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The last frontier? Lifting the lid on the blood-brain divide

Brain MRI scan

While vaccines and infectious diseases provide major challenges for immunologists, there are other aspects of immunology that are no easier to crack. For many years the brain was considered a fortress cut-off  from the rest of the body. A hard bony skull protected it from outside threats, while the tight cellular junctions of the blood–brain barrier shielded it from inner ones – including the immune system. There were good reasons for this assumption: immune activation is associated with inflammation and swelling – processes there’s little space for within the rigid confines of the skull – while cell death and the regeneration it unleashes would surely result in the disruption of learned actions and memories. 

These assumptions were backed up by physical evidence, too. With the exception of microglia – immune-derived support cells that populate the brain – there was little sign of any immune cell activity in the way of peripheral white blood cells such as T and B cells in the central nervous system. Additionally, early experiments that involved transplanting foreign tissue into the brain failed to prompt the usual immune rejection. “Because we couldn’t really see any evidence of any white blood cells in there, the possibility of having an immune response in the brain was thought to be remote,” says Clive Holmes, Professor of Biological Psychiatry at the University of Southampton. The discovery of T and B cells in the brains of people with multiple sclerosis only confirmed suspicions that when the immune and nervous systems got together, bad things happened.

Infiltrating the brain

The past 20 years has seen a dramatic re-evaluation of this model. Not only can white cells from the blood infiltrate healthy brain tissue, their presence might be a necessary means of keeping out and stopping foreign invaders like viruses from causing damage. Immune cells also gather on the meninges – a fibrous membrane that surrounds the brain and central nervous system – and communicate with a whole network of microglia and astrocytes in deeper brain structures. 

Our understanding of the function of these immune-derived cells has also been turned on its head: once considered passive support cells, we now know that microglia are crucial in shaping the neuronal network by trimming away weak connections between neurons. Both microglia and astrocytes release signalling molecules of their own to influence brain function as well as producing growth factors that aid neuronal growth during development and also repair neuron and myelin damage in diseases such as multiple sclerosis. 

There’s a growing sense that T cells need to go into the brain – that they have this surveillance role in health – and they almost certainly go in during infection

However, as well as being an essential component of healthy brain function, this brain-immune relationship could have a dark side. From Alzheimer’s to Parkinson’s disease, schizophrenia and depression, diseases that were once considered to be purely neurological are increasingly being linked to a dysfunctional immune system – which could in turn open up new opportunities for treating them. 

Sickness behaviour

Some of the first clues that the immune system might be influencing the brain came from studies of sickness behaviour, a coordinated set of symptoms including lethargy, depression and loss of appetite that will be familiar to anyone who has been ill. “When people get a peripheral infection, they feel psychologically impaired by it,” says Holmes. “They might have mood changes and loss of concentration, which implies that there is something going on in the brain.” 
These same symptoms can also be triggered in experimental situations following an injection of lipopolysaccharide (LPS) – a major component of some bacterial outer cell membranes – into the bloodstream, suggesting it’s not simply being ill that causes this behaviour. Indeed, experiments have revealed that an injection of LPS prompts immune cells to release inflammatory cytokines that both stimulate the vagus nerve (a major communication channel into the brain) and immune-like cells living on the brain’s edges, which in turn activate microglia deeper in the brain.   

All of this makes sense from an evolutionary perspective: if you feel tired and anti-social when you’re fighting off an infection, you’re less likely to go out and spread that infection to other people, or pick up more infections when your immune system is already activated. 

Immune functions within the healthy brain

The immune system may also play a role in the healthy brain. Experiments by Professor Jonathan Kipnis at the University of Virginia and his colleagues have revealed that mice engineered to lack CD4+ T cells perform poorly on learning and memory tasks, but improve if they are injected with T cells taken from healthy mice. Further research has revealed that learning a new task seems to prompt a mild stress response in the brain which causes T cells to rally to the meninges, where they release signalling molecules that prompt astrocytes to release a protein called brain-derived neurotrophic factor that enhances learning.  “Even though the immune cells are sitting at the edges of the brain, they are still important for its function,” says Kipnis. 

However, T cells may be able to penetrate into the brain’s deeper layers as well. For a long time this was only thought to occur in neurological diseases such as multiple sclerosis, when aggressive immune T cells primed to attack the myelin coating that speeds up transmission of nerve signals broke through the blood–brain barrier.  However, advances in microscopy and the ability to fluorescently tag immune cells have recently revealed that the passage of these T cells into the brain is an active process that involves the cooperation of healthy cells living in the meninges.  “There’s a growing sense that T cells need to go into the brain – that they have this surveillance role in health – and they almost certainly go in during infection,” says Professor Sandra Amor, Head of Multiple Sclerosis Research at VU University Medical Center in Amsterdam. Indeed, T cells may play an important role in regulating immune responses within the brain and ensuring they don’t get out of control. 

Lymphatic vessels have also recently been discovered in the meninges that shuttle molecules and immune cells from the cerebrospinal fluid surrounding the brain and spinal cord to a group of lymph nodes buried deep in the neck.  “We think immune cells in these lymph nodes will see these molecules, become activated and then go back into the brain and perform their effect,” says Kipnis, who led the team that discovered them. In most cases, the immune cells will travel to the meninges and release signals that indirectly influence brain function via the microglia. But in extreme circumstances, immune cells may cross the blood–brain barrier and influence the brain more directly.

New approaches for multiple sclerosis

Such discoveries are prompting a radical rethink of the role the immune system plays in the healthy brain. “Even twenty years ago, if you told someone that the central nervous system recruits immune cells into its tissues for its benefit, they would think you were crazy. Today, the question is not: are they beneficial or not, but what exactly are they doing, and how can we augment the beneficial response?” says Kipnis.

So what could this new understanding of the brain’s immune system mean for patients? It’s early days, but these insights are already translating into new therapies for people with multiple sclerosis (MS), a neurological condition characterised by damage to the protective myelin coating that surrounds nerve fibres. An early example is natalizumab (Tysabri) – a monoclonal antibody-based drug which targets a molecule on the lining of blood vessels that T cells bind to in order to gain entry to the brain. This approach is very effective in blocking T cells going into the brain and thus very effective in early MS. The trouble is that taking this drug also raises the risk of developing another rare, but severe, brain disease called progressive multifocal leukoencephalopathy, which is triggered by the John Cunningham virus – further evidence that T cells play a role in healthy brain function. “If you’re blocking all the T cells from going into the brain, you’re also going to block the good ones that control such infections” Amor points out. 

Another strategy might be to target microglia instead. Whereas MS has long been considered a disease of dysfunctional  T cells, Amor believes they might be a secondary consequence of something happening to the oligodendrocyte cells that produce myelin, and the microglia they communicate with.  Specifically, the microglia seem to become activated in response to a kind of stress signal put out by the oligodendrocytes – though what triggers this signal is unknown. 

“Generally T cells don’t go into the brain in large numbers unless they’re called in for some reason – maybe because the microglia can’t control the situation and they need back up by the peripheral immune cells,” says Amor. “In most cases the microglia and astrocytes can control so-called danger situations but are not armed with munitions to fight major battles. In these cases, signals are sent to the T and B cells to enter the central nervous system.” Once the T cells reach the site of the problem, Amor believes the T cells start attacking the oligodendrocytes, resulting in the loss of myelin. However, as the disease progresses there is accumulating evidence that microglia, rather than T cells, play a role in the neurodegeneration that occurs.  Developing drugs that directly target microglia might therefore be an alternative therapeutic option. One such approach that has been shown to modulate microglia in experiments is a heat shock protein called HSPB5. It has been used in clinical trials in early MS, but has not yet been tested in late disease. 

Alzheimer’s implications

Dysfunctional microglia are also the focus of new strategies to treat and prevent other brain conditions. Take degenerative diseases like Alzheimer’s.  Until recently, there was little evidence that the immune system played any role in this disease; most research had instead focused on the amyloid plaques that are its hallmark. Yet there’s a growing suspicion that, at the very least, infection or inflammation outside the brain might be part of the problem. It might even be the initial trigger for amyloid production. 

One of the first clues that the immune system could be involved in Alzheimer’s disease came from observations of mice predisposed to develop neurodegenerative disease. When Professor Hugh Perry at the University of Southampton injected these mice with LPS to mimic a bacterial infection outside the brain, their microglial cells became more activated, their neurons started to die, and their performance on cognitive tasks began to suffer. Intrigued, Perry called Holmes, and asked whether his Alzheimer’s patients similarly deteriorated if they got an infection. “Of course they do,” Holmes replied. But when he turned to the published literature, he could find little to back up his assertion and so he started researching it himself.

Cognitive declines

Since then, he and Perry have discovered that it’s not just infection, but chronic inflammation caused by other diseases such as rheumatoid arthritis, atherosclerosis, and even gum disease, that can hasten the cognitive decline of people with Alzheimer’s. “Infections, such as urinary tract infections, roughly double the rate of decline, while chronic low grade inflammation increases it about four-fold,” says Holmes. 

He suspects that the presence of amyloid somehow primes microglia, putting them into a state of high alert. If they then encounter inflammatory signals coming from elsewhere in the body they overreact, and ultimately start killing brain cells.  “We think these very low grade infections – things that you or I wouldn’t necessarily even be aware of – are enough to cause major damage in people with Alzheimer’s,” Holmes says.

Inflammation could even be what triggers the production of amyloid in the first place. Alzheimer’s is a highly heritable disease, and of the genes that have been linked to the most common form of Alzheimer’s so far, around half are involved in inflammatory processes. Animal studies have demonstrated that infections elsewhere in the body can trigger amyloid production in the brain, while studies in cell culture have suggested that amyloid has antimicrobial properties. “Possibly it’s a protective mechanism against bacteria entering the brain,” says Holmes.

New leads to novel treatments

Such discoveries raise the prospect of using anti-inflammatory drugs to treat the disease; indeed, epidemiological studies have suggested that people who take non-steroidal antiinflammatory drugs (NSAIDs) are at reduced risk of developing Alzheimer’s. However, trials that have involved giving NSAIDs prospectively have produced mixed results. Possibly this is because the drugs they used aren’t specific enough. One cytokine that has consistently been associated with cell damage in the brain is TNF-α, and “a lot of non-steroidal drugs don’t hit TNF-α at all,” says Holmes. In a small pilot study of 41 patients, he and his colleagues gave patients either the TNF-α blocker etanercept or a placebo for six months. Those on etanercept saw no progression of their disease while those on the placebo drug deteriorated.

TNF-α blockers are also being tested in people with depression. Here too, the link between systemic inflammation and psychological symptoms has been growing for some time, and activated microglia seem to be involved in at least a subset of cases. People with multiple sclerosis, diabetes and rheumatoid arthritis all have higher than average baseline levels of inflammation, and are at greater risk of depression. “This risk seems to be separate from the disease itself,” says Amor. 

Not only can white cells infiltrate healthy brain tissue their presence might be a means of keeping out and. stopping foreign invaders like viruses from causing damage

In one recent trial, 60 people with treatment-resistant depression were either given the TNF-α blocker infliximab, or a placebo drug over 12 weeks. Although at first glance there was little difference in the outcomes of the two groups, when the researchers focused in on volunteers who had started out with high levels of inflammation, those in the infliximab group showed an improvement in their symptoms. 

A new age of understanding

Although we’ve come a long way in our appreciation of the role the immune system plays in the brain, there’s still plenty we don’t understand. Why, for instance, does inflammation result in depression in one individual, and dementia in another? “Clearly the triggers of the brain’s immune system are different in these diseases,” says Amor. And how could ageing and the changes in immune status it brings affect the brain?  “I think we’re just at the very tip of the iceberg in terms of our understanding,” says Kipnis.

But one thing is now certain: the brain is anything but isolated from the rest of the body. By studying the immune system, we’re likely to learn far more about what makes us tick than by considering the brain alone.

This article was written by Linda Geddes as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.