Thymic Epithelium Determines a Spontaneous Chronic Neuritis in Icam1tm1JcgrNOD Mice
Thymic Epithelium Determines a Spontaneous Chronic Neuritis in Icam1tm1JcgrNOD Mice
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DOI：
10.4049/jimmunol.1400367
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发表时间：
2014-09-01
影响因子：
4.4
通讯作者：
Kieseier, Bernd C.
中科院分区：
文献类型：
--
作者：
Horste, Gerd Meyer Zu;Mausberg, Anne K.;Kieseier, Bernd C.
NOD小鼠品系自发地发展自身免疫性糖尿病。NOD遗传背景上的共刺激分子（如B7-2）的缺乏可预防糖尿病，但相反会引发炎症性周围神经病变。这构成了自身免疫靶点的转移，但其潜在机制仍不清楚。在这项研究中，我们证明了NOD小鼠缺乏ICAM-1亚型，这喜剧共刺激功能，自发地发展成慢性自身免疫性周围神经炎，而不是糖尿病。该疾病通过CD 4（+）T细胞转移，其与巨噬细胞和B细胞一起浸润外周神经，并且对外周髓磷脂蛋白零具有自身反应性。这些Icam 1（tm 1 Jcgr）NOD小鼠表现出调节性T细胞数量不变，但产生IL-17的T细胞增加，这决定了自身免疫的严重性，但不是靶特异性。Ab介导的ICAM-1阻断仅在年轻NOD小鼠中引发神经炎。胸腺上皮细胞从Icam 1（tm 1 Jcgr）NOD小鼠的功能改变共刺激分子的表达，并诱导神经炎和髓鞘自身反应移植到裸鼠体内后。Icam 1（tm 1 Jcgr）NOD小鼠表现出特异性改变的TCR库。我们的研究结果介绍了一种新的慢性炎症性神经病变的动物模型，并表明胸腺上皮细胞ICAM-1表达的改变使自身免疫特异性地向周围神经转移。这提高了我们对周围神经系统中自身免疫与人类疾病潜在相关性的理解。
The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases.