YOUR brain enjoys a life of privilege. That extraordinary lump of jelly-like tissue between your ears makes up only 2 per cent of your body mass, but demands 25 per cent of your daily energy requirements. It is surrounded by the fortress of your skull to shield it from the outside world, and cushioned in a bath of nourishing fluid. It is even protected from you, insulated from the caprices of the body’s immune system to guard against inflammation.
Hold fire on that last one. It turns out that the barrier between the brain and the body’s defence forces isn’t as impassable as we thought. Yes, it stops all sorts of unwanted interlopers, as well as frustrating attempts to get drugs into the brain via the bloodstream. But there is communication across this frontier. Over the past few years, we have begun to see that the brain is in constant dialogue with the immune system and even allows some foreign agents in – discoveries that are shedding new light on everything from epilepsy and ´ˇ±ôłúłó±đľ±łľ±đ°ů’s disease to autism.
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The brain got its aloof reputation in the late 19th century, when German immunologist Paul Ehrlich noticed something odd. The dyes he was injecting under the skin of lab animals perfused virtually every tissue, turning organs a striking blue – except the brain. Later, people noticed that dye injected into the brain didn’t stain the rest of the body.
Only in the 1960s did we figure out why. As some of the first images captured by electron microscope showed, the endothelial cells lining blood vessels in the brain are different from those elsewhere in the body. Here they form tight junctions with their neighbours, creating a seal known as the blood-brain barrier that keeps out dangerous interlopers such as bacteria. Experiments showed the seal also blocked immune cells – prompting the idea that, as far as the brain was concerned, the body’s trusted guardians were dangerous too.
“Immune cells, which were the only part of the immune system we knew about, did not get into the brain, period,” says  at the University of Washington in Seattle. The one known exception, seen in multiple sclerosis, only seemed to prove the rule: the disease is a result of immune cells invading the central nervous system.
The idea of a border closed to the body’s immune system soon established itself as dogma. And yet when researchers began to inspect the blood-brain barrier more closely, they saw that it was not entirely impenetrable.
As it became clear that various immune cells secrete a flood of signalling molecules called cytokines, researchers began to wonder if those molecules could breach the border. In 1989, Banks was among the first to show that they do. He demonstrated that a cytokine called interleukin-1 alpha, which can induce fever, is pumped across the border – a situation since proven with other immune messengers. The result was a dramatic shift in our understanding of the blood-brain barrier.
“One component of ´ˇ±ôłúłó±đľ±łľ±đ°ů’s is slow damage to the blood-brain barrier”
“It is still critical, but now we look at it as an interface,” says Banks. “First it creates the barrier, and then it allows exceptions.” Indeed, it turns out that the cells forming the seal are in constant communication with the brain cells they protect, but also with immune cells circulating in the blood – a conversation that determines what is blocked and what is allowed to cross.
In some cases, their chatter is disrupted by acute damage: a stroke, say, or repeated concussive blows (See “When dementia strikes“). But it can also shift more subtly. And by eavesdropping on the elaborate crosstalk, we have recently discovered that the blood-brain barrier is implicated in various neurological problems. “With any type of chronic infection, or with diseases like epilepsy or ´ˇ±ôłúłó±đľ±łľ±đ°ů’s disease, one of the components is the long, slow, irreversible damage of the blood-brain barrier,” says at the Institute for Functional Genomics in Montpellier, France.
Take epilepsy. Using animal models, and by observing people whose blood-brain barrier is deliberately disrupted to allow chemotherapy drugs into the brain, Marchi has demonstrated that . It also works the other way round. “If you have recurrent seizures, that’s sufficient to promote inflammation in the brain and the opening of the blood-brain barrier,” he says.
It’s hard to figure out whether changes in the barrier are a cause or consequence, but there seems to be a vicious circle. Marchi hopes to develop drugs to halt this by pinning down the mechanism by which seizures lead to the leakiness that in turn allows inflammatory molecules to flood the brain. He has been focusing on pericytes, one of the most important cells forming the blood-brain barrier. In epilepsy, the connections between these and other cells in the barrier loosen, and Marchi suspects this is down to pro-inflammatory cytokines. He is plying pericytes with various cytokines to try to identify the culprit, which he would block with a drug.
Escalating inflammation in the brain seems to be a common factor in neurodegenerative diseases, Marchi says. “It’s a concept that can be applied to many brain disorders.”
Perhaps the most compelling case is ´ˇ±ôłúłó±đľ±łľ±đ°ů’s. Neuron damage associated with this form of dementia is usually thought of as a result of the build-up of a protein called beta-amyloid. In recent years, however, the spotlight has also begun to fall on disruptions of the blood-brain barrier associated with the disease. We have long known about these, but generally viewed them as a consequence rather than a cause.
Now we’re not so sure. In 2012, a team led by at the University of Southern California in Los Angeles showed that alterations in pericytes in mice bred to develop ´ˇ±ôłúłó±đľ±łľ±đ°ů’s-like symptoms preceded the onset of neurodegeneration. , opening up the brain to neurotoxins.
A year later, the same team showed how the failure of pericytes might relate to beta-amyloid accumulation. These specialist cells are equipped with a type of protein that acts as a pump, which is one of the major routes by which beta-amyloid is cleared from the brain. . By targeting one component in the cascade of signalling molecules that drives inflammation in pericytes, the team was able to heal the blood-brain barrier and reverse neuronal damage.
Nobody expects that patching these brain-body interfaces will be a complete solution. “I don’t think that by fixing the blood-brain barrier you will cure epilepsy, just like I don’t think by fixing the barrier you will cure ´ˇ±ôłúłó±đľ±łľ±đ°ů’s,” says Marchi. “But if you fix it then maybe an antiepileptic drug will function better.”
It doesn’t end there, though. As our understanding of the brain’s border control has evolved, we have also been forced to confront long-held assumptions that the immune system, and in particular molecules that promote inflammation, are unwelcome in the brain.
The idea has never sat well with , a neuroscientist at the Weizmann Institute for Science in Rehovot, Israel. Why would an organ as indispensable as the brain not avail itself of the sophisticated protection and repair services offered by the immune system? “It didn’t make sense to me, so I decided to revisit the whole issue,” Schwartz says.
Slowly but surely, she broke down the misconception. First she showed that immune cells called macrophages help restore nerve function following a spinal cord injury. Then, in 2004, Schwartz and her colleague Jonathan Kipnis showed that , such as finding a hidden platform in a pool of water.
But there were puzzles: how do macrophages enter the brain when they can’t cross the blood-brain barrier? And how do T-cells, a class of white blood cells that patrol the body, influence brain function when they aren’t found in brain tissue? It was in the process of answering these questions that Schwartz discovered a link between certain immune infiltrations in the brain and protection against neurodegeneration.
In 2013, she and her colleagues found that the normal blood-brain barrier rules don’t apply at a structure called the choroid plexus. Here, a different kind of cellular seal separates blood from brain – one which macrophages can cross, a process controlled in part by a cytokine called interferon gamma. Schwartz found that . She later found that the communication across this border was shut down completely in mice bred to have a condition equivalent to ´ˇ±ôłúłó±đľ±łľ±đ°ů’s – “just when you need the macrophages most”, Schwartz says.
Intrigued, Schwartz decided to see what happens to these mice when you block the signals that suppress interferon gamma production and gum up the barrier. . What’s more, the mice showed improvements in their symptoms. Schwartz’s team is now working towards human clinical trials of the technique.
Whole new gateway
The notion that inflammation in the brain isn’t always bad, and that encouraging it might help us to treat intractable neurological diseases, is radical. “It’s like treating frostbite with ice – totally counter-intuitive,” Schwarz says. But the idea received a big shot in the arm in 2015, when , now at the University of Virginia in Charlottesville, and his colleagues discovered yet another gateway between the body’s defence system and grey matter: via the lymphatic system.
This network of waste-disposal channels is how immune cells of every stripe get to every corner of the body, and how they pass signals back and forth. It was thought to stop at the brain – that was a big part of the reason we assumed the brain was immune privileged. An accidental discovery with some lab mice revealed that we just hadn’t been looking in the right place, says Kipnis.
“One of my postdocs was taking out brains, and didn’t do the step every neuroscientist does and peel the covering of the brain, the meninges. And we looked for immune cells and there were tons of them!” Later they found lymphatic vessels here too. This is like the trailhead of that system – T-cell patrollers can get that far, and then they send their cytokines on into the brain proper.
The discovery adds to the case that when it comes to immune system surveillance, the brain may not be so different to the rest of the body. It’s just that, “in order not to disturb the neurons, the brain pushed all other activity to the fringes”, says Kipnis.
His team is looking at how this connection between the brain and immune systems alters with age, and how that changes in ´ˇ±ôłúłó±đľ±łľ±đ°ů’s. One of the group’s most interesting recent insights, however, involves social behaviour.
Following on from Schwartz’s study showing that T-cell-deprived mice struggle cognitively, Kipnis has been unpicking the mechanism at play. His team has revealed that .
That study revealed something even more intriguing: that the adaptive immune system’s access to the brain might be involved in how we behave towards other people. “We showed mice without proper immune cells will be socially abnormal,” says Kipnis.
“This new strategy is like treating frostbite with ice: totally counter-intuitive”
Interferon gamma was responsible for this too, leading Kipnis to muse on an explanation. “If you think that bugs and pathogens drove our evolution, then in primordial species, for two creatures to become social maybe they had to be sure they could withstand pathogens from each other,” he says. So perhaps when the brain doesn’t get the interferon gamma signal that all’s well with the immune system, the animals become less social.
The finding could have implications for autism and schizophrenia, Kipnis says: perhaps an immune system change is an underlying cause in some cases.
Either way, Kipnis is convinced the immune system is a normal part of healthy brain function. “The initial thought was, if we see immune cells in the brain they are part of the disease,” he says. “I’m saying no, they are part of the solution. Of course the immune system can get out of control, but the aim is to make things better.”
This suggests a whole new approach. “Neuroscience research today, unfortunately, is probably still 90 per cent oriented to neurons,” Marchi says. “All the other cells are neglected. Considering that most brain disorders are of neurovascular origin, we need to start targeting more than just neurons.”
Schwartz goes further. “You don’t target treatment at the brain, you target the immune system, which does all the rest,” she says. “It’s a big, big turning point.”
When dementia strikes
When died from an accidental overdose of painkillers, aged 45, his autopsy revealed the cause of his tragic descent from respected professional American football player and successful businessman to depressed drug addict. McHale was one of the first former football players diagnosed with chronic traumatic encephalopathy (CTE) – a neurodegenerative disease that causes memory loss, impulsive behaviour, depression and dementia.
He was not the last. CTE is rare in the general population, but it seems common among American football players: of the 94 posthumously tested at Boston University since 2008, 90 were diagnosed. It is also familiar in soldiers who served in Iraq and Afghanistan, apparently due to close proximity to explosions. CTE doesn’t require severe head trauma, though. Repeated mild knocks seem to be enough.
So how can a series of minor blows to the head have such catastrophic consequences? Earlier this year, at Trinity College Dublin in Ireland came up with an answer: disruptions in the blood-brain barrier, a protective cellular seal around blood vessels in the brain (see main story). Campbell’s team showed that .
CTE remains mysterious, and the blood-brain barrier probably isn’t the whole story. Even so, if we could design a drug to repair the cells of the blood-brain barrier after a blow to the head, we might be able to prevent CTE and other neurological injuries.
This article appeared in print under the headline “Border control”
