Oral communication, PS7 / C99

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

A new mouse model of vitiligo with epidermal depigmentation reveals a critical role for IFN-gamma in autoreactive T cell homing to the skin

BACKGROUND AND OBJECTIVES: Vitiligo is a devastating, disfiguring disease of the skin that results from melanocyte destruction and subsequent patchy depigmentation of the epidermis. Both intrinsic melanocyte abnormalities and autoimmune mechanisms contribute to disease pathogenesis, and an essential autoimmune component is the direct destruction of melanocytes by CD8+ T cells, which migrate from the blood into the skin. Preliminary data from our laboratory reveal that the expression of IFN-gamma (IFNg) and IFNg target genes is increased within affected skin of patients with vitiligo, while the expression pattern of other inflammatory pathways is normal. Existing mouse models of vitiligo consist primarily of depigmentation of the hair, rather than skin. Our objective was to develop a mouse model of vitiligo with epidermal depigmentation, and to test our hypothesis that IFNg is required for disease pathogenesis. METHODS: We developed the first mouse model of vitiligo to display prominent depigmentation of the skin, which is the hallmark of human disease. In this model, melanocyte-specific CD8+ T cells were adoptively transferred to hosts with high melanocyte density in the epidermis, which results in black skin as well as black hair. Gene expression was quantified by quantitative PCR, and T cell accumulation in the skin was measured through microscopy and flow cytometry. RESULTS: Five weeks after transfer, hosts develop patchy depigmentation of exposed epidermal surfaces, including the ears, nose, feet, and tail. Histology of depigmenting skin reveals a patchy mononuclear infiltrate at the dermoepidermal junction, single-cell infiltration of the epidermis, and melanocyte loss, all features of active human vitiligo. Depigmentation is accompanied by accumulation of autoreactive CD8+ T cells in the skin, quantifiable loss of tyrosinase expression, and local IFNg production. Neutralization of IFNg results in defective T cell accumulation within the skin and abrogates disease, demonstrating a critical role for the cytokine in driving pathogenesis. CONCLUSION: We have established a new mouse model of vitiligo that closely mimics human disease through clinical appearance, histology, and IFNg expression. Our data implicate IFNg as a critical cytokine in vitiligo pathogenesis, and reveal its role in autoreactive T cell migration to the skin. We propose that targeting IFNg signaling is a promising strategy for the development of new treatments.

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