Dai Zhenpeng, Xing Luzhou, Cerise Jane, Wang Eddy Hsi Chun, Jabbari Ali, de Jong Annemieke, Petukhova Lynn, Christiano Angela M, Clynes Raphael
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, NY 10032;
Department of Pathology, Columbia University, New York, NY 10032; and.
J Immunol. 2016 Aug 15;197(4):1089-99. doi: 10.4049/jimmunol.1501798. Epub 2016 Jul 13.
Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D(+)CD8(+) T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D(+)CD8(+) T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.
斑秃（AA）是一种毛囊自身免疫性疾病，会导致不同程度的脱发。最近，我们发现产生干扰素-γ的NKG2D(+)CD8(+) T细胞会主动浸润毛囊，并导致C3H/HeJ AA小鼠的毛囊破坏。我们对人和小鼠斑秃皮肤进行的转录谱分析表明，干扰素途径是参与斑秃的主要信号通路。我们发现，干扰素诱导趋化因子（CXCL9/10/11）在AA病变皮肤中显著上调，此外，干扰素诱导趋化因子受体CXCR3在斑秃效应T细胞上上调。为了证明CXCL9/10/11趋化因子是否是AA发病所必需的，我们用CXCR3阻断抗体处理小鼠，这在移植模型中阻止了AA的发生，抑制了NKG2D(+)CD8(+) T细胞在皮肤和皮肤淋巴结中的积累。这些数据证明了一个概念验证，即通过阻断干扰素诱导趋化因子来干扰AA中的Tc1反应可以预防AA的发生。CXCR3阻断在人类AA中可以通过生物制剂或小分子抑制剂进行临床应用，后者作为一种局部治疗方法尤其引人关注。
