Division of Dermatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Sci Transl Med. 2014 Feb 12;6(223):223ra23. doi: 10.1126/scitranslmed.3007811.
Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no U.S. Food and Drug Administration-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8(+) T cells in the skin and blood, which are directly responsible for melanocyte destruction. We report that gene expression in lesional skin from vitiligo patients revealed an interferon-γ (IFN-γ)-specific signature, including the chemokine CXCL10. CXCL10 was elevated in both vitiligo patient skin and serum, and CXCR3, its receptor, was expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we used a mouse model of disease that also exhibited an IFN-γ-specific gene signature, expression of CXCL10 in the skin, and up-regulation of CXCR3 on antigen-specific T cells. Mice that received Cxcr3(-/-) T cells developed minimal depigmentation, as did mice lacking Cxcl10 or treated with CXCL10-neutralizing antibody. CXCL9 promoted autoreactive T cell global recruitment to the skin but not effector function, whereas CXCL10 was required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo and thereby support inhibiting CXCL10 as a targeted treatment strategy.
白癜风是一种皮肤自身免疫性疾病，导致出现难看的白斑。目前美国食品和药物管理局尚未批准任何用于治疗白癜风的方法，大多数非适应证治疗方法的效果都不尽如人意。白癜风患者的皮肤和血液中存在大量自身反应性、黑素细胞特异性 CD8(+)T 细胞，这些细胞直接导致黑素细胞破坏。我们的研究报告显示，白癜风患者皮损皮肤的基因表达显示出干扰素-γ（IFN-γ）特异性特征，包括趋化因子 CXCL10。CXCL10 在白癜风患者的皮肤和血清中均升高，其受体 CXCR3 表达于致病性 T 细胞上。为了研究 CXCL10 在白癜风中的作用，我们使用了一种疾病小鼠模型，该模型也表现出 IFN-γ 特异性基因特征、皮肤中 CXCL10 的表达以及抗原特异性 T 细胞上 CXCR3 的上调。接受 Cxcr3(-/-)T 细胞的小鼠出现最小程度的色素减退，缺乏 Cxcl10 的小鼠或用 CXCL10 中和抗体治疗的小鼠也是如此。CXCL9 促进自身反应性 T 细胞向皮肤的整体募集，但不促进效应功能，而 CXCL10 则是效应功能和在皮肤内定位所必需的。令人惊讶的是，在已建立的、广泛色素减退的小鼠中中和 CXCL10 会诱导疾病逆转，表现为复色。这些数据表明 CXCL10 在白癜风的进展和维持中起着关键作用，从而支持抑制 CXCL10 作为一种靶向治疗策略。
