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The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell-mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-γ-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose of Review: Vitiligo and alopecia areata are common, disfiguring skin diseases. Treatment options are limited and include nontargeted approaches, such as corticosteroids, topical calcineurin inhibitors, narrow band ultraviolet B phototherapy, and other immune-modifying agents. The purpose of this article is to review shared, novel mechanisms between vitiligo and alopecia areata, as well as discuss how they inform the development of future targeted treatments., Recent Findings: Vitiligo and alopecia areata are both autoimmune diseases, and striking similarities in pathogenesis have been identified at the level of both the innate and adaptive immune system. Increased reactive oxygen species and high cellular stress level have been suggested as the initiating trigger of the innate immune system in both diseases, and genome-wide association studies have implicated risk alleles that influence both innate and adaptive immunity. Most importantly, mechanistic studies in mouse models of vitiligo and alopecia areata have specifically implicated an interferon (IFN)γ-driven immune response, including IFNγ, IFNγ-induced chemokines, and cytotoxic CD8 T cells as the main drivers of disease pathogenesis. These recent discoveries may reveal an effective strategy to develop new treatments, and several proof-of-concept clinical studies support this hypothesis., Summary: The identification of IFNγ-driven immune signaling pathways has enabled discoveries of potential new treatments for vitiligo and alopecia areata, and supports initiation of larger clinical trials.

For decades, research in autoimmunity has focused primarily on immune contributions to disease. Yet recent studies report elevated levels of reactive oxygen species and abnormal activation of the unfolded protein response in cells targeted by autoimmunity, implicating cellular stress originating from the target tissue as a contributing factor. A better understanding of this contribution may help to answer important lingering questions in organ-specific autoimmunity, as to what factors initiate disease and what directs its tissue specificity. Vitiligo, an autoimmune disease of the skin, has been the focus of translational research for over 30 years, and both melanocyte stress and immune mechanisms have been thought to be mutually exclusive explanations for pathogenesis. Chemical-induced vitiligo is a unique clinical presentation that reflects the importance of environmental influences on autoimmunity, provides insight into a new paradigm linking cell stress to the immune response, and serves as a template for other autoimmune diseases. In this review, I will discuss the evidence for cell stress contributions to a number of autoimmune diseases, the questions that remain, and how vitiligo, an underappreciated example of organ-specific autoimmunity, helps to answer them., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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. [ABSTRACT FROM AUTHOR]

Tissue resident memory T cells (TRM) are a critical component of the immune system, providing the body with an immediate and highly specific response against pathogens re-infecting peripheral tissues. More recently, however, it has been demonstrated that TRM cells also form during autoimmunity. TRM mediated autoimmune diseases are particularly destructive, because unlike foreign antigens, the self-antigens are never cleared, continuously activating self-reactive TRM T cells. In this article, we will focus on how TRMs mediate disease in autoimmune skin conditions, specifically vitiligo, psoriasis, cutaneous lupus erythematosus, alopecia areata and frontal fibrosing alopecia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disease of the skin that targets pigment-producing melanocytes and results in patches of depigmentation that are visible as white spots. Recent research studies have yielded a strong mechanistic understanding of this disease. Autoreactive cytotoxic CD8+ T cells engage melanocytes and promote disease progression through the local production of IFN-γ, and IFN-γ-induced chemokines are then secreted from surrounding keratinocytes to further recruit T cells to the skin through a positive-feedback loop. Both topical and systemic treatments that block IFN-γ signaling can effectively reverse vitiligo in humans; however, disease relapse is common after stopping treatments. Autoreactive resident memory T cells are responsible for relapse, and new treatment strategies focus on eliminating these cells to promote long-lasting benefit. Here, we discuss basic, translational, and clinical research studies that provide insight into the pathogenesis of vitiligo, and how this insight has been utilized to create new targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Summary: Autoimmune skin diseases are complex processes in which autoreactive cells must navigate through the skin tissue to find their targets. Regulatory T cells in the skin help to mitigate autoimmune inflammation and may in fact be responsible for the patchy nature of these conditions. In this review, we will discuss chemokines that are important for global recruitment of T cell populations to the skin during disease, as well as signals that fine‐tune their localization and function. We will describe prototypical disease responses and chemokine families that mediate these responses. Lastly, we will include an overview of chemokine‐targeting drugs that have been tested as new treatment strategies for autoimmune skin diseases. [ABSTRACT FROM AUTHOR]

Vitiligo is an autoimmune disease of the skin that is characterized by patchy depigmentation (i.e., white spots) and results from the loss of melanocytes, which are pigment-producing cells. The pathogenesis of human vitiligo consists of an interaction between intrinsic melanocyte defects, environmental factors, and autoimmune mechanisms that target these cells for destruction. Human clinical and translational studies have outlined pathways that are important in human disease; however, combining human correlative studies with mechanistic studies in representative preclinical animal models is a powerful approach to study disease pathogenesis and develop new treatments. Because of the complex pathogenesis of vitiligo, it is unlikely that any one single animal model will adequately reflect all factors implicated in the initiation, progression, and maintenance of the disease. Therefore, vitiligo is best modeled by multiple systems—each with its strengths and weaknesses—that allow insight into specific components of vitiligo pathogenesis. In this paper, we describe some of the available animal models that have been developed to study vitiligo. [ABSTRACT FROM AUTHOR]

Vitiligo and alopecia areata are common autoimmune diseases of the skin. Vitiligo is caused by the destruction of melanocytes and results in the appearance of white patches on any part of the body, while alopecia areata is characterized by patchy hair loss primarily on the scalp, but may also involve other areas as well. At first glance, the two diseases appear to be quite different, targeting different cell types and managed using different treatment approaches. However, the immune cell populations and cytokines that drive each disease are similar, they are closely associated within patients and their family members, and vitiligo and alopecia areata have common genetic risk factors, suggesting that they share a similar pathogenesis. Like apples and oranges, vitiligo and alopecia areata have some obvious differences, but similarities abound. Recognizing both similarities and differences will promote research into the pathogenesis of each disease, as well as the development of new treatments. [ABSTRACT FROM AUTHOR]

Background Vitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies. Objective To investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects. Methods Patient skin was sampled via a modified suction-blister technique, allowing for minimally invasive, objective assessment of cytokines and T-cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups. Results In screening and validation, CD8 + T-cell number and C-X-C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T-cell infiltrate, which overwhelmingly expresses C-X-C motif chemokine receptor 3. Limitations A small number of patients were enrolled for the study, and only a single patient was used to define the treatment response. Conclusion Measuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction-blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification. [ABSTRACT FROM AUTHOR]

Highlights: [•] Melanocytes from vitiligo patients display features of elevated cellular stress. [•] Stressed cells produce damage-associated molecular patterns (DAMPs). [•] DAMPs activate innate immune cell populations through pattern recognition receptors. [•] Activated innate immune cells can promote adaptive immunity in vitiligo. [•] Activated stress pathways appear to play a role in organ-specific autoimmunity. [ABSTRACT FROM AUTHOR]

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9. [ABSTRACT FROM AUTHOR]