Translational Research in Vitiligo

Abstract

Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past 30 years, but only through perseverance, collaboration, and open-minded discussion. Early hypotheses considered roles for innervation, microvascular anomalies, oxidative stress, defects in melanocyte adhesion, autoimmunity, somatic mosaicism, and genetics. Because theories about pathogenesis drive experimental design, focus, and even therapeutic approach, it is important to consider their impact on our current understanding about vitiligo. Animal models allow researchers to perform mechanistic studies, and the development of improved patient sample collection methods provides a platform for translational studies in vitiligo that can also be applied to understand other autoimmune diseases that are more difficult to study in human samples. Here we discuss the history of vitiligo translational research, recent advances, and their implications for new treatment approaches.

Keywords: autoimmunity; genetics; melanocyte oxidative stress; translational research; vitiligo.

Figure 1

Graph showing the exponential increase of publications available on Pubmed with titles including vitiligo published over time.

Figure 2

Overview of pathogenesis for vitiligo. (A) Neuronal involvement – neurons within the skin release neuropeptides like catecholamines, which act on melanocytes and lead to depigmentation. (B) Microvascular theory – vitiligo lesions have increased blood flow during segmental vitiligo, which allows for increased infiltration of lymphocytes that results in autoimmune attack of melanocytes. (C) Somatic mosaicism – depigmentation develops because a somatic mutation in melanocytes leads to genetically distinct populations that are susceptible to autoimmune attack. (D) Melanocyte adhesion – friction or oxidative stress in melanocytes or keratinocytes leads to melanocyte loss because of reduced adhesion to the skin. (E) Degenerative theory – depigmentation occurs because of intrinsic melanocyte defects, such as increased susceptibility to environmental stressors and dysregulation of reactive oxidative species (ROS). (F) Autoimmunity theory – autoreactive immune cells attack and kill melanocytes, ultimately leading to depigmentation. (G) Genetics – underlies all pathways leading to vitiligo. Genetic studies most clearly implicate autoimmunity, but also melanocyte contributions. Neuronal and microvascular theories are least supported, represented by (A, B) being grayed. Figure created in BioRender.com.

Figure 3

Translational tools to study vitiligo. Vitiligo is uniquely positioned for translational studies because of ready access to the skin and multiple collection techniques for human skin samples such as shave, punch, and suction blister biopsies. These biopsies can then be used for the identification and characterization of cell populations on the single cell level with technologies like flow cytometry and single cell RNA sequencing. Animal models are available for studying initiating factors and adaptive immune responses, as well as cell culture techniques like 3D skin models that have been useful for elucidating mechanisms during vitiligo pathogenesis. Figure created in BioRender.com.

Figure 4

Vitiligo pathogenesis revealed through translational research. A simple overview of the current understanding of vitiligo pathogenesis. Autoreactive CD8+ T cells are recruited to the skin by CXCL10 produced by keratinocytes and kill melanocytes. These cells convert to resident memory T cells, which maintain vitiligo and require IL-15 signaling in the skin. JAKi and IL15i, outlined in red, may be effective treatments for vitiligo and are currently being tested in clinical trials. Some questions that remain include how melanocyte abnormalities initiate autoimmunity, the mechanism by which CD8+ T cells kill melanocytes, how Tregs suppress disease, and how changes in metabolism effect disease activity. Existing and developing translational tools will help to answer these and other questions. Figure created in BioRender.com.