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.