Last week, researchers announced they had discovered a physical connection between the immune system and the brain’s blood supply. The finding gives researchers a novel approach to understanding diseases ranging from autism to multiple sclerosis, and strengthens the bridge between neuroscience and immunology.
Maps of the lymphatic system: old (left) and updated to reflect the discovery discovery. Image credit: University of Virginia Health System.
In last week’s issue of Nature, researchers led by University of Virginia neuroscientist Jony Kipnis describe their discovery of lymphatic vessels in the tissues beneath a mouse’s skull. Their observation was unexpected, to say the least. Lymphatic vessels complement the body’s blood vessels, carrying immune cells throughout the body instead of blood. But for decades, researchers had assumed that the lymphatic system stopped short of the brain. Kipnis’ team’s discovery turns that assumption on its head. “They’ll have to change the textbooks,” Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, recounted telling his colleagues upon hearing of their finding.
The science linking the brain and the body has come a long way in the past decade. Disorders like autism are anecdotally associated with gastrointestinal problems in children, and mouse models of autism have been empirically associated with the balance of their gut microbes. Similarly, an over-reacting immune system is associated with autism-like behaviors in mice, and can even transform strep throat into a psychiatric illness called PANDAS, a deceivingly cuddly acronym that stands for pediatric autoimmune neuropsychiatric disorders associated with streptococci.
But how are gut microbes, the immune system, and neurons connected in the first place? Until recently, this was anyone’s bet. The immune system, which tracks and addresses threats to the body by way of the bloodstream, is directly exposed to neither the inside of the gut nor the brain. The gut microbiome is separated from the bloodstream by the lining of the intestines, and from the brain by the aptly named blood-brain barrier (BBB). Indeed, the brain was long considered to be “immune privileged,” or exempt from normal immune surveillance, both good and bad—a necessity given that, for instance, the brain can’t tolerate swelling from inside the skull.
Blood vessels are sequestered from direct contact with the brain via the blood brain barrier - keeping the peripheral immune system at bay. Ben Brahim Mohammed CC BY 3.0
But in the last twenty years, the notion that the brain is immune privileged has been slowly dismantled. Careful studies have shown that the brain does interact with the peripheral immune system, albeit in unique ways. Immune cells do, somehow, circulate through the brain, and antigens—which would normally stoke an immune response—do drain from the brain into the lymph nodes. Moreover, neurological diseases like multiple sclerosis and Alzheimer’s have long been linked to changes in immune system function, and autoimmune diseases of the gut, like Crohn’s disease, correlate with psychiatric illness.
One major problem for the field, though, has been the lack of a physical connection between the brain and the body that could help explain the mystery behind these diseases. But last week, scientists at the University of Virginia stumbled across such a bridge: a network of lymphatic vessels that appears to directly link the brain with the immune system.
Kipnis’ team was studying the circulation of immune cells in the meninges, the blood-vessel-rich tissue that lies between the skull and the brain. They were looking at T-cells, specifically, a class of immune cell that detect trouble in the body and communicate it to the rest of the immune system. Other labs had noticed that T-cells injected into the brain eventually found their way to the cervical lymph nodes. What wasn’t clear was how they got there. (The BBB, certainly, would not allow T-cells to travel back and forth.)
A post-doctoral scientist in the Kipnis lab, Anthoine Louveau, came up with a nifty method for visualizing the meninges of a mouse brain without destroying it. “It was fairly easy, actually,” he explained in a press release. “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.”
Louveau and his colleagues processed the carefully-mounted tissue so they could see immune cells and lymphatic vessels, which normally connect the rest of the body to the lymph nodes. Shockingly, there were lymphatic vessels that closely followed blood vessels down into the sinuses of the brain—anatomists had apparently missed this direct conduit for decades. In the press release, Louveau recalled the moment when he realized the import of what he was looking at: “I called Jony [Kipnis] to the microscope and I said, ‘I think we have something.’”
Outside experts say it’s a big discovery. Caltech biologist Elaine Hsiao—who studies the interaction between gut microbes, the immune system, and the brain, but was unaffiliated with the study—told me that Louveau’s team’s findings suggest “there may be more intimate interactions between the peripheral immune system and brain than we’ve ever realized.”
Hsiao has been at the forefront of the overlapping fields of neuroscience, immunology, and microbiology for nearly a decade. In recent years, along with others at Caltech, she characterized the importance of both the immune system and particular gut microbes in mouse models of autism. This past April, her lab showed that a particular type of gut microbe is responsible for spurring cells in the gut to produce serotonin—nearly all the serotonin found in the body.
A model system of gut microbes believed to play a role in human diseases like Alzheimer’s. Pacific Northwest National Laboratory CC BY-NC-SA 2.0.
While little of this peripheral serotonin crosses the blood-brain barrier, Hsiao says “there is an increasing appreciation that serotonin mediates pro-inflammatory responses.” Her recent study showed that without this microbe-induced serotonin production, a host of problems with gastrointestinal function emerge. Her lab is intrigued by the potential impact of this serotonin on other elements of physiology, such as immunity. Moreover, the recent discovery from the Kipnis lab “raises the question of whether microbial influences on the neuroimmune system, or neuro-immune interactions, can lead to changes in brain function and/or behavior.”
Could autism, or PANDAS, result from some alteration to the gut microbiome that impacts the immune system via serotonin, and then spurs some change in the brain? Is the lymphatic system of the brain failing to clear out the proteins that accumulate into toxic plaques and tangles during Alzheimer’s? Or is the immune system malfunctioning during multiple sclerosis, due to its encounters with the brain via these lymphatic vessels? All these speculations become fair game with this newfound appreciation of the brain’s connection to the immune system.
Wendy Ingram, a postdoctoral researcher in human translational genomics at Geisinger Medical Center in Pennsylvania, wonders whether this finding could shed light on her 2013 discovery that a particular parasite, Toxoplasma gondii, can cause mice to lose their fear of cat urine. After mice consume feces containing this parasite, the parasite somehow gets into the brain, and permanently disables an innate fear circuit—but until now, the options for traveling from gut to brain weren’t well understood.
One compelling route for the parasite could directly involve this new lymphatic connection to the brain. After crossing into the bloodstream from the gut, T. gondii might hitch a ride with immune cells destined for the brain, “allowing them to transit into the CNS in a ‘trojan horse’ type of parasite delivery,” Ingram explains. Is the lymphatic system lighting the way for these parasites to get into the brain? Even our brains?
Given that T. gondii permanently alters mouse behavior, even after it has been cleared from the brain, Ingram speculates there are numerous ways that the parasite might leave an indelible mark on brain function, though more research will be required to figure out how a microscopic parasite can actually eliminate the fear of cats in a mouse. “Suffice to say, there are likely many connections and interactions between the brain and the immune system which are completely unknown,” she says.
Hsiao is confident that scientists will waste no time in exploring the implications of Louveau’s team’s discovery. “In the next decade, I think that the collective ‘we’ will be on our way toward achieving an understanding of the neuro-immune system that matches the depth and breadth of our knowledge of the peripheral immune system,” she says. “I hope that we’ll be seeing new ways of using peripheral pathways to hack into brain function and behavior, to treat symptoms of neurological disease.”
But no matter exactly how this work is followed up, neuroscience and immunology now have even greater reason to collaborate. These findings “are going to crack open the chasm of the field of neuroimmunology in a wonderful way,” Ingram says. “Immunologists and neuroscientists have been politely ignoring each other for far too long.”