Recent clinical and mechanistic insights into vitiligo offer new treatment options for cell-specific autoimmunity

Abstract

Vitiligo is an autoimmune disease that has been recognized, stigmatized, and treated for millennia. Recent translational research has revealed key mechanisms of disease, including cellular stress, innate immune activation, T cell-mediated elimination of melanocytes from the skin resulting in clinically apparent white spots, as well as stem cell regeneration that reverses established lesions. Many of these pathways have been targeted therapeutically, leading to the first FDA-approved medication to reverse the disease, with many more in clinical trials. Despite these impressive advances, many questions remain, which will be answered through integration of additional basic, translational, and clinical research studies. This vitiligo revolution has led to great excitement for individuals with vitiligo, those who know them, and the dermatologists who care for their patients. But just as importantly, these advances have great potential to shed light on autoimmune diseases that are more difficult to study, possibly leading to treatment advances that could not be achieved otherwise.

Figure 1. Clinical presentations of vitiligo.

(A and B) Individuals with nonsegmental vitiligo, displaying characteristic symmetrical lesions on the body. Note normal body hair pigmentation in A. (C and D) Segmental vitiligo, with asymmetric lesions limited by the midline. Note depigmented lesional hairs in C. (E) Mixed vitiligo, characterized by segmental lesions that stop at the midline on the left anterior trunk as well as symmetric nonsegmental lesions on the hands. Photos are shown with patient consent.

Figure 2. Clinical signs of active vitiligo lesions.

(A) Koebner phenomenon illustrated by focal, linear depigmentation at a site of previous injury, indicated by arrow. (B) Trichrome lesions on the trunk, characterized by 3 colors including normal skin, depigmented skin, and intervening hypopigmentation. (C) Inflammatory vitiligo on the lower leg, with erythema and scale present at the lesional border, but sparing the center. (D) Confetti vitiligo on the foot, represented by clusters of small depigmented macules. (E) Lesions in fair skin can be difficult to appreciate by room light, while lesions fluoresce under illumination by Wood’s lamp, making examination more accurate. Photos are shown with patient consent.

Figure 3. Perifollicular repigmentation of a large area with vitiligo.

Pigmented spots are located around hair follicles. Photo is shown with patient consent.

Figure 4. Mechanisms of vitiligo pathogenesis.

Upper left: Initiation of pathogenesis within the vitiligo lesion is linked to intrinsic cellular stress and/or environmental exposures that induce release of damage-associated molecular patterns and antigen, which is acquired by phagocytic cells that travel to the draining lymph node (not shown) for initial priming of the T cell response. Tyrosine analogs such as rhododendrol and monobenzone (top left) are well-characterized examples of chemical exposures that induce autoimmunity. Lower left: Melanocyte-reactive CD8⁺ T cells enter the lesional skin and encounter their target melanocytes, promoting the release of IFN-γ, which induces production of CXCL9/10 from keratinocytes and fibroblasts that amplify the response by recruiting additional CD8⁺ T cells. Tregs, recruited to skin via CCR6, require CCR5 signaling for suppression of CD8⁺ T cell responses. Treg-mediated suppression is sufficient to block melanocyte-reactive T cell function in nonlesional skin, but is insufficient in lesional skin. Targets for therapeutic intervention are indicated in the upper panels (pink text), and candidate genetic variants from GWAS that influence initiation of the disease are indicated in the lower panels (dark blue text).