Modern vitiligo genetics sheds new light on an ancient disease

Abstract

Vitiligo is a complex disorder in which autoimmune destruction of melanocytes results in white patches of skin and overlying hair. Over the past several years, extensive genetic studies have outlined a biological framework of vitiligo pathobiology that underscores its relationship to other autoimmune diseases. This biological framework offers insight into both vitiligo pathogenesis and perhaps avenues towards more effective approaches to treatment and even disease prevention.

Figure 1

“Circuit” of melanocyte damage, melanocyte autoantigen presentation, immune triggering and propagation, T-cell programming and melanocyte target cell killing in vitiligo. Skin is damaged by ultraviolet (UV) or other trauma, perhaps facilitating microinfection. Molecules displaying pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP) interact with NLRP1 in the cytoplasm of Langerhans cells, stimulating nucleation of an NLRP1 inflammasome, thereby activating caspases that cleave the interleukin (IL)-1b precursor to biologically active secreted IL-1β. Langerhans cells take up peptide autoantigens presented by human leukocyte antigen (HLA) class I molecules expressed on the surface of nearby melanocytes, including peptides derived from tyrosinase (TYR), OCA2 and the melanocortin-1 receptor (MC1R), and these peptide autoantigens are then transferred to HLA class II molecules expressed on the Langerhans cell surface. Perhaps stimulated by IL-1β and facilitated by interaction of CD80 with CTLA4 and by the action of PTPN22, these melanocyte-derived peptide autoantigens are then presented to immature T cells that express cognate T-cell receptors (TCR), the response of which is regulated by PTPN22. The activated T cells express IL-2, which binds to the IL-2 receptor expressed on their surface, stimulating maturation to cytotoxic T cells that express granzyme B (GZMB). The TCR expressed by these autoreactive cytotoxic T cells binds its cognate autoantigen presented on the surface of target melanocytes by HLA class I molecules, and GZMB is introduced into the target melanocyte, inducing apoptosis.