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 that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin revealed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients revealed that keratinocytes were the major chemokine-producers throughout the course of disease, and functional studies using a conditional STAT1 knockout mouse revealed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, as topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.

Totipotent stem cells have the potential to differentiate into every cell type. Renewal of totipotent stem cells in the germline and cellular differentiation during early embryogenesis rely upon posttranscriptional regulatory mechanisms. The Caenorhabditis elegans RNA binding protein, MEX-3, plays a key role in both processes. MEX-3 is a maternally-supplied factor that controls the RNA metabolism of transcripts encoding critical cell fate determinants. However, the nucleotide sequence specificity and requirements of MEX-3 mRNA recognition remain unclear. Only a few candidate regulatory targets have been identified, and the full extent of the network of MEX-3 targets is not known. Here, we define the consensus sequence required for MEX-3 RNA recognition and demonstrate that this element is required for MEX-3 dependent regulation of gene expression in live worms. Based on this work, we identify several candidate MEX-3 targets that help explain its dual role in regulating germline stem cell totipotency and embryonic cell fate specification.embryogenesis ͉ nematode ͉ RNA-binding protein ͉ post-transcriptional regulation ͉ maternal effect

Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no FDA-approved treatments, and current treatments are time-consuming, expensive, and have 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. STAT1 activation 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.

Tissue resident memory T cells (Trm) form in the skin in vitiligo and persist to maintain disease, as white spots often recur rapidly after discontinuing therapy. We and others have recently described melanocyte-specific autoreactive Trm in vitiligo lesions. Here, we characterize the functional relationship between Trm and recirculating memory T cells (Tcm) in our vitiligo mouse model. We found that both Trm and Tcm sensed autoantigen in the skin long after stabilization of disease, producing IFN-g, CXCL9, and CXCL10. Blockade of Tcm recruitment to the skin with FTY720 or depletion of Tcm with low-dose Thy1.1 antibody reversed disease, indicating that Trm cooperate with Tcm to maintain disease. Taken together, our data provide characterization of skin memory T cells in vitiligo, demonstrate that Trm and Tcm work together during disease, and indicate that targeting their survival or function may provide novel, durable treatment options for patients.