《Nature》T细胞“错乱”机制

　　

生物通报道，德国Max Planck研究所神经生物学系，Ludwig-Maximilians大学等处的科学家在T细胞与自体免疫疾病的课题上取得新进展，相关成果文章Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions发表在最新一期的Nature杂志上。

 

免疫系统不但能辨识危险的入侵物，亦可移除癌细胞，然而免疫系统亦可能出现偏差，当它开始攻击健康组织，结果便会造成所谓的自体免疫性疾病。

 

正常情况下，血脑屏障受到免疫系统的监控，这种结构可使脑组织少受甚至不受循环血液中有害物质的损害，从而保持脑组织内环境的基本稳定，对维持中枢神经系统正常生理状态具有重要的生物学意义。

 

多发性硬化症(MS)就是一种自体免疫疾病，它的发生与血脑屏障的破坏有极大的关联。当血脑屏障受到破坏时，免疫系统可能主动攻击神经中枢，而导致多发性硬化症的发生。

 

多发性硬化症是一种中枢神经系统的疾病，也就是说它的病变位于脑部或脊髓。我们的神经细胞有许多树枝状的神经纤维，这些纤维就像错纵复杂的电线一般，在我们的中枢神经系统中组织成绵密复杂的网络。大自然很巧妙的在我们神经纤维的外面包裹着一层叫「髓鞘」的物质，髓鞘不仅像电线的塑料皮一样让不同的电线不致短路，同时人体的髓鞘还可以加速我们神经讯号的传导。　

 

当这些髓鞘被破坏后，我们神经讯号的传导就会变慢甚至停止。多发性硬化症就是因为在中枢神经系统中产生大小不一的块状髓鞘脱失而产生症状。所谓「硬化」指的是这些髓鞘脱失的区域因为组织修复的过程中产生的疤痕组织而变硬。这些硬块可能会有好几个，随着时间的进展，新的硬块也可能出现，所以称作「多发性」。

 

实验性变应性脑脊髓炎(EAE)是研究多发性硬化症的最佳模型，研究小组以Lewis小鼠为模型动物，对这些实验动物用一项双光子荧光显微镜技术进行追踪。

 

研究发现触发自体免疫疾病的免疫系统中的T-细胞先是直接附着在脊髓脑膜脉管内表面上，在对其内表面进行扫描，有时会逆血流方向爬行。一旦穿过血-脑障碍，这些T-细胞便会与表现抗原的吞噬细胞结合，后者又会刺激它们进一步的分化和组织渗透，导致炎症反应，产生一系列的病变。

 

研究小组得出结论，与T-细胞的这些相互作用中所涉及的结构，有可能成为自体免疫脑病治疗方法的潜在候选目标。

（生物通 小茜）

Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions

Ingo Bartholomäus1,7, Naoto Kawakami1,7, Francesca Odoardi1,2,3, Christian Schläger1,2, Djordje Miljkovic1, Joachim W. Ellwart4, Wolfgang E. F. Klinkert1, Cassandra Flügel-Koch5, Thomas B. Issekutz6, Hartmut Wekerle1 & Alexander Flügel1,2,3

 

Max Planck Institute for Neurobiology, 82152 Martinsried, Germany

Department of Neuroimmunology, Institute for Multiple Sclerosis Research, Gemeinnützige Hertie-Stiftung and University Medical Centre Göttingen, 37073 Göttingen, Germany

Institute for Immunology, Ludwig-Maximilians-University, 80336 Munich, Germany

Institute for Experimental Hematology, Helmholtz Centre, 81377 Munich, Germany

Institute for Anatomy 2, Friedrich-Alexander-University, 91054 Erlangen, Germany

Division of Immunology, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada

These authors contributed equally to this work.

Correspondence to: Hartmut Wekerle1Alexander Flügel1,2,3 Correspondence and requests for materials should be addressed to A.F. (Email: [e-mail]) or H.W. (Email: [e-mail]).

 

【Abstract】

The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks1. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.