Innate immune mechanisms in vitiligo: danger from within

Abstract

Vitiligo is an autoimmune disease of the skin in which melanocytes are destroyed by antigen-specific T cells, resulting in patchy depigmentation. Although adaptive immunity plays a clear role in disease progression, initiating factors are largely unknown. Many studies report that cellular stress pathways are dysregulated in melanocytes from vitiligo patients, suggesting that melanocyte-intrinsic defects participate in disease pathogenesis. Recent studies reveal that melanocyte stress generates damage-associated molecular patterns that activate innate immunity, thus connecting stress to organ-specific inflammation. Genetic studies in vitiligo support a role for stress, innate immunity, and adaptive mechanisms. Here, we discuss advances in the field that highlight how cellular stress, endogenous danger signals, and innate immune activation promote the onset of vitiligo.

Figure 1

Vitiligo is characterized by disfiguring white patches on the skin due to the loss of melanocytes.

Figure 2. Innate signaling pathways activated by cellular stress lead to adaptive autoimmune responses against melanocytes

The production of melanin results in cellular stress [1]. Environmental insults, including UV light and chemical phenols such as monobenzone, exacerbate this response [2]. Melanocyte stress is characterized by intracellular ROS and activation of the UPR [3], which are both capable of activating PRRs [4] either directly, or through the production of HSP70i and antigen-containing exosomes [5]. These signals function as DAMPs to activate dendritic cells [6] and subsequent priming of CD8⁺ T-cells for autoimmune attack of melanocytes [7]. Stressed melanocytes secrete low levels of IL-6 and IL-8, which may recruit immune populations and/or antagonize the suppressor function of regulatory T cells (Treg). Abbreviations: DAMP – damage-associated molecular pattern, DC – dendritic cell, GWAS – genome-wide association study, HSP – heat shock protein, NLR – NOD-like receptor, PRR – pattern recognition receptor, RLR – RIG-I-like receptor, ROS – reactive oxygen species, TLR – toll-like receptor, UPR – unfolded protein response. Numbers in brackets correspond to references.