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 is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. While 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.

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.

scRNA-seq of human vitiligo samples reveals complex autoimmune networks, including a role for CCR5 in T reg function.

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.

IL-10 + regulatory B cell migration into inflamed skin limits cutaneous inflammation

Vitiligo is an acquired autoimmune depigmentation of the skin, affecting 2%of the population with great impact on quality of life, which is more devastating in people with skin of color. The most important selection criterion in vitiligo for considering melanocyte keratinocyte transplantation procedure (MKTP) is stability. However, there is no consensus regarding the required period to define clinical stability. Moreover, despite being performed on clinically stable lesions, transplantation is more successful in segmental vitiligo (SV), compared to non segmental (NSV) patients in terms of repigmentation and durability of the response. To investigate this observation, we performed suction blister biopsies on clinically stable vitiligo patients undergoing MKTP divided in 2 groups: SV (n¼7), and NSV (n¼7) and a pibaldism patient as a control. Lesions undergoing surgery were sampled, as well as non lesional skin for comparison. The immune infiltrate was phenotyped by flow cytometry, and levels of inflammatory cytokines in skin and serum was measured by ELISA. The number of lesional CD8 T cells and their ratio to CD4 were significantly higher in the lesions of NSV group when compared to nonlesional skin, while no increase was present in the SV group. Subtyping analysis of T cells revealed higher resident memory CD8 T cells in lesional skin of NSV group and higher FoxP3+CD4+ T cells in their non lesional skin. Cytokine levels were low in both groups. These findings suggest that the improved surgical responses reported in SV over NSV are due to subclinical instability in the NSV lesions, reflected by an elevated T cell infiltrate. Sampling the lesions of vitiligo patients who are surgical candidates may improve selection of patients for this procedure, and preoperative treatment of lesions with immunosuppressives may improve the outcomes.

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