Vitiligo: Mechanisms of Pathogenesis and Treatment.

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.

Vitiligo: Mechanistic insights lead to novel treatments.

Vitiligo is an autoimmune disease of the skin characterized by patchy depigmentation. Current treatments are moderately effective at reversing disease by suppressing autoimmune inflammation in the skin and promoting melanocyte regeneration. Recent basic and translational research studies have significantly improved our understanding of disease pathogenesis, which is now leading to emerging treatment strategies based on targeted therapy. Here we discuss important clinical characteristics of vitiligo, current therapies and their limitations, advances in understanding disease pathogenesis, emerging targeted treatments, and strategies to optimize clinical trials to efficiently and effectively test these new treatments.

Lesional CD8+ T-Cell Number Predicts Surgical Outcomes of Melanocyte-Keratinocyte Transplantation Surgery for Vitiligo.

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.

scRNA-seq of human vitiligo reveals complex networks of subclinical immune activation and a role for CCR5 in Treg function.

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 (Tregs) to restrain disease progression in nonlesional skin. We determined that CCL5-CCR5 signaling served as a chemokine circuit between effector CD8+ T cells and Tregs, and mechanistic studies in a mouse model of vitiligo revealed that CCR5 expression on Tregs was required to suppress disease in vivo but not in vitro. CCR5 was not required for Treg recruitment to skin but appeared to facilitate Treg 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.

Treatment with Modified Heat Shock Protein Repigments Vitiligo Lesions in Sinclair Swine.

HSP70i is secreted by stressed melanocytes, is associated with human vitiligo lesions, and functionally contributes to a mouse model of vitiligo. Henning et al. report that treatment with a modified version of the protein reversed depigmentation in Sinclair swine, a useful animal model of vitiligo. These studies provide the rationale for testing in human studies.

Innate immune mechanisms in vitiligo: danger from within.

Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.