Vitiligo is a T-cell mediated skin disorder characterized by progressive loss of skin color. In individuals genetically predisposed to the disease, various triggers contribute to the initiation of vitiligo. Precipitating factors can stress the skin, leading to T-cell activation and recruitment. Though hereditary factors are implicated in the pathogenesis of vitiligo, it is unknown whether precipitating, stressful events play a role in vitiligo. To understand this, we utilized a validated perceived stress scale (PSS) to measure this parameter in vitiligo patients compared to persons without vitiligo. Additionally, we probed a clinical database, using a knowledge linking software called ROCKET, to gauge stress-related conditions in the vitiligo patient population. From a pool of patients in an existing database, a hundred individuals with vitiligo and twenty-five age- and sex-matched comparison group of individuals without vitiligo completed an online survey to quantify their levels of perceived stress. In parallel, patients described specifics of their disease condition, including the affected body sites, the extent, duration and activity of their vitiligo. Perceived stress was significantly higher among vitiligo individuals compared to those without vitiligo. ROCKET analyses suggested signs of metabolic-related disease (i.e., ‘stress’) preceding vitiligo development. No correlation was found between perceived stress and the stage or the extent of disease, suggesting that elevated stress may not be a consequence of pigment loss alone. The data provide further support for stress as a precipitating factor in vitiligo development.

Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivityin vitroandin vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.

Vitiligo is characterized by progressive loss of skin pigmentation. The search for aetiologic factors has led to the biochemical, the neurologic and the autoimmune theory. The convergence theory was then proposed several years ago to incorporate existing theories of vitiligo development into a single overview of vitiligo aetiology. The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time. New findings have since informed the description of progressive depigmentation. Understanding the relative importance of such aetiologic factors combined with a careful selection of the most targetable pathways will continue to drive the next phase in vitiligo research: the development of effective therapeutics. In that arena, it is likewise important to acknowledge that pathways affected in some patients may not be altered in others. Taken together, the convergence theory continues to provide a comprehensive viewpoint of vitiligo aetiology. The theory serves to intertwine aetiologic pathways and will help to define pathways amenable to disease intervention in individual patients.