Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice.
Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice.
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DOI：
10.4049/jimmunol.0902778
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发表时间：
2010-02-15
期刊：
影响因子：
--
通讯作者：
Engelhard VH
中科院分区：
文献类型：
--
作者：
Gregg RK;Nichols L;Chen Y;Lu B;Engelhard VH
泛发性白癜风被认为是一种自身免疫性病因，并与黑素细胞分化抗原特异性CD8T细胞的存在有关。然而，有限的动物模型阻碍了对该疾病的理解。因此，我们产生了识别黑素细胞蛋白酪氨酸酶表位的TCR转基因小鼠。这些动物患上了白癜风，其特征与人类疾病极为相似。白癜风在时间和空间上发展，幼年皮损在头部和面部两侧形成，只有在成年动物体内才会出现。白癜风完全依赖CD8T细胞，而CD4T细胞则发挥负调节作用。重要的是，CD8T细胞可以在稳定状态下广泛存在于皮肤中，而不会在大多数地区引发白癜风。这表明随着时间的推移，或在不同的身体部位，黑素细胞易感性和/或免疫效应机制的发育差异。疾病对干扰素γ和CXCR3都有很强的依赖性，而对CCR5的依赖性更有限，CCR4和穿孔素都是必不可少的。基因消融CXCR3或干扰素γ也导致CD8T细胞进入皮肤的稀少。我们的结果确定了白癜风发展过程中意想不到的复杂性，并指出了可能的治疗干预措施。
Generalized vitiligo is thought to have an autoimmune etiology, and has been correlated with the presence of CD8 T cells specific for melanocyte differentiation antigen. However, limited animal models for the disease have hampered its understanding. Thus, we generated TCR transgenic mice that recognize an epitope of the melanocyte protein, tyrosinase. These animals develop vitiligo with strikingly similar characteristics to the human disease. Vitiligo develops temporally and spatially, with juvenile lesions forming bilaterally in head and facial areas, and only arising later in the body of adult animals. Vitiligo is entirely dependent on CD8 T cells, while CD4 T cells exert a negative regulatory effect. Importantly, CD8 T cells can be pervasively present in the skin in the steady state without inducing vitiligo in most areas. This points to developmental differences in melanocyte susceptibility and/or immunological effector mechanisms over time, or in different body locations. Disease is strongly dependent on both IFNγ and CXCR3, while dependence on CCR5 is more limited, and both CCR4 and perforin are dispensable. Genetic ablation of CXCR3 or IFNγ also resulted in scarce CD8 T cell infiltration into the skin. Our results identify unexpected complexity in vitiligo development and point towards possible therapeutic interventions.
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作者：
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作者：
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DOI：
10.1073/pnas.0804286105
发表时间：
2008-07-22
影响因子：
11.1
作者：
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通讯作者：
Viola, Antonella