For several decades, scientific and popular understanding had characterised the central nervous system as lacking of a classical lymphatic drainage system despite an established consensus that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment. The mechanisms involving the movement of immune cells in and out of the central nervous system remained poorly understood. Thus, the direct link between the brain and immune system was thought to be non-existent.
However, researchers Antoine Louveau et al made a groundbreaking discovery that overturns decades of textbook teaching and widespread understanding.
“The first time these guys showed me the basic result, I just said one sentence: ‘They’ll have to change the textbooks,’” said Kevin Lee, PhD, co-author and chairman of the UVA Department of Neuroscience. “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.”
In searching for T-cell gateways into and out of the meninges, the researchers discovered functional lymphatic vessels lining the dural sinuses linking the brain and immune system. The structures of these vessels corresponded to all of the molecular characteristics of lymphatic endothelial cells. In addition, they function by carrying both fluid and immune cells from the cerebrospinal fluid. Mapping further these vessels reveal connection to the deep cervical lymph nodes.
Louveau specifically developed a method to mount the meninges, the membranes covering the brain, of a mouse on a single slide to examine it as a whole. After observing vessel-like patterns in the distribution of immune cells on his slides, he tested them to determine if they were lymphatic vessels. Results verified that these vessels in the meninges corresponded to the characteristic of lymphatic endothelial cells.
“I really did not believe there are structures in the body that we are not aware of. I thought the body was mapped,” said Jonathan Kipnis, PhD, co-author, professor at the University of Virginia School of Medicine, and director of Center for Brain Immunology and Glia at UVA. “I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not.”
There is one likely explanation as to why previous research that involved mapping of the central nervous system and immune system had missed the vessels discovered by Louveau et al. According to the researchers, these vessels are located in areas that are hard to locate. They follow ajor blood vessels down into the sinuses making them difficult to map and image.
Nonetheless, the groundbreaking discovery not only overturns previous textbook teachings but also raises numerous questions about the workings of the brain and the diseases that plague it. Louveau et al believe that the true significance of this discovery lies in the effect it could have on the study and treatment of neurological diseases. It now requires a reassessment of basic assumptions in neuroimmunology and a further investigation involving the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
It is worth mentioning that a growing body of literature has explored the correlation between infection and decline in cognitive functions or development of mental illnesses. There are also specific studies hypothesising the viral origin of schizophrenia and other mental disorders.
“Now we can approach this mechanistically,” said Kipnis. “Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels.
“We believe that for every neurological disease that has an immune component to it, these vessels may play a major role,” added Kipnis. “It is hard to imagine that these vessels would not be involved in a neurological disease with an immune component.”
Further details of the study of Louveau et al are in the article “Structural and functional features of central nervous system lymphatic vessels” published in 2015 in the journal Nature. Complete author list includes ouveau, 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, and Jonathan Kipnis. Photo credit: Allan Ajifo & aboutmodifinil.com/Adapted/CC 2.0