Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease
Department of Medicine, Division of Dermatology; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Dermatology | Molecular Biology
Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-gamma and IFN-gamma-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-gamma signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and gammadelta T cells were not required. These results have important clinical implications, because topical therapies that target IFN-gamma signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.
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Citation: J Invest Dermatol. 2017 Feb;137(2):350-358. Epub 2016 Sep 26. Link to article on publisher's site
Richmond, Jillian M.; Bangari, Dinesh S.; Essien, Kingsley I.; Currimbhoy, Sharif D.; Groom, Joanna R.; Pandya, Amit G.; Youd, Michele E.; Luster, Andrew D.; and Harris, John E., "Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease" (2017). UMass Metabolic Network Publications. 29.