Bertolini Marta, Zilio Federica, Rossi Alfredo, Kleditzsch Patrick, Emelianov Vladimir E, Gilhar Amos, Keren Aviad, Meyer Katja C, Wang Eddy, Funk Wolfgang, McElwee Kevin, Paus Ralf
Department of Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Münster, Münster, Germany.
Department of Dermatology, University of Lübeck, Lübeck, Germany.
PLoS One. 2014 May 15;9(5):e94260. doi: 10.1371/journal.pone.0094260. eCollection 2014.
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.
斑秃（AA）是一种毛囊（HF）的CD8 + T细胞依赖性自身免疫性疾病，其中毛囊免疫豁免（IP）的崩溃起着关键作用。肥大细胞（MCs）是至关重要的免疫调节细胞，参与T细胞依赖性免疫、IP和毛发生长的调节。因此，我们探讨了MCs在AA发病机制中的作用，重点关注MCs与人类和小鼠AA病变皮肤中CD8 + T细胞的体内相互作用。定量（免疫）组织形态计量学显示，与健康或非病变对照皮肤相比，人类AA病变中毛囊周围MCs的数量、脱颗粒和增殖显著增加，在亚急性AA中最为明显。在AA患者中，毛囊周围MCs显示TGFβ1和IL - 10减少，但类胰蛋白酶免疫反应性增加，表明MCs从免疫抑制表型转变为促炎表型。这一概念得到了IL - 10 +和PD - L1 + MCs数量减少的支持，而OX40L +、CD30L +、4 - 1BBL +或ICAM - 1 + MCs在AA中增加。病变的AA - HF与健康或非病变人类对照皮肤相比，还显示出更多的毛囊周围和毛囊内CD8 + T细胞以及更多的MC/CD8 + T细胞物理接触。在与CD8 + T细胞相互作用期间，AA MCs显著表达MHC I类和OX40L，有时还表达4 - 1BBL或ICAM - 1，表明MC可能向CD8 + T细胞呈递自身抗原和/或共刺激信号。在移植的AA C3H/HeJ小鼠模型和新的AA人源化小鼠模型中也观察到MC数量、活性以及与CD8 + T细胞相互作用的异常。这些体内现象学数据提示了新的AA病理生物学概念，即毛囊周围MCs倾向于促炎活动，在这种疾病中促进与CD8 + T细胞的相互作用，从而导致AA中HF - IP的崩溃。如果得到证实，MCs及其与CD8 + T细胞的相互作用可能成为未来AA治疗的一个有前景的新靶点。
