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Impressive Immune System Discoveries

20160725-13

Maps of the lymphatic system: old (left) and updated to reflect UVA’s discovery.

Credit: University of Virginia Health System; ScienceDaily.com

 

 

In a discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the 1) ___ 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?’ And, ‘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 2) ___ 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 3) ___ 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 4) ___. But apparently they have not.“ 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 5) ___ 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 6) ___ 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. 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 7) ___ 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.

 

Interesting Developments Based on the Initial Discovery

In a startling discovery (discussed above) that raises fundamental questions about human behavior, researchers at the University of Virginia School of Medicine have determined, based on their research last year, that the immune system directly affects — and even controls — creatures’ social behavior, such as their desire to interact with others. So could immune system problems contribute to an inability to have normal social interactions? The answer appears to be yes, and that finding could have great implications for neurological conditions such as autism-spectrum disorders and schizophrenia.

 

“The brain and the adaptive immune system were thought to be isolated from each other, and any immune activity in the brain was perceived as sign of a pathology. And now, not only are we showing that they are closely interacting, but some of our behavior traits might have evolved because of our immune response to pathogens,“ explained Jonathan Kipnis, PhD, chairman of UVA’s Department of Neuroscience. “It’s crazy, but maybe we are just multicellular battlefields for two ancient forces: pathogens and the immune system. Part of our personality may actually be dictated by the immune system.“

 

Evolutionary Forces at Work

The follow-up finding is equally illuminating, shedding light on both the workings of the brain and on evolution itself. The relationship between people and pathogens, the researchers suggest, could have directly affected the development of our social behavior, allowing us to engage in the social interactions necessary for the survival of the species while developing ways for our immune systems to protect us from the diseases that accompany those interactions. Social behavior is, of course, in the interest of8) ___, as it allows them to spread. The UVA researchers have shown that a specific immune molecule, interferon gamma, seems to be critical for social behavior and that a variety of creatures, such as flies, zebrafish, mice and rats, activate interferon gamma responses when they are social. Normally, this molecule is produced by the immune system in response to bacteria, viruses or parasites. Blocking the molecule in mice using genetic modification made regions of the brain hyperactive, causing the mice to become less social. Restoring the molecule restored the brain connectivity and behavior to normal. In a paper outlining theirfindings, the researchers note the immune 9) ___ plays a “profound role in maintaining proper social function.“

 

“It’s extremely critical for an organism to be social for the survival of the species. It’s important for foraging, sexual reproduction, gathering, hunting,“ said Anthony J. Filiano, PhD, Hartwell postdoctoral fellow in the Kipnis lab and lead author of the study. “So the hypothesis is that when organisms come together, you have a higher propensity to spread infection. So you need to be social, but [in doing so] you have a higher chance of spreading pathogens. The idea is that interferon gamma, in evolution, has been used as a more efficient way to both boost social behavior while boosting an anti-pathogen response.“

 

The researchers note that a malfunctioning immune system may be responsible for “social deficits in numerous neurological and psychiatric disorders.“ But exactly what this might mean for autism and other specific conditions requires further investigation. It is unlikely that any one molecule will be responsible for disease or the key to a cure, the researchers believe; instead, the causes are likely to be much more complex. But the discovery that the immune system — and possibly germs, by extension — can control our interactions raises many exciting avenues for scientists to explore, both in terms of battling neurological disorders and understanding human 10) ___. “Immune molecules are actually defining how the brain is functioning. So, what is the overall impact of the immune system on our brain development and function?“ Kipnis said. “I think the philosophical aspects of this work are very interesting, but it also has potentially very important clinical implications.“ Kipnis and his team worked closely with UVA’s Department of Pharmacology and the group of Vladimir Litvak, PhD, at the University of Massachusetts Medical School. Litvak’s team developed a computational approach to investigate the complex dialogue between immune signaling and brain function in health and disease. “Using this approach we predicted a role for interferon gamma, an important cytokine secreted by T lymphocytes, in promoting social brain functions,“ Litvak said. “Our findings contribute to a deeper understanding of social dysfunction in neurological disorders, such as autism and schizophrenia, and may open new avenues for therapeutic approaches.“

 Source: University of Virginia School of Medicine; University of Massachusetts Medical School; NIH.gov; ScienceDaily.com

Journal Reference:

 

  1. Antoine Louveau, Igor Smirnov, Timothy J. Keyes, Jacob D. Eccles, Sherin J. Rouhani, J. David Peske, Noel C. Derecki, David Castle, James W. Mandell, Kevin S. Lee, Tajie H. Harris, Jonathan Kipnis. Structural and functional features of central nervous system lymphatic vessels. Nature, 2015; DOI: 10.1038/nature14432

 

  1. The findings have been published online in the journal Nature. The article was written by Filiano, Yang Xu, Nicholas J. Tustison, Rachel L. Marsh, Wendy Baker, Igor Smirnov, Christopher C. Overall, Sachin P. Gadani, Stephen D. Turner, Zhiping Weng, Sayeda Najamussahar Peerzade, Hao Chen, Kevin S. Lee, Michael M. Scott, Mark P. Beenhakker, Litvak and Kipnis.

 

This work was supported by the National Institutes of Health (grants No. AG034113, NS081026 and T32-AI007496) and the Hartwell Foundation.

ANSWERS: 1) brain; 2) system; 3) nervous; 4) century; 5) cells; 6) blood; 7) protein; 8) pathogens; 9) molecule; 10) behavior

 

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