In a paradigm-shifting discovery, neuroscientists at the University of Virginia School of Medicine have found that the brain is directly connected to the immune system by lymphatic vessels that were previously undiscovered, and not thought to exist, defying current textbook teachings. The finding may have substantial implications in the study and treatment of major neurological diseases, including multiple sclerosis.
"We believe that for every neurological disease that has an immune component to it, these vessels may play a major role," Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA’s Center for Brain Immunology and Glia (BIG) said in a press release. "Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component."
‘They'll have to change the textbooks.’
Previously thought to end at the base of the brain, the lymphatic system is comprised of vessels that carry lymph, a clear-to-white fluid filled with white blood cells that help remove toxins from the body. The lymphatic system has been very well mapped and is known to be connected to various systems in the body, but this is the first time that it has been detected in the tissues surrounding the brain, known as the meninges.
Maps of the lymphatic system: old (left) and updated to reflect UVA's discovery.
Credit: University of Virginia Health System
Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, said: “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 [CNS], 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.”
Excitement surrounding this discovery is understandable, but the findings have yet to be confirmed or replicated. Funded by an NIH grant, this research was conducted in mice. It is believed that humans may also have lymphatic vessels surrounding the brain, but that theory has not been tested.
‘Very well hidden’
The vessels were detected after postdoctoral fellow, Antoine Louveau, PhD, 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," Louveau 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."
How did the brain's lymphatic vessels manage 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."
Findings of this discovery have been published online in the journal Nature and will appear in an upcoming print edition.
“Because the brain is like every other tissue [in the body] connected to the peripheral immune system through meningeal lymphatic vessels,” says Kipnis, researchers can begin to ask mechanistic questions, rather than trying to answer questions such as ‘Why do MS patients have immune attacks?’
Keep in mind that most of the disease-modifying therapies for MS act on the immune system. Tysabri binds to T-cells preventing them from entering the CNS, Gilenya sequesters immune cells in lymph nodes, and Aubagio stops certain immune cells from multiplying.
The unexpected presence of lymphatic vessels in the brain raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. While textbooks may need to be changed, these findings begin to fill a major gap in the understanding of how the human body works.
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University of Virginia Health System. (June 1, 2015). Missing link found between brain, immune system -- with major disease implications [Press release]