Has the human brain been hiding a dirty secret? While studying the membranes around a mouse brain, neuroscientist Antoine Louveau stumbled across something that wasn’t supposed to be there: a web of drainage channels called lymphatic vessels, the body’s waste disposal system.
Generations of medical students have been taught the mammalian brain has no connection to the lymphatic system, to help keep the brain isolated and protected from infection. Louveau’s discovery will force a rewrite of anatomy textbooks, and could change the way researchers treat neurological diseases from Alzheimer’s to multiple sclerosis.
Along with Jonathan Kipnis and colleagues at the University of Virginia, Louveau published his discovery in Nature. “This research opens up a whole bunch of possibilities,” says Ben Hogan, geneticist at the University of Queensland.
Two major pipework systems run through your body. Blood pumps through the cardiovascular system, carrying nutrients and oxygen to the tissues. And the lymphatic system acts like a sewerage system to whisk away waste.
This clean-up is particularly important during an immune response. When you cut your finger, for instance, lymphatic vessels start draining away pathogens, immune cells and accumulating fluid from the injured tissue.
These immune cells, including T cells, travel through lymphatic vessels to lymph nodes, where they sound the alarm that bacteria have entered the cut. They recruit more immune cells, which are briefed on their bacterial target before being released into the blood to hunt down the invaders.
Meanwhile, the brain has been considered “immune privileged”, separated from the rest of the body by the blood-brain barrier, a layer of cells that protects against pathogens but also stops immune cells entering. Should the brain come under attack, it has its own immune cells – microglia – to chew up foreign invaders. The cerebrospinal fluid, which bathes the brain and the spinal cord, also contains T cells.
But Kipnis says if the brain did become infected, it was not known how it could recruit new T cells trained to recognise the invader, given that in the rest of the body, it’s via the lymphatic system that the immune system calls for backup and sends out a description of the invader. “How do you get a precise immune response without lymphatic drainage?”
Then last year, Louveau found himself looking down a microscope at lymphatic vessels in mouse meninges – the membranes surrounding the brain.
Kipnis was blown away: “We thought holy moly! This must be wrong, or it’s published and we somehow overlooked it, or we just discovered something cool.”
The team had made a discovery. Louveau was using a new method he’d developed to dissect and image the mouse meninges, which involves “fixing” the membranes (to stabilise them for analysis) before removing them from the skullcap then dissecting and imaging them as a whole. This new method of sample preparation revealed that the web of lymphatic vessels previously thought to stop at the base of the skull continues up into the meninges around the brain. These vessels run right alongside blood vessels – Kipnis believes this close relationship is the reason they remained undiscovered for so long. His team went on to image the lymphatic vessels in anaesthetised mice and showed they could carry both cerebral spinal fluids and various immune cells – possibly acting as a brain drain.
The researchers think they have also found similar lymphatic vessel structures in human brain samples, which may provide a fresh angle for neurological disease treatment. In multiple sclerosis, immune cells breach the central nervous system and attack the neurons’ insulating layers of myelin. And in Alzheimer’s disease, cell death is accompanied by protein clumping between neurons. Kipnis speculates that inefficient brain drainage could play a role in these conditions. His team is now looking into how the vessels differ in the brain of patients with brain diseases.
Tweaking the lymphatic system could become a medical treatment. Boosting growth of lymphatic vessels in the brain, for example, may help clear protein clumps in Alzheimer’s or rogue immune cells in multiple sclerosis.
Meanwhile some cancer treatments stunt the development of lymphatic drainage around a tumour to stop rogue metastatic cells from spreading to new tissues. Doing the same to the brain’s drainage system may also halt certain tumours.
Hogan is excited by the work but remains cautious. “We’d love to think this will give us a new angle on diseases like Alzheimer’s but we now need to start with the very basics,” he says.
Back in 1998, Michal Schwartz, immunologist at Israel’s Weizmann Institute, was the first to suggest the immune system and the brain are in close dialogue. She’s pleased with the finding but not surprised by it.
“It’s a very nice demonstration of something that’s been floating in the area for a while but has never been demonstrated before,” Schwartz says. She stresses that even though Louveau and Kipnis have discovered lymphatic vessels around the brain, whether they act like the lymphatic vessels of the rest of the body remains to be uncovered by further experiments.