Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata.

Marta Bertolini,Eddy Wang,Aviad Keren,Amos Gilhar,Kevin Mcelwee,Ralf Paus,Vladimir E Emelianov,Katja C Meyer,Wolfgang Funk,Alfredo Rossi,Federica Zilio,Patrick Kleditzsch

doi:10.1371/journal.pone.0094260

Abstract

Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFβ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4–1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4–1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA.

Highlights

Alopecia areata (AA), one of the most common human autoimmune disorders, represents a T-cell-dependent organspecific autoimmune disease that is clinically characterized by sudden, mostly focal, hair loss [1,2]
We sought to resolve the controversy in the published literature on whether or not the number of Mast cells (MCs) is increased in lesional AA skin [12,14,15,16,62]
The final functional MC marker we examined in this series of experiments was the important immuno-inhibitory ‘‘no dangersignal’’, CD200, which plays a key role in hair follicle (HF)-immune privilege (IP) maintenance [8,59,110] and whose receptor is expressed on T-cells [111]

Summary

Introduction

Alopecia areata (AA), one of the most common human autoimmune disorders, represents a T-cell-dependent organspecific autoimmune disease that is clinically characterized by sudden, mostly focal, hair loss [1,2]. Transfer of CD8(+) cells alone induces localized AA-like hair loss in the C3H/HeJ mouse model [1,3], while CD8+ T-cell depletion abrogates AA onset in a rat model [4]. Growing (anagen) HFs exhibit relative immune privilege (IP) based on the suppression of MHC class I molecules and the overexpression of IP guardians like TGFb1/2 [1,2,6,7,8,9]. The development of AA requires that the normal IP of growing HFs collapses, induced by excessive release of interferon-c (IFNc) for example [5,10,11] (for prevalent AA pathogenesis concepts, see [2])

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Results

Conclusion