Understanding mechanisms of autoimmunity through translational research in vitiligo

Abstract

Vitiligo is an autoimmune disease of the skin that leads to life-altering depigmentation and remains difficult to treat. However, clinical observations and translational studies over 30-40 years have led to the development of an insightful working model of disease pathogenesis: Genetic risk spanning both immune and melanocyte functions is pushed over a threshold by known and suspected environmental factors to initiate autoimmune T cell-mediated killing of melanocytes. While under cellular stress, melanocytes appear to signal innate immunity to activate T cells. Once the autoimmune T cell response is established, the IFN-γ-STAT1-CXCL10 signaling axis becomes the primary inflammatory pathway driving both progression and maintenance of vitiligo. This pathway is a tempting target for both existing and developing pharmaceuticals, but further detailing how melanocytes signal their own demise may also lead to new therapeutic targets. Research in vitiligo may be the future key to understand the pathogenesis of organ-specific autoimmunity, as vitiligo is common, reversible, progresses over the life of the individual, has been relatively well-defined, and is quite easy to study using translational and clinical approaches. What is revealed in these studies can lead to innovative treatments and also help elucidate the principles that underlie similar organ-specific autoimmune diseases, especially in cases where the target organ is less accessible.

Figure 1

“Disfiguring white patches characteristic of vitiligo.”

Figure 2

“The IFN-γ-STAT1-CXCL10 Axis Drives Melanocyte Destruction.” IFNγ signals through the IFN-γ receptor (IFN-γR), which then requires JAK1 and JAK2 to phosphorylate the transcription factor STAT-1. Phosphorylated STAT1 homodimerizes and then translocates into the nucleus where IFN-γ-dependent genes, including CXCL9 and CXCL10, are transcribed(47). Autoreactive CXCR3-expressing CD8+ T cells follow these ligands to the skin where they kill melanocytes(46).

Figure 3

“Working Model of Vitiligo Pathogenesis” Inherited genetic risk (HLA (11)(10), XBP1 (16), TYR (13), OCA2 (15), M1CR1 (15)) and environmental insults (MBEH and 4-TBP) induce a state of melanocyte stress, exemplified by ER stress. Stressed melanocytes signal to local innate and resident skin cell types via exosomes containing antigen and DAMPs, soluble HSP70, and/or other factors (30-34). Responding cell types are activated by these signals and some may migrate to the draining lymph nodes where they activate T cells. Other responding cells in the skin secrete chemokines to recruit autoreactive T cells, which are directly responsible for killing melanocytes. In active disease, one or more cell types may respond to IFN-γ and secrete CXCL10 to recruit T cells to the skin where melanocytes reside.