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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., Competing Interests: JH is the founder of Villaris Therapeutics and NIRA Biosciences. JH and JR are inventors on patent application #62489191, “Diagnosis and Treatment of Vitiligo” which covers targeting IL-15 and TRM for the treatment of vitiligo; and on patent application #15/851,651, “Anti-human CXCR3 antibodies for the Treatment of Vitiligo” which covers targeting CXCR3 for the treatment of vitiligo. JR is a reviewer for Frontiers Immunology journal., (Copyright © 2021 Ryan, Harris and Richmond.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 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., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction/Background Vitiligo is a chronic autoimmune disease characterized by melanocyte destruction, leading to skin depigmentation. Limited data are available regarding the efficacy of long-term topical vitiligo treatment. In 2 randomized, double-blinded, vehicle-controlled phase 3 studies in adults and adolescents (aged ≥12 y) with nonsegmental vitiligo (TRuE-V1 [NCT04052425]; TRuE-V2 [NCT04057573]), ruxolitinib cream application resulted in statistically superior improvements in repigmentation versus vehicle in the primary and all key secondary endpoints at Week 24 and was well tolerated. In the open-label period of TRuE-V1/TRuE-V2 (Weeks 24-52) and the TRuE-V long-term extension (LTE; Weeks 52-104) study (NCT04530344), further improvements in facial and body repigmentation (as assessed by Vitiligo Area Scoring Index [VASI] responses) were observed through Week 104 among patients who continued to apply ruxolitinib cream. Objectives: In this pooled analysis, we evaluated shifts in facial and total body VASI (F-VASI/T-VASI) responses among patients with vitiligo who had limited or no repigmentation at Week 24 and who continued to apply ruxolitinib cream for an additional 80 weeks. Methods: In TRuE-V1/TRuE-V2, patients were randomized 2:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply 1.5% ruxolitinib cream through Week 52. Patients who completed TRuE-V1/TRuE-V2 were eligible to enroll in the TRuE-V LTE. Patients who did not achieve ≥90% improvement in F-VASI at Week 52 continued to apply open-label 1.5% ruxolitinib cream until Week 104. Patients initially randomized to apply ruxolitinib cream who had <25% improvement from baseline in F-VASI or T-VASI at Week 24 and had non-missing VASI assessments at the evaluated time points were included in this analysis. Shifts in F-VASI and T-VASI were assessed among patients with no facial/body repigmentation or worsening depigmentation (≤0% improvement in F-VASI/T-VASI) and patients with limited facial/body repigmentation (>0%- <25% improvement in F-VASI/T-VASI) at Week 24. Results: Among patients with no facial repigmentation at Week 24, improvements in F-VASI at Weeks 52 and 104 were observed in 77.8% (49/63) and 97.1% (34/35) of patients, respectively. Among patients with limited facial repigmentation at Week 24, F-VASI improvements at Weeks 52 and 104 were observed in 64.0% (32/50) and 83.3% (30/36) of patients, respectively. Across both groups, 54.9% (39/71) of patients achieved =75% improvement from baseline in F-VASI (F-VASI75) at Week 104. Among those with no body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 79.6% (39/49) and 93.3% (28/30) of patients, respectively. For those with limited body repigmentation at Week 24, T-VASI improvements at Weeks 52 and 104 were observed in 64.5% (80/124) and 81.6% (62/76) of patients, respectively. Across both groups who had <25% improvement in total body repigmentation at Week 24, 50.0% (53/106) of patients achieved ≥50% improvement in T-VASI (T-VASI50) at Week 104. Conclusions: In the TRuE-V studies, ruxolitinib cream application for an additional 80 weeks resulted in improved repigmentation among patients with nonsegmental vitiligo who had limited or no repigmentation at Week 24. These 2-year TRuE-V results highlight the importance of prolonged treatment in patients with vitiligo, even when minimal or no repigmentation is achieved after 6 months of treatment. [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]

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]

Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no Food and Drug Administration (FDA)-approved treatments, and current treatments are time-consuming, expensive, and of low efficacy. We sought to identify new treatments for vitiligo, and first considered repurposed medications because of the availability of safety data and expedited regulatory approval. We previously reported that the IFN-γ-induced chemokine CXCL10 is expressed in lesional skin from vitiligo patients, and that it is critical for the progression and maintenance of depigmentation in our mouse model of vitiligo. We hypothesized that targeting IFN-γ signaling might be an effective new treatment strategy. Activation of signal transducer and activator of transcription 1 (STAT1) is required for IFN-γ signaling and recent studies revealed that simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro. Therefore, we hypothesized that simvastatin may be an effective treatment for vitiligo. We found that simvastatin both prevented and reversed depigmentation in our mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8+ T cells in the skin. Treatment of melanocyte-specific, CD8+ T cells in vitro decreased proliferation and IFN-γ production, suggesting additional effects of simvastatin directly on T cells. Based on these data, simvastatin may be a safe, targeted treatment option for patients with vitiligo. [ABSTRACT FROM AUTHOR]