Author Topic: Brain may be connected to immune system by lymphatic vessels not known before  (Read 121 times)

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Offline agate

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From Medical News Today, June 2, 2015:

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Missing link found between brain, immune system -- with major disease implications




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.

"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."

New Discovery in Human Body

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."

'Very Well Hidden'

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.'"

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.

Alzheimer's, Autism, MS and Beyond

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.

Citations

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

The study was funded by National Institutes of Health grants R01AG034113 and R01NS061973. Louveau was a fellow of Fondation pour la Recherche Medicale.
« Last Edit: August 15, 2015, 11:27:52 am by agate »
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Offline agate

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Some observations on these findings by a neurologist--in MedPage Today, August 14, 2015:

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Cohen's Brain Bits: Brainsweeper

By Joshua Cohen MD, MPH

Having survived medical school anatomy and seemingly learned every part of the body down to the minutest detail, I was surprised to learn of the discovery of a lymphatic system in the brain, challenging long-held dogma that the brain does not experience classical lymphatic drainage.

While this is inherently fascinating as it demonstrates that there are still important anatomical discoveries to be made, it is even more profound in its potential to alter our understanding and treatment of neurologic disease.

Originating in the eyes, climbing up above the olfactory bulb, and then running along the sinuses, this lymphatic network is less complex with less branching than lymphatics in peripheral tissues, likely due to the high pressure of cerebrospinal fluid (CSF). These vessels carry leukocytes to draining lymph nodes and are responsible for transport of cellular and soluble constituents of CSF to deep cervical lymph nodes.

This discovery follows closely on the heels of another drainage system known as the glymphatic system which drains interstitial fluid from the brain parenchyma into the cerebrospinal fluid. If these newly discovered meningeal lymphatics drain the CSF, this creates a 2-step pathway from parenchyma to periphery, as noted by the researchers in the conclusion of their study.

With two different systems at play controlling protein egress and moderating immunologic function, there are multiple opportunities for things to go wrong. When meningeal lymphatics are ligated, CSF and T cells no longer drain to deep cervical lymph nodes. Abnormal glymphatic function has been implicated in the pathology of traumatic brain injury, stroke, and a variety of neurodegenerative disorders.

Think about the underlying pathology of neurologic diseases and you can begin to imagine the ramifications of these discoveries. ...

Multiple sclerosis (MS) is an immune-mediated inflammatory disorder of the central nervous system characterized by demyelination, axonal loss, and gliosis. Cellular and soluble mediators of the immune system, including T cells, B cells, macrophages, microglia, cytokines, antibodies, and others, infiltrate the inflammatory lesions and resolution of the inflammation corresponds with clinical improvement.

Treatment of MS has primarily targeted immune suppression; however, this new knowledge of a pathway for immune system mediators to reach the brain from the periphery and vice versa may allow for other treatment strategies that target this pathway. Given the intrinsic risks of immunosuppressive therapies, the opportunity to potentially approach the disease in a completely different manner is extremely exciting.

These discoveries may also aid in diagnosing a range of conditions. Biomarkers of neurologic disease make their way from the parenchyma to the periphery, but to date it has been difficult to discern how they may be utilized in diagnosis, monitoring treatment response, and tracking recovery as their concentrations in the periphery fluctuate.

Understanding the pathway by which these substances make it from the parenchyma to the periphery allows researchers the opportunity to monitor them as they are drained from parenchyma to CSF and then CSF to peripheral lymphatics. Hopefully this will improve diagnosis and monitoring of conditions like traumatic brain injury and Alzheimer's disease.

The key to effective treatment and diagnosis of neurologic disease may be in understanding the connections between the brain and the rest of the body. The discovery of the brain's lymphatic system will hopefully propel this understanding and offer promise for millions of patients suffering from neurologic disease.

_____

Joshua Cohen, MD, MPH, is a neurologist at the Headache Institute at the Icahn School of Medicine at Mount Sinai in New York City.

The entire article can be seen here.
MS Speaks--online for 13 years

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Offline agate

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Missing link found between brain, immune system...
« Reply #2 on: July 16, 2016, 08:45:50 pm »
Another article on this in Science Daily, June 1, 2015:

https://www.sciencedaily.com/releases/2015/06/150601122445.htm
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.

Offline agate

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MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.