Missing link found between brain, immune system

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Missing link found between brain, immune system                                                          寻找大脑和免疫系统之间失落的联系
引：Virginia 大学的研究者在nature发表的相关文章，和大家共享。
     In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.
     这是一个颠覆传统教科书的全新发现：来自于Virginia大学医学部的研究人员称他们找到了之前认为不存在的直接联系大脑和免疫系统的管路，虽然当我们画出全身淋巴系统的时候，这些脉管并没有被检测到，但是这个发现的重大意义在于许多神经系统疾病的诊治开辟了新纪元，从自闭症到阿尔兹海默病，再到多发性硬化，无不如此。
     
      "Instead of asking, 'How do we study the immune response of the brain?' 'Why do multiple sclerosis patients have the immune attacks?' now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG). "It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can't be studied. But now we can ask mechanistic questions."
      "We believe that for every neurological disease that has an immune component to it, these vessels may play a major role," Kipnis said. "Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component."
      Jonathan Kipnis博士是来自UVA神经科学系的教授，大脑免疫和神经胶质中心的主任。他表示，如今我们再追问研究大脑免疫反应的初衷，以及多发性硬化的机制，因为大脑和其他连接脑膜淋巴管的其他外周免疫系统一样，如果采用机械的原理推导，神经免疫反应没有什么神秘可言。他认为每一个神经系统的疾病机制都有免疫成分在里面，很难想象这些脉管没有参与在神经免疫发病中。


      

Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, described his reaction to the discovery by Kipnis' lab: "The first time these guys showed me the basic result, I just said one sentence: 'They'll have to change the textbooks.' There has never been a lymphatic system for the central nervous system, and it was very clear from that first singular observation - and they've done many studies since then to bolster the finding - that it will fundamentally change the way people look at the central nervous system's relationship with the immune system."

Even Kipnis was skeptical initially. "I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped," he said. "I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not."

      Kevin Lee博士是UVA神经科学系的主席，他说他第一眼看到基础实验的结果，就丢下一句话，他们将会改变医学教科书的。从来也没有人发现中枢神经系统的淋巴途径，他很清楚这个单一的观察将会转变人们关于中枢神经系统和免疫系统联系的看法，事实上，kipnis教授作了很多后续研究来支持这个发现，尽管最初他以为人体所有的结构早已在上个世纪中叶就全部发现了，可是实际上是我们没有意识到。

     

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'Very Well Hidden'非常隐蔽
The discovery was made possible by the work of Antoine Louveau, PhD, a postdoctoral fellow in Kipnis' lab. The vessels were detected after Louveau developed a method to mount a mouse's meninges - the membranes covering the brain - on a single slide so that they could be examined as a whole. "It was fairly easy, actually," he said. "There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn't have worked."After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: "I called Jony [Kipnis] to the microscope and I said, 'I think we have something.'"
最初，kipnis实验室的一个博士后Antoine Louveau用自己开发的一种在切片上数老鼠脑膜的方法找的了那些脉管。其实很简单，不过如果用其他办法，就可能不奏效。博士后说，“我们把脑膜固定在头盖骨，让它保持生理的状态，然后我们解剖开来，注意到切片里面的免疫细胞有脉管样的物质分布”，“我检测到这的确是淋巴管，这个（既往）不可能的现象存在！我立马把Jony请到显微镜旁边说我们有了新发现”。Louveau平和地回忆那个时刻。
As to how the brain's lymphatic vessels managed to escape notice all this time, Kipnis described them as "very well hidden" and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. "It's so close to the blood vessel, you just miss it," he said. "If you don't know what you're after, you just miss it."
"Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris," Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the "phenomenal" surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.
至于大脑里的淋巴管这些年来一直被忽视的原因，Kipnis认为它们很隐蔽，科研人员跟踪淋巴管沿着一条大血管一直到鼻窦，一个很难显像的解剖位置，发现淋巴管非常毗邻血管，因此很容易错过。“如果你不知道你在寻找什么，你就直接视若无睹”。多亏与BIG中心Tajie Harris副教授的合作，实验室得以通过淋巴管的实时成像进一步展现他们的功能，Kipnis盛赞了实验室里一位研究助理 Igor Smirnov的外科技能。

The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.

The findings have been published online by the prestigious journal Nature and will appear in a forthcoming print edition

.大脑内淋巴管的意外发现引发一系列关于大脑工作机制和神经疾病发病机理的疑问，比如阿尔兹海默病患者的大脑里有许多大分子蛋白沉积，Kipnis说我们现在认为可能是因为淋巴管无法有效的搬运清除这些蛋白，还有不同年龄的大脑，淋巴管看上去不一样，因此它们在人体衰老中的作用也需要进一步探讨，而诸如自闭症，多发性硬化等许多其他神经疾病，也可以从淋巴管的存在这个角度进行考虑。

这篇报道已经在权威杂志《自然》在线发表，大家很快能看到印刷版。

More information: Structural and functional features of central nervous system lymphatic vessels, DOI: 10.1038/nature14432