and 90 controls by qPCR, along with correlation of relative telomere length with in vitro Treg suppressive capacity. Interestingly, we found significantly decreased relative telomere length in Tregs of GV patients as compared to controls(p = 0.0001). Additionally, age based-analysis suggested significant decrease in relative telomere length in elderly GV patients(>40 years) in comparison to young GV patients(0-20 years; p = 0.0027). Furthermore, age of onset analysis suggested for reduced relative telomere length in early onset GV patients (0-20 years) in comparison to late onset GV patients(>40 years; p = 0.0036). The correlation analysis suggested positive correlation for relative telomere length with in vitro Tregs suppressive capacity(r = 0.68 & r = 0.45; p < 0.0001). Additionally, the in vitro Tregs suppressive capacity was significantly reduced in elderly GV patients(p = 0.003) and early onset GV patients(p = 0.0074). Overall, our study for the first time demonstrated that, the Tregs ageing due to telomere shortening may be responsible for altered Treg functions and number., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal roles. However, the association between circulating immune cells and vitiligo continues to be enigmatic., Materials and Methods: We extracted single nucleotide polymorphisms (SNPs) associated with immune circulating cells at a genome-wide significance level from the BLOOD CELL CONSORTIUM's genome-wide association study (GWAS) dataset. Summary data for 385,801 cases of vitiligo were obtained from a large-scale Finnish genome-wide association study (ncases=292, ncontrols=385,509). The inverse variance weighted (IVW) method was employed as the primary analytical approach for Mendelian randomization (MR) analysis. Additionally, heterogeneity was assessed using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses., Results: The risk of vitiligo was found to increase with the elevation of 4 circulating immune cells, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs): basophils (OR=1.81; 95% CI: 1.01-3.24, p=0.0450), monocytes (OR=1.67; 95% CI: 1.23-2.26, p=0.0009), eosinophils (OR=1.78; 95% CI: 1.22-2.59, p=0.0028), and neutrophils (OR=1.65; 95% CI: 1.08-2.54, p=0.0208). After removing outliers, the sensitivity analysis of the above indicators did not show heterogeneity and pleiotropy., Conclusion: Our findings illuminate the association between circulating immune cells and vitiligo, offering insights that could guide clinical practices in the treatment of vitiligo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xin, Yuan and Wang.)

Chronic inflammatory skin diseases are multifactorial diseases that combine genetic predisposition, environmental triggers, and metabolic disturbances associated with abnormal immune responses. From an immunological perspective, the better understanding of their physiopathology has demonstrated a large complex network of immune cell subsets and related cytokines that interact with both epidermal and dermal cells. For example, in type-1-associated diseases such as alopecia areata, vitiligo, and localized scleroderma, recent evidence suggests the presence of a type-2 inflammation that is well known in atopic dermatitis. Whether this type-2 immune response has a protective or detrimental impact on the development and chronicity of these diseases remains to be fully elucidated, highlighting the need to better understand its involvement for the management of patients. This mini-review explores recent insights regarding the potential role of type-2-related immunity in alopecia areata, vitiligo, and localized scleroderma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Migayron, Bordes, Closs, Seneschal and Boniface.)

Vitiligo belongs to a frequent chronic autoimmune skin disease with the features of pigmented plaques on the diseased skin along with potential damage of melanocytes. There are many factors underlying the pathogenesis of vitiligo, among which oxidative stress is extensively regarded to be the critical factor leading to the loss of melanocytes. The changed redox state resulting from oxidative stress, containing ROS overproduction along with the reduced activity of the skin's antioxidant system, makes melanocytes less resistant to exogenous or endogenous stimuli, and ultimately pushes normal defense mechanisms, resulting in the loss of melanocytes. Given the crucial potential of innate together with adaptive immunity in vitiligo, there is growing evidence of a relation between oxidative stress and autoimmunity. Our review offers estimable insights into the possible properties of oxidative stress and autoimmunity in pathogenesis of vitiligo, as well as the potential role of antioxidant-based supportive therapy in vitiligo repigmentation, providing a hopeful value for further research and development of effective treatments.

Introduction: Vitiligo is an acquired de-pigmentation disorder characterized by the post-natal loss of epidermal melanocytes (pigment-producing cells) resulting in the appearance of white patches in the skin. The Smyth chicken is the only model for vitiligo that shares all the characteristics of the human condition including: spontaneous post-natal loss of epidermal melanocytes, interactions between genetic, environmental and immunological factors, and associations with other autoimmune diseases. In addition, an avian model for vitiligo has the added benefit of an easily accessible target tissue (a growing feather) that allows for the repeated sampling of an individual and thus the continuous monitoring of local immune responses over time., Methods: Using a combination of flow cytometry and gene expression analyses, we sought to gain a comprehensive understanding of the initiating events leading to expression of vitiligo in growing feathers by monitoring the infiltration of leukocytes and concurrent immunological activities in the target tissue beginning prior to visual onset and continuing throughout disease development., Results: Here, we document a sequence of immunologically significant events, including characteristic rises in infiltrating B and αβ T cells as well as evidence of active leukocyte recruitment and cell-mediated immune activities (CCL19, IFNG, GZMA) leading up to visual vitiligo onset. Examination of growing feathers from vitiligo-susceptible Brown line chickens revealed anti-inflammatory immune activities which may be responsible for preventing vitiligo (IL10, CTLA4, FOXP3). Furthermore, we detected positive correlations between infiltrating T cells and changes in their T cell receptor diversity supporting a T cell-specific immune response., Conclusion: Collectively, these results further support the notion of cell-mediated immune destruction of epidermal melanocytes in the pulp of growing feathers and open new avenues of study in the vitiligo-prone Smyth and vitiligo-susceptible Brown line chickens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Falcon, Byrne, Sales and Erf.)

Both alopecia areata (AA) and vitiligo are distinct, heterogenous, and complex disease entities, characterized by nonscarring scalp terminal hair loss and skin pigment loss, respectively. In AA, inflammatory cell infiltrates are in the deep reticular dermis close to the hair bulb (swarm of bees), whereas in vitiligo the inflammatory infiltrates are in the epidermis and papillary dermis. Immune privilege collapse has been extensively investigated in AA pathogenesis, including the suppression of immunomodulatory factors (e.g., transforming growth factor-β (TGF-β), programmed death-ligand 1 (PDL1), interleukin-10 (IL-10), α-melanocyte-stimulating hormone (α-MSH), and macrophage migration inhibitory factor (MIF)) and enhanced expression of the major histocompatibility complex (MHC) throughout hair follicles. However, immune privilege collapse in vitiligo remains less explored. Both AA and vitiligo are autoimmune diseases that share commonalities in pathogenesis, including the involvement of plasmacytoid dendritic cells (and interferon-α (IFN- α) signaling pathways) and cytotoxic CD8+ T lymphocytes (and activated IFN-γ signaling pathways). Blood chemokine C-X-C motif ligand 9 (CXCL9) and CXCL10 are elevated in both diseases. Common factors that contribute to AA and vitiligo include oxidative stress, autophagy, type 2 cytokines, and the Wnt/β-catenin pathway (e.g., dickkopf 1 (DKK1)). Here, we summarize the commonalities and differences between AA and vitiligo, focusing on their pathogenesis.

Vitiligo is a chronic skin condition marked by the gradual loss of pigmentation, leading to the emergence of white or depigmented patches on the skin. The exact cause of vitiligo remains not entirely understood, although it is thought to involve a blend of genetic, autoimmune, and environmental factors. While there is currently no definitive cure for vitiligo, diverse treatments exist that may assist in managing the condition and fostering repigmentation in specific instances. Animal models play a pivotal role in comprehending the intricate mechanisms that underlie vitiligo, providing valuable insights into the progression and onset of the disease, as well as potential therapeutic interventions. Although induced experimental models lack the nuanced characteristics observed in natural experimental models, relying solely on a single animal model might not fully capture the intricate pathogenesis of vitiligo. Different animal models simulate specific aspects of human vitiligo pathogenesis to varying degrees. This review extensively explores the array of animal models utilized in vitiligo research, shedding light on their respective advantages, disadvantages, and applications., Competing Interests: Declaration of competing interest We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023. Published by Elsevier B.V.)

Vitiligo is a T cell-mediated depigment skin disease caused by the complex interplay between melanocyte dysfunction, environmental stimulation, and dysregulated immune signals. Transforming growth factor-β1 (TGF-β1), which typically derives from regulatory T cells, has long been identified at low levels in the peripheral system of vitiligo patients. Here, through RNA-sequencing and transcription factor enrichment, we revealed that in response to CD8 + T cell-secreted interferon-gamma (IFN-γ), stromal fibroblast downregulates early growth response 1 (EGR1) activity, leading to TGF-β1 deficiency. The defective immune regulation loop further exacerbated local CD8 + T cell inflammation and promoted inflammatory cell migration in vitiligo. Thus, fibroblast-derived TGF-β1 plays an important stromal signal in vitiligo pathogenesis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The melanocyte-keratinocyte transplantation procedure (MKTP) treats stable and recalcitrant vitiligo. Despite careful selection of candidates based on clinical stability, the success of the procedure is unpredictable. The aim of our study was to define the immunological profile of stable vitiligo lesions undergoing MKTP and correlate them with clinical outcomes. We included 20 MKTP candidates with vitiligo and a patient with piebaldism as a control. Prior to MKTP, T-cell subsets and chemokines in the recipient skin were measured by flow cytometry and ELISA. During MKTP, melanocytes in the donor skin were quantified by flow cytometry. After MKTP, patients were followed for 12 months and repigmentation was assessed clinically and by ImageJ analysis of clinical photographs. Baseline immunologic biomarkers, duration of clinical stability, and transplanted melanocyte number were correlated to postsurgical repigmentation scores. CD8+ T cells were elevated in 43% of the clinically stable vitiligo lesions. CD8+ T-cell number negatively correlated with postsurgical repigmentation scores (r = -0.635, P = 0.002). Duration of clinical stability, skin chemokines, and transplanted melanocyte number did not influence postsurgical repigmentation. This study demonstrates that CD8+ T-cell number correlates negatively with success of postsurgical repigmentation and can be a biomarker to identify ideal surgical candidates., (Copyright © 2023. Published by Elsevier Inc.)

The skin is exposed to environmental challenges and contains skin-resident immune cells, including mast cells (MCs) and CD8 T cells that act as sentinels for pathogens and environmental antigens. Human skin MCs and their mediators participate in the maintenance of tissue homeostasis and regulate the recruitment and activity of immune cells involved in the pathogenesis of skin diseases. The cutaneous CD8 T cell compartment is comprised of long-persisting resident memory T cells (T RM ) and migratory or recirculating cells; both populations provide durable site immune surveillance. Several lines of evidence indicate that MC-derived products, such as CCL5 and TNF-α, modulate the migration and function of CD8 T cells. Conversely, activated CD8 T cells induce the upregulation of MC costimulatory molecules. Moreover, the close apposition of MCs and CD8 T cells has been recently identified in the skin of several dermatoses, such as alopecia areata. This review outlines the current knowledge about bidirectional interactions between human MCs and CD8 T cells, analyses the alteration of their communication in the context of three common skin disorders in which these cells have been found altered in number or function-psoriasis, atopic dermatitis, and vitiligo-and discusses the current unanswered questions.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment 1-3 . Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body 4-6 . Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8 + T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8 + cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Vitiligo is an autoimmune disease of the skin characterized by epidermal melanocyte loss resulting in white patches, with an approximate prevalence of 0.5-2% worldwide. Several precipitating factors by chemical exposure and skin injury present commonly in patients with vitiligo. Although the diagnosis appears to be straightforward for the distinct clinical phenotype and specific histological features, vitiligo provides many challenges including chronicity, treatment resistance, frequent relapse, associated profound psychosocial effect, and negative impact on quality of life. Multiple mechanisms are involved in melanocyte disappearance, including genetics, environmental factors, and immune-mediated inflammation. Compelling evidence supports the melanocyte intrinsic abnormalities with poor adaptation to stressors leading to instability and release of danger signals, which will activate dendritic cells, natural killer cells, and innate lymphoid cells to initiate innate immunity, ultimately resulting in T-cell mediated adaptive immune response and melanocyte destruction. Importantly, the cross- talk between keratinocytes, melanocytes, and immune cells, such as interferon (IFN)-γ signaling pathway, builds inflammatory loops that give rise to the disease deterioration. Improved understanding of the immune pathogenesis of vitiligo has led to the development of new therapeutic options including Janus kinase (JAK) inhibitors targeting IFN-γ signaling pathways, which can effectively reverse depigmentation. Furthermore, definition of treatment goals and integration of comorbid diseases into vitiligo management have revolutionized the way vitiligo is treated. In this review, we highlight recent developments in vitiligo clinical aspects and immune pathogenesis. Our key objective is to raise awareness of the complexity of this disease, the potential of prospective therapy strategies, and the need for early and comprehensive management., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study aims to explore biomarkers associated with vitiligo and analyze the pathological role of immune cell infiltration in the disease. We used the robust rank aggregation (RRA) method to integrate three vitiligo data sets downloaded from gene expression omnibus database, identify the differentially expressed genes (DEGs) and analyze the functional correlation. Then, the comprehensive strategy of combined weighted gene coexpression network analysis (WGCNA) and logical regression of the selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) machine learning algorithm are employed to screen and biomarkers associated with vitiligo. Finally, the immune cell infiltration of vitiligo was evaluated by CIBERSORT, and the correlation between biomarkers and infiltrating immune cells was analyzed. Herein, we identified 131 robust DEGs, and enrichment analysis results showed that robust DEGs and melanogenesis were closely associated with vitiligo development and progression. TYR, TYRP1, DCT and LARP7 were identified as vitiligo-related biomarkers. Immune infiltration analysis demonstrated that CD4 T Cell, CD8 T Cell, Tregs, NK cells, dendritic cells, and macrophages were involved in vitiligo's pathogenesis. In summary, we adopted a comprehensive strategy to screen biomarkers related to vitiligo and explore the critical role of immune cell infiltration in vitiligo. Abbreviations : TYR, Tyrosinase; TYRP1, Tyrosinase-related protein-1; DCT, dopachrome tautomerase; LARP7, La ribonucleoprotein domain family, member-7; RRA, robust rank aggregation; DEGs, differentially expressed genes; WGCNA, weighted gene coexpression network analysis; LASSO, logical regression of the selection operator; SVM-RFE, support vector machine recursive feature elimination; RF, random forest; GWAS, Genome-wide association study; FasL, Fas-Fas ligand; Tregs, T-regulatory cells; NK, natural killer; GEPCs, gene expression profiling chips; GO, gene ontology; GSEA, gene set enrichment analysis; FDR, false discovery rate; AUC, area under the curve; ROC, receiver-operating characteristic; BP, biological process; CC, cellular component; MF, molecular function.

Vitiligo shows insufficient response to current therapies largely owing to T-lymphocyte dysfunction, abnormal inflammatory activation, and excessive oxidative stress in lesions. Cold atmospheric plasma (CAP) possesses pleiotropic antioxidant and anti-inflammatory properties and may offer an improvement to current treatment options. In this study, the efficacy and safety of CAP were investigated in a mouse model of vitiligo and a randomized and controlled trial of patients with active focal vitiligo. Skin biopsies showed that topical treatment of vitiligo-like lesions on mouse dorsal skin by CAP restored the distribution of melanin. In addition, CAP treatment reduced the infiltration of CD11c + dendritic cells, CD3 + T cells, and CD8 + T cells; inhibited the release of CXCL10 and cytokine IFN-γ; and enhanced cellular resistance to oxidative stress and excessive immune response by enhancing the expression of the transcription factor NRF2 and attenuating the activity of inducible nitric oxide synthase. In a randomized and controlled trial, CAP treatment achieved partial and complete repigmentation in 80% and 20% of vitiligo lesions, respectively, without hyperpigmentation in surrounding areas or other adverse events during the treatment period and its follow-up period. In conclusion, CAP offers a promising option for the management of vitiligo., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In autoimmune onset of vitiligo, perilesional area shows inflammatory cells including T cytotoxic, helper cells and macrophages. Dendritic Cells (DCs) regulate immune activities by antigen presentation to T cells or cytokine production. It is evident that pro- and anti-inflammatory DCs are responsible for their respective cytokines release. However, role of DCs in vitiligo is enigmatic. In the present study, we assessed DCs markers (CD11b and CD11c) along with pro- and anti-inflammatory cytokines (IL-17A, IL-10 and IL-12p70) in stable and active vitiligo patients. Our results revealed a significant augmented expression of CD11b + CD11c + (pro-inflammatory DC) in peripheral blood mononuclear cells (PBMCs) and skin tissues of active vitiligo patients versus control and stable vitiligo group. Unlikely, CD11b + (anti-inflammatory DC) levels were significantly impeded in active vitiligo group as compared to another two groups. CD11c (T helper 1 stimulating DC) presented no significant alterations in any group. Furthermore, we perceived significantly up-regulated IL-17A (pro-inflammatory cytokine) and down-regulated IL-10 (anti-inflammatory cytokine) expressions in active vitiligo group as compared to control and stable group (in sera, PBMCs and skin tissue). Also, a significant positive correlation was observed between CD11b + CD11c + and IL-17A; and CD11b + and IL-10. Contrarily, CD11b + CD11c + and CD11b + were negatively correlated with IL-10 and IL-17A, respectively. In conclusion, modulation of pro- and anti-inflammatory DCs in active vitiligo patients may affect cytokines production and thereby, lead to further depigmentation of skin., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitiligo is an autoimmune skin disease characterized by the targeted destruction of melanocytes by T cells. Cytokine signaling between keratinocytes and T cells results in CD8 + T cell infiltration of vitiligo lesions, but the full scope of signals required to coordinate autoimmune responses is not completely understood. We performed single-cell RNA sequencing on affected and unaffected skin from patients with vitiligo, as well as healthy controls, to define the role of each cell type in coordinating autoimmunity during disease progression. We confirmed that type 1 cytokine signaling occupied a central role in disease, but we also found that this pathway was used by regulatory T cells (T regs ) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8 + T cells and T regs , and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on T regs was required to suppress disease in vivo but not in vitro. CCR5 was not required for T reg recruitment to skin but appeared to facilitate T reg function by properly positioning these cells within the skin. Our data provide critical insights into the pathogenesis of vitiligo and uncover potential opportunities for therapeutic interventions.

Vitiligo is an autoimmune disease characterized by patchy, white skin owing to melanocyte loss. Commensal cutaneous or gut dysbiosis has been linked to various dermatological disorders. In this study, we studied the skin and gut microbiota of patients with vitiligo compared with those of healthy controls. We obtained swabs and biopsies from both lesional and nonlesional skin as well as stool and blood samples from each individual. We detected reduced richness and diversity of microbiota in the stools of subjects with vitiligo compared with the stools of the controls (P < 0.01). Skin swabs had greater α-diversity than biopsies (P < 0.001); swabs from lesional sites were primarily depleted of Staphylococcus compared with those from nonlesional sites (P < 0.02). Sampling deeper layers from the same patients showed differences in both α- and β-diversity between samples with decreased richness and distribution of species (P < 0.01) in the lesional site. Biopsy microbiota from the lesional skin had distinct microbiota composition, which was depleted of protective Bifidobacterium and Bacteroides but was enriched in Proteobacteria, Streptococcus, Mycoplasma, and mtDNA (P < 0.001); the latter increased in the same patients with heightened innate immunity and stress markers in their blood (P < 0.05). These data describe vitiligo-specific cutaneous and gut microbiota and a link between skin dysbiosis, mitochondrial damage, and immunity in patients with vitiligo., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune dysregulation is critical in vitiligo pathogenesis. Although the presence and roles of numerous CD4 + T-cell subsets have been described, the presence of Th9 cells and more importantly, roles of IL-9 on melanocyte functions are not explored yet. Here, we quantified the T helper cell subsets including Th9 cells in vitiligo patients by multicolor flowcytometry. There was an increased frequency of skin-homing (CLA + ) and systemic (CLA - ) Th9 cells in vitiligo patients compared to healthy donors. However, there was no difference in Th9 cell frequency in vitiligo patients with early and chronic disease. There was negligible IL-9 receptor (IL-9R) expression on human primary melanocytes (HPMs); however, IFNγ upregulated IL-9R expression on HPMs. Functionally, IL-9/IL-9R signaling reduced the production of IFNγ-induced toxic reactive oxygen species (ROS) in HPMs. There was no effect of IL-9 on expression of genes responsible for melanosome formation (MART1, TYRP1, and DCT), melanin synthesis (TYR), and melanocyte-inducing transcription factor (MITF) in HPMs. In conclusion, this study identifies the presence of Th9 cells in vitiligo and their roles in reducing the oxidative stress of melanocytes, which might be useful in designing effective therapeutics., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitiligo, an autoimmune disorder, is associated with altered cytokine levels and T lymphocytes. Lenalidomide modulates immune system components by altering cytokine production and regulating T-cell stimulation. In this study, effect of lenalidomide was checked on the development of vitiligo lesions, level of various cytokines, and T lymphocytes in the mouse model. The vitiligo mouse model was developed by immunizing C57BL/6 mouse with anti-mouse tyrosine-related protein 2. Lenalidomide was orally given to mice daily, and the effect was observed on the development of vitiligo lesions. The level of T lymphocytes in blood was checked by flow cytometry. Serum cytokine levels were checked by enzyme-linked immunosorbent assay. Vitiligo lesions were found significantly smaller in lenalidomide-treated mice models. It significantly decreased the serum levels of IFN-γ, TNF-α, IL-1β, and IL-6 but elevated the levels of IL-4 and IL-10. It non-significantly elevated CD4 + /CD8 + T-cell ratio. Lenalidomide had an inhibitory effect on the development of vitiligo lesions in mice models by suppressing the serum level of pro-inflammatory cytokines and increasing anti-inflammatory cytokine levels. It modulated the immune response in vitiligo mice models toward an anti-inflammatory profile suggesting its use in the management of vitiligo., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In health, the non-recirculating nature and long-term persistence of tissue-resident memory T cells (TRMs) in tissues protects against invading pathogens. In disease, pathogenic TRMs contribute to the recurring traits of many skin diseases. We aimed to conduct a systematic literature review on the current understanding of the role of TRMs in skin diseases and identify gaps as well as future research paths. EMBASE, PubMed, SCOPUS, Web of Science, Clinicaltrials.gov and WHO Trials Registry were searched systematically for relevant studies from their inception to October 2020. Included studies were reviewed independently by two authors. This study was conducted in accordance with the PRISMA-S guidelines. This protocol was registered with the PROSPERO database (ref: CRD42020206416). We identified 96 studies meeting the inclusion criteria. TRMs have mostly been investigated in murine skin and in relation to infectious skin diseases. Pathogenic TRMs have been characterized in various skin diseases including psoriasis, vitiligo and cutaneous T-cell lymphoma. Studies are needed to discover biomarkers that may delineate TRMs poised for pathogenic activity in skin diseases and establish to which extent TRMs are contingent on the local skin microenvironment. Additionally, future studies may investigate the effects of current treatments on the persistence of pathogenic TRMs in human skin.

Both systemic inflammation and oxidative stress play crucial roles in the pathogenesis of vitiligo. In recent studies, monocyte to high-density lipoprotein cholesterol ratio (MHR), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), mean platelet volume (MPV) and plateletcrit (PCT) have been shown to reflect inflammation and oxidative stress in chronic inflammatory and autoimmune diseases. In this study, we aimed to investigate the hematological and inflammatory parameters in patients with vitiligo and to evaluate their possible relationship with disease severity. The parameters including MHR, MLR, NLR, PLR, MPV, and PCT were retrospectively investigated in patients with vitiligo and healthy controls. Disease severity was evaluated using the vitiligo extent tensity index (VETI) score. A total of 180 patients with vitiligo, and age-gender-matched 180 healthy controls were enrolled in the study. MHR, MLR, PLR, PCT values were found to be significantly higher in patients with vitiligo (p < 0.05). MPV and NLR values showed no statistically significant difference between the two groups. A positive correlation was also detected between MHR and MLR values, disease duration, and VETI score (p < 0.05). We suggest that MHR and MLR can be used as markers of inflammation and oxidative stress in patients with vitiligo. Both markers may also reflect disease severity.

The objective of this meta-analysis was performed to compare the effects of tacrolimus plus phototherapy in the treatment of patients with vitiligo. Relevant studies were identified by searching PubMed, Embase, and Web of Science databases. The main outcomes of interest included excellent response (≥ 75% repigmentation), good response (50-75% repigmentation), moderate response (25%-50% repigmentation), and poor response (< 25% repigmentation). Risk ratio (RR) with 95% confidence intervals (95% CIs) was used to calculate the data. Eleven studies were included in this study. Compared with phototherapy alone, combination treatment of tacrolimus and phototherapy significantly improved excellent response rate (RR = 1.40, 95% CI 1.16, 1.69; P < 0.001) and reduced the poor response rate (RR = 0.37, 95% CI 0.22, 0.61; P = 0.001). However, the good response rate (RR = 1.00, 95% CI 0.59, 1.69, P = 1.000) and moderate response rate (RR = 0.91, 95% CI 0.60, 1.38; P = 0.653) were not significantly different between the two treatments. Subgroup analysis suggested that combination treatment had a higher excellent response rate than phototherapy alone for lesions located in the face and proximal limbs. Both NB-UVB and EL, when added to tacrolimus, resulted in a significantly higher excellent response rate than they were used alone. Meta-regression analysis showed that age was a predictive factor that influenced the effect of combination treatment on an excellent response, in which children had a high excellent response to the treatment. Other demographic and clinical variables, including gender, disease duration, family history, and type of vitiligo, did not have any impact on the treatment effect. Combination treatment with tacrolimus and phototherapy was more effective than phototherapy monotherapy for patients with vitiligo, especially in the lesions located in the face and proximal limbs. More large-scale, well-performed trials are needed to verify our findings.

Several studies demonstrated a major pathological role of melanocyte-specific cytotoxic CD8 + T cells in the pathogenesis of vitiligo. It has been suggested that apoptosis, rather than necrosis, is the mechanism of melanocyte depletion in vitiligo. The aim of this study was to evaluate the expression and distribution of perforin and apoptosis stimulation fragment ligand (FasL) in the epidermis and dermis of the perilesional and non-lesional skin of vitiligo patients in comparison to controls, to assess their possible role in mediating apoptosis in vitiligo. Twenty patients with active non-segmental vitiligo and 20 healthy controls were enrolled in the study. Skin biopsies were taken from perilesional and non-lesional skin of patients with vitiligo, as well as covered skin of controls. Immunostaining for perforin and FasL was performed and the quantitative analysis for the expression of perforin and FasL was carried out in the epidermis and dermis of biopsied specimens. Epidermal perforin, dermal perforin, epidermal FasL, dermal FasL were significantly higher in perilesional as well as non-lesional skin than controls. There was a statistically significant positive correlation between epidermal and dermal perforin in perilesional skin. There was a statistically significant positive correlation between epidermal and dermal perforin, as well as epidermal and dermal FasL in non-lesional skin. In conclusion, the significant expression of perforin and FasL in the epidermis and dermis of both perilesional and non-lesional skin of active vitiligo patients suggests the role of cytotoxic granules and apoptotic cell death pathways in the pathogenesis of active vitiligo.

Vitiligo is an autoimmune skin disease in which epidermal melanocytes are targeted for destruction by CD8 + T cells specific for melanocyte/melanoma-shared antigens. IFNγ is the central cytokine driving disease, but the role of type I IFN in vitiligo remains unclear. We investigated the functional role of type I IFN during vitiligo progression using two different mouse models: one induced with a vaccinia virus (VV) vaccine and one induced with dendritic cells to prime autoimmune T cells. Induction of vitiligo by VV in IFNaR-deficient mice led to the development of severe vitiligo compared with wild-type (WT) mice and was characterized by a significantly enhanced effector CD8 + T-cell response. Severe vitiligo in this model was a result of VV persistence, because exacerbation of disease in IFNaR-deficient mice was not observed when antigen-pulsed dendritic cells were used to induce vitiligo instead of virus. Treatment of B16F10 melanoma-inoculated mice with VV vaccine therapy also induced a significantly enhanced anti-tumor response in IFNaR-deficient mice compared with WT. These results not only help define the pathways responsible for vitiligo progression but also suggest that blockade of type I IFNs following administration of a VV vaccine may provide increased immunogenicity and efficacy for melanoma immunotherapy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This is an exciting phase of vitiligo research with the current understanding of vitiligo pathogenesis and its translation to successful treatment. The pathogenetic origin of vitiligo revolves around autoimmunity with supporting role from many other factors like oxidative stress, inherent melanocyte defects, or defective keratinocytes and fibroblasts. Vitiligo can be classified into segmental or non-segmental depending upon the clinical presentation, or it can be classified as progressing or stable based on the activity of the disease. Vitiligo treatments need to be stratified depending upon which type of vitiligo we are treating and at which phase the vitiligo patient presents to us. There are two different aims of treatment of vitiligo. The first involves rescuing the melanocytes from the damage to arrest the depigmentation. The second strategy focuses on replenishing the melanocytes so that successful repigmentation is achieved. It is also important to maintain the disease in a stable phase or prevent relapse. As stability in non-segmental vitiligo is a dynamic process, maintenance of the stability of repigmentation is also an important consideration in the management of vitiligo. In this review, we shall briefly discuss the current options and future insight into the management of vitiligo., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: JH is a Scientific Founder of Villaris Therapeutics, Inc. JS and KB received financial support from Sanofi Genzyme and Calypso Biotech that is separate from this proposed editorial. IP is the CSO for Temprian Therapeutics, a company hoping to bring an HSP70iQ435A-based treatment to clinical trials for vitiligo. The approach for this treatment is different and separate from the proposed Research Topic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

In this review we show how the neuronal theory is relevant to the convergence theory for the mechanism causing vitiligo, especially the segmental type. Neuropeptides and neurotransmitters, such as neuropeptide Y and dopamine, can be central to the pathological mechanisms of melanocyte destruction. They link into a bidirectional network connecting cutaneous nerves, the neuroendocrine axis and the immune system, and through their local influence on cutaneous inflammation, to the antigen-specific regulatory T cells and the chemokine ligand type 9/chemokine receptor type 1 axis, which is thought to be the final pathway for melanocyte destruction., (© 2020 British Association of Dermatologists.)

Self-specific CD8 + T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8 + T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct , which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/K b -specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct -deficient ( Dct -/- ) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/K b -specific cells showed blunted expansion and less readily differentiated into a CD25 + proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/K b -specific cells mediated vitiligo much less efficiently. Hence, CD8 + T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells., Competing Interests: ET, KB, TK, HB, KB, SO, KS, KR, SJ No competing interests declared, AH is affiliated with AgenTus Therapeutics, Inc. The author has no financial interests to declare. RF is affiliated with HiFiBio, Inc. The author has no financial interests to declare.

T cell-mediated autoimmune skin diseases develop as a result of the aberrant immune response to the skin cells with T cells playing a central role. These chronic inflammatory skin diseases encompass various types including psoriasis, lichen planus and vitiligo. These diseases show similarities in their immune-pathophysiology. In the last decade, immunomodulating agents have been very successful in the management of these diseases thanks to a better understanding of the pathophysiology. In this review, we will discuss the immunopathogenic mechanisms and highlight the role of T lymphocytes in psoriasis, lichen planus and vitiligo. This study could provide new insights into a better understanding of targeted therapeutic pathways and biological therapies., (© 2020 The Scandinavian Foundation for Immunology.)

Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past 30 years, but only through perseverance, collaboration, and open-minded discussion. Early hypotheses considered roles for innervation, microvascular anomalies, oxidative stress, defects in melanocyte adhesion, autoimmunity, somatic mosaicism, and genetics. Because theories about pathogenesis drive experimental design, focus, and even therapeutic approach, it is important to consider their impact on our current understanding about vitiligo. Animal models allow researchers to perform mechanistic studies, and the development of improved patient sample collection methods provides a platform for translational studies in vitiligo that can also be applied to understand other autoimmune diseases that are more difficult to study in human samples. Here we discuss the history of vitiligo translational research, recent advances, and their implications for new treatment approaches., Competing Interests: JEH is a consultant for Pfizer, Genzyme/Sanofi, Aclaris Therapeutics Inc, Incyte, Rheos Medicines, Sun Pharmaceuticals, LEO Pharma, Villaris Therapeutics Inc, Dermavant, Temprian, AbbVie Inc, Janssen, TeVido BioDevices, EMD Serono, Almirall, Boston Pharma, Sonoma Biotherapeutics Inc, Methuselah Health, Twi Biotech, Pandion, Cogen Therapeutics Inc, Admirx, BridgeBio, AnaptysBio, Avita, and Frazier Management. JEH is an investigator for Pfizer, Genzyme/Sanofi, Aclaris Therapeutics Inc, Incyte, Rheos Medicines, Sun Pharmaceuticals, LEO Pharma, Villaris Therapeutics Inc, Dermavant, AbbVie, TeVido BioDevices, EMD Serono, and Pandion. JEH is scientific founder of Villaris Therapeutics, Inc, which develops therapeutic treatments for vitiligo, and NIRA Biosciences. JEH is an inventor on patent #62489191 “Diagnosis and Treatment of Vitiligo” that includes targeting IL-15 and Trm for treatment of vitiligo, as well as #067988 “Anti-Human CXCR3 Antibodies for Treatment of Vitiligo” and #029531 “Compositions and Methods for Treating Vitiligo”. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Katz and Harris.)

Vitiligo, the most common depigmenting disorder of the skin, is undergoing a period of intense advances in both disease understanding and therapeutic possibilities leading the way to the beginning of a new era for the disorder. Its pathophysiology has gathered the attention of researchers for years, and many advances have been made in the clarification of the interaction between different factors that result in depigmented macule formation. The complex interplay between non-immunological and immunological factors in vitiligo is key for the development of the disease, and the participation of cells other than melanocytes, such as keratinocytes, fibroblasts, natural killer cells, and innate lymphoid cells, has been shown. Recent advances have also brought to the understanding of the complex part played by a specific subtype of T cells: T-resident memory cells. This review analyzes some of the most recent insights in vitiligo pathogenesis underlining the interactions between different cell types, which are the basis for the therapeutic approaches under development., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Vitiligo is an acquired multifactorial disease that affects melanocytes and results in skin depigmentation. In this review, we examine the role of cells stress and self-reactive T cells responses. Given the canonical and non-canonical functions of NKG2D, such as authenticating stressed target and enhance TCR signaling, we examine how melanocyte stress leads to the expression of ligands that are recognized by the activating receptor NKG2D, and how its signaling results in the turning of T cells against self (melanocyte suicide by proxy). We also discuss how this initiation phase is followed by T cell perpetuation, as NKG2D signaling results in self-sustained long-lasting T cells, with improved cytolytic properties., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Plaza-Rojas and Guevara-Patiño.)

Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jadeja, Mayatra, Vaishnav, Shukla and Begum.)