Ito Taisuke, Ito Natsuho, Saatoff Matthias, Hashizume Hideo, Fukamizu Hidekazu, Nickoloff Brian J, Takigawa Masahiro, Paus Ralf
Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
J Invest Dermatol. 2008 May;128(5):1196-206. doi: 10.1038/sj.jid.5701183. Epub 2007 Dec 27.
Hair follicles (HFs) enjoy a relative immune privilege (IP) that is characterized by downregulation of major histocompatibility complex (MHC) class I and local expression of potent immunosuppressants. Normally, natural killer (NK) cells attack cells with absent/low MHC class I expression. However, because few perifollicular NK cells are found around healthy human anagen HFs, we asked how HFs escape from NK cell attack. This study suggests that this happens via an active NK cell suppression. Alopecia areata (AA), an organ-specific autoimmune disease thought to result from a collapse of HF-IP, in contrast, shows striking defects in NK cell inhibition/containment. We show that the NK cell inhibitor macrophage migration inhibitory factor is strongly expressed by the HF epithelium, and very few CD56(+)/NKG2D(+) NK cells are observed in and around normal anagen HFs compared to AA with prominent aggregations of CD56(+)/NKG2D(+) NK around AA-HFs. By flow cytometry, many fewer NK function-activating receptors (NKG2D, NKG2C) and significantly more killer cell Ig-like receptors-2D2/2D3 were found to be expressed on peripheral blood CD56(+) NK cells of healthy controls than on those of AA patients. In addition, only weak immunoreactivity for MHC class I chain-related A gene was observed in normal anagen HFs compared to AA. To our knowledge, this defect is previously unreported and must be taken into account in AA pathogenesis and its management.
毛囊（HFs）享有相对的免疫特权（IP），其特征是主要组织相容性复合体（MHC）I类下调以及强效免疫抑制剂的局部表达。正常情况下，自然杀伤（NK）细胞会攻击MHC I类表达缺失/低下的细胞。然而，由于在健康人生长期毛囊周围几乎找不到毛囊周围NK细胞，我们不禁要问毛囊是如何逃脱NK细胞攻击的。本研究表明，这是通过主动抑制NK细胞来实现的。相比之下，斑秃（AA）是一种器官特异性自身免疫性疾病，被认为是由于毛囊免疫特权的崩溃所致，在NK细胞抑制/控制方面存在明显缺陷。我们发现，毛囊上皮强烈表达NK细胞抑制剂巨噬细胞迁移抑制因子，与AA患者毛囊周围有大量CD56(+)/NKG2D(+) NK细胞聚集相比，在正常生长期毛囊及其周围观察到的CD56(+)/NKG2D(+) NK细胞很少。通过流式细胞术发现，与AA患者相比，健康对照外周血CD56(+) NK细胞上表达的NK功能激活受体（NKG2D、NKG2C）要少得多，而杀伤细胞免疫球蛋白样受体-2D2/2D3的表达则明显更多。此外，与AA相比，在正常生长期毛囊中仅观察到与MHC I类链相关A基因的弱免疫反应性。据我们所知，这一缺陷此前未被报道，在AA的发病机制及其治疗中必须予以考虑。
