Maps of the lymphatic system: old
(left) and updated to reflect UVA's discovery.
Credit: University of Virginia
Health System
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.
https://www.sciencedaily.com/releases/2015/06/150601122445.htm
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