Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease

Abstract

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-γ and IFN-γ-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 found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin revealed 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 revealed that keratinocytes were the major chemokine-producers throughout the course of disease, and functional studies using a conditional STAT1 knockout mouse revealed that IFN-γ 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 γδ T cells were not required. These results have important clinical implications, as topical therapies that target IFN-γ 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.

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure

“…7,13–16,23 Originally, we hypothesized that inhibition of IFN-γ signaling using JAK inhibitors would lead to repigmentation, and results of 2 patients 19,20 using 2 different oral JAK inhibitors, tofacitinib and ruxolitinib, supported this hypothesis. Recently, a case series evaluating topical ruxolitinib also demonstrated efficacy 21 .…”

Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity

“…CXCL10 was elevated in the non-lesional skin of some subjects, which could be partially from blister trauma and might explain why it is a less specific marker using this method. Alternatively, CXCL9 protein may be more bioavailable for detection by ELISA than CXCL10 in blister fluid based on their different spatial and temporal expression in the skin 23 , binding affinities to structural elements 24,25 , and/or oligomerization within tissues 26 . We previously reported that both CXCL9 and CXCL10 had functional roles in our mouse model of vitiligo, however only CXCL10-deficient mice were protected from clinical disease 4 .…”

“…We previously reported that both CXCL9 and CXCL10 had functional roles in our mouse model of vitiligo, however only CXCL10-deficient mice were protected from clinical disease 4 . Although both chemokines are expressed in active disease, they are produced by different cell types and with different kinetics during vitiligo progression 23 . CXCL9 is expressed earliest in murine vitiligo lesions and may be a more specific marker of disease activity 23 .…”

“…Although both chemokines are expressed in active disease, they are produced by different cell types and with different kinetics during vitiligo progression 23 . CXCL9 is expressed earliest in murine vitiligo lesions and may be a more specific marker of disease activity 23 .…”

Role of chemokines and the corresponding receptors in vitiligo: A pilot study

“…Similarly, in skin lesions, CTL remarkably infiltrate into the epidermis and accumulate around the dying melanocytes . Generally, CTL migrate into the skin following various chemokine signals . Chemokines are important inflammatory factors that participate in many autoimmune responses.…”