Vitiligo

Abstract

Vitiligo is an autoimmune disease of the skin that affects approximately 1 % of the population. It is mediated by self-reactive CD8⁺ T cells that target and kill melanocytes in the basal epidermis. Patients present with patchy depigmentation, which commonly appears on the face, hands, feet and genitals, but may affect any part of the body. Depigmentation is typically progressive and chronic, slowly developing over the life of the patient. There are currently no FDA-approved treatments for vitiligo, and while some therapies are effective for disease, they primarily work through general immunosuppression. Like most autoimmune diseases, both genetic and environmental factors contribute to the risk of developing vitiligo. These factors promote immune dysregulation, which then initiates depigmentation and disease progression. Genes that confer susceptibility to vitiligo have been identified in Genome-Wide Association Studies (GWAS), implicating both innate and adaptive immunity. Environmental triggers for vitiligo include a number of common household commercial products that contain chemical phenols, which act as tyrosine analogs and induce stress responses in the melanocyte. Several recent studies connecting cellular stress and innate immune activation have shed light on possible mechanisms by which vitiligo is triggered through exposure to these environmental insults. Studies of the “effector” phase of vitiligo reveal that disease is driven by IFN-γ and its target genes, including chemokines. Here we will outline the clinical presentation and treatment options, immunopathogenesis, basic and translational research strategies, and future prospects for the treatment of vitiligo.

Questions

• 1. Briefly describe the clinical presentation of vitiligo. What is required for a definitive diagnosis?

  Vitiligo presents as patches of depigmentation, most commonly on the hands, feet, face, and genitals, followed by the trunk/back. Depigmentation may be bilateral or unilateral, and is thus classified as either non-segmental or segmental, respectively. Signs for highly active vitiligo include confetti or trichrome depigmentation, as well as the koebner phenomenon. A definitive diagnosis of vitiligo requires biopsy demonstrating a lack of melanocytes by immunohistochemical staining, although this is not commonly required.

• 2. What are current treatment options and how do they work? How would future treatment options improve upon these?

  Current treatment options for vitiligo include general immunosuppressants, including topical steroids and calcineurin inhibitors like tacrolimus, and narrow band UVB, which is thought to both suppress autoimmune inflammation and promote melanocyte differentiation/melanin production in the skin. Melanocyte transplantation surgery, or MKTP, often works for patients with stable disease such as segmental vitiligo patients. Future treatment options would improve upon these by more specifically targeting the immune cells responsible for vitiligo maintenance and progression, and through direct stimulation of melanocytes to better promote repigmentation.

• 3. Briefly describe the pathophysiology of vitiligo. Be sure to discuss cellular stress, innate immunity, adaptive immunity?

  Vitiligo is caused by a combination of genetic susceptibility and environmental exposures that lead to immune activation. Melanocyte stress is thought to be the first step in vitiligo pathogenesis. Genetic factors may cause increased basal melanocyte stress, and/or exposure to phenolic chemicals would cause increased melanocyte stress through interaction with tyrosinase. This stress is likely sensed by innate immune cells that reside in tissues, such as dendritic cells and macrophages, who in turn present melanocyte antigens to T cells in skin draining lymph nodes. These T cells then infiltrate the skin to target and kill melanocytes.

• 4. What are some genetic contributions to vitiligo? Please describe the functions of these genes in relation to disease pathogenesis.

  Some genetic contributions to vitiligo include HLA-A2, which is important for presentation of melanocyte antigens to T cells; innate immune genes such as NLRP1, which may play a role in sensing melanocyte stress; XBP-1, a chaperone that may contribute to melanocyte stress; genes affecting Treg function including PTPN22, IL2RA, FOXP3; and genes affecting effector T cell function such as granzyme B.

• 5. Name two research tools currently being used to better understand mechanisms of vitiligo. How does each tool help to identify new potential treatments?

  Two research tools currently used to better understand vitiligo are animal models and translational studies using human skin biopsies. Animal models help identify disease mechanisms and potential treatments, as T cell responses may be assessed in skin and lymphoid tissues following experimental treatments at specific time points, which cannot be assessed in humans. Skin biopsies, however, provide insight into human disease and may be assessed for inflammatory markers and cellular phenotypes.