Guarding the Brain: A Special Immune System That Protects the Brain's Gray Matter Nature's long article

Originally written by Diana Kwon

The nervous system and immune system are closely intertwined
.
Deciphering its interactions may help address many brain dysfunctions and diseases
.

The brain is the master of the body, and it is closely protected
by its important identity.
Brain cells have a long lifespan and are placed in
powerful fortifications called the blood-brain barrier.
For a long time, scientists thought that the brain was completely cut off from conflict with other body parts, especially away from its keen defense system — mainly the large number of immune cells fighting infections — whose actions could ripple through the brain
during battle.

But over the past decade, scientists have discovered that protecting the brain from aggression is not as straightforward as previously thought
.
They have found that this barrier has gates and voids, and many immune cells
are active near its boundary.

Figure 1 | The brain's immune system consists of a vascular transport network (blue) and autoimmune cells produced in the bone marrow (green).

Photo by Siling Du, Kipnis lab, Washington University in St.
Louis

There is already plenty of evidence that the brain and immune system are closely intertwined
.
Scientists already know that the brain has its own resident immune cells, called microglia; Recent discoveries concretely map their function and reveal the characteristics of other immune cells located in areas around the
brain.
Some cells come from other parts of the body; Others arise locally from the bone marrow
of the skull.
By studying these immune cells and mapping their interactions with the brain, the researchers found that they play an important role
in both healthy and diseased or damaged brains.
Interest in the field has exploded: from fewer than 2,000 papers per year on the topic in 2010, it has skyrocketed to more than 10,000 in 2021, and researchers have made several major discoveries
over the past few years.

Scientists no longer think of the brain as a special, enclosed area
.
Kiavash Movahedi, a neuroimmunologist at the Vrije Universiteit Brussels (VUB), said: "The whole idea of immunity exemptions is now quite outdated
.
" He added that while the brain is still immunologically unique — its barrier prevents immune cells from moving in and out at will — it's clear that the brain and immune system are constantly interacting (see "Brain immune barriers").

Figure 2 | Source: Nik Spencer/Nature

This shift in attitude is common among the researchers, Leonardo Tonelli said
.
He is the Director
of the Neuroendocrinology and Neuroimmunology Program at the National Institute of Mental Health.
In his experience, nearly every neurologist reviewing grant applications for the institute has embraced this link, though many still need to keep up with the latest findings in neuroimmunology that have begun to reveal underlying mechanisms
.

Tony Wyss-Coray, a neuroimmunologist at Stanford University in California, says the rush to understand how the brain and immune system work together raises a plethora of questions
.
"How important is this for normal brain function or disease? This is a difficult question
to answer.
”

Immunity exemption areas

More than two decades ago, when neuroimmunologist Michal Schwartz had just set up her lab at the Weizmann Institute of Science in Rehovot, Israel, she couldn't help but ask herself an unwelcome question: Is the brain really completely cut off immune protection? "It used to be widely believed that the brain could not withstand any immune activity
.
Everyone thinks that if there is any immune activation, it is a sign of
a pathology.
She said
.
But it doesn't make sense that an extremely important organization like the brain can't benefit from the help of the immune system
.
”

The idea that the brain is a forbidden area of the immune system took root decades ago
.
In the 20s of the 20th century, Japanese scientist Y.
Shirai reports [1] that when tumor cells were implanted into mice, the immune response destroyed them, but when they were implanted in the brain, they survived – indicating a weak or absent
immune response.
Similar discoveries
were made in the 40s of the 20th century.

Most scientists also believe that the brain lacks a system for transporting immune molecules in and out — that is, a lymphatic drainage system found elsewhere in the body — even though such systems in the brain were first described more than two centuries ago [2].

The prevailing view at the time was that the brain and immune system were largely separate
.
It is thought that the two interact only in adverse circumstances: when immune cells get out of control and attack autologous cells, such as multiple sclerosis
.

Thus, in the late '90s, Schwartz and her team reported [3] that after acute damage to the central nervous system, two types of immune cells—macrophages and T cells—protected neurons from damage and supported their recovery, which many scientists doubted
.
In retrospect, Schwartz said, "Everyone told me you were completely wrong
.
”

Since those early experiments, Schwartz's team and others have amassed a wealth of evidence that immune cells do play an important role
in the brain, even without autoimmune diseases.
For example, the researchers showed that neurodegenerative diseases such as motor neuron disease (amyotrophic lateral sclerosis) and Alzheimer's disease appeared to progress more rapidly in mice genetically modified with immune system deficiencies [4], while restoring the immune system slowed their progression
.
Scientists have also revealed a potential role
for microglia in Alzheimer's disease.

Figure 3 | Cerebrospinal fluid (red) penetrates into brain tissue (blue)
through tiny gaps in blood vessels that flow through the protective layer of the brain.
Photo by Antoine Drieu, Kipnis lab, Washington University in St.
Louis

Recently, scientists have shown that immune cells at the edge of the brain are active
in neurodegenerative diseases.
After examining cerebrospinal fluid from Alzheimer's patients, Wyss-Coray and colleagues found evidence of an increased number of T cells in the fluid-filled boundaries of the brain [5].

Wyss-Coray said the increase in the number of these immune cells suggests they may play a role
in the disease.

But whether immune cells are bad or good for the brain is an open question
.
In studies of Alzheimer's disease and other neurodegenerative diseases, Wyss-Coray and colleagues propose that the immune system may destroy neurons
by releasing inflammatory factors that promote inflammation and trigger cell death.
Others believe that T cells and other immune cells play a protective role
.
For example, Schwartz's team reports [6] that in mouse models of Alzheimer's disease, an enhanced immune response can clear amyloid plaques (a pathological feature of the disease) and improve cognitive performance
.

Busy borders

It is becoming increasingly clear that the immune system at the edge of the brain is very diverse: almost any type of immune cell can be found
in the peripheral areas of the brain.
The meninges — fluid-filled membranes that envelop the brain — are an "immune playground," Movahedi said, and his work focuses on macrophages
at the edge of the brain.
"There's
so much going on there.
"

Some cells are found only in the large front.

In 2021, neuroimmunologist Jonathan Kipnis at the University of Washington and his colleagues reported [7] that immune cells have a local source, the bone marrow
of the skull.

When they explored how bone marrow mobilizes these cells, Kipnis and his colleagues demonstrated [8] that when the central nervous system is damaged or pathogens are present, signals carried in the cerebrospinal fluid are transmitted to the skull bone marrow, prompting it to produce and release these cells (see "Private Protector").

Figure 4 | Source: Nik Spencer/Nature

The function of these locally produced immune cells remains to be seen, but Kipnis' team believes they may play a gentler role than immune cells from other parts of the body, regulating the immune response rather than preparing for battle
.
Kipnis says that if the difference does exist, it will have therapeutic potential
.
For diseases like multiple sclerosis, he said, symptoms may be improved by blocking immune cells from other parts of the body from
entering.
In contrast, for brain tumors, "what you need is a warrior.
"

His team also discovered a network of channels that snake off the surface of the brain that are filled with immune cells that form the brain's own lymphatic system [9].

These tubes, located in the outermost layer of the meninges, provide immune cells with a vantage point close to the brain, where they can monitor for any signs of
infection or damage.

Regardless of illness or health

As evidence mounts that immune cells are involved in brain injury and disease, researchers have also been exploring their function
in healthy brains.
Beth Stevens, a neurologist at Boston Children's Hospital, said: "I think the most exciting part of neuroimmunology is that it is associated with so many different diseases and normal physiology
.
”

Many teams, including Stevens' group, have found that microglia are important
for brain development.
These cells are involved in neuronal connection pruning, and studies have shown that problems during pruning can lead to neurodevelopmental problems
.

Boundary immune cells have also been shown to be essential for
a healthy brain.
For example, Kipnis, Schwartz, and colleagues have shown that mice lacking these cells exhibit problems with learning and social behavior [10].

Other researchers reported in 2020 [11] that mice without a specific population of T cells in the brain and other parts of the body had defects in their microglia
.
Their microglia have difficulty pruning neuronal connections during development, resulting in an excessive number of synapses and abnormal behavior
.
The authors propose that during this critical period, T cells can migrate to the brain to help microglia mature.

One big mystery is how immune cells—especially those near borders—communicate with the brain
.
Although there is some evidence that they may occasionally enter this organ, most studies to date have shown that these cells communicate
through molecular messengers called cytokines.
This, in turn, affects behavior
.

Figure 5 | The signals carried in the cerebrospinal fluid (blue) are presented to immune cells in the outer blood vessels of the brain protecting (magenta).

Source: Justin Rustenhoven, Kipnis lab, Washington University in St.
Louis

Researchers have been studying how cytokines affect behavior
for decades.
For example, they found that when infected, cytokines released by immune cells trigger "disease behaviors," such as increased sleep time [12].

They also found in animal models that alterations in cytokines can lead to changes in memory, learning, and social behavior [13], which can be induced
by consuming cytokines throughout the body or knocking out specific cytokine receptors on neurons.
How cytokines enter the brain and function remains an active area of research
.

Cytokines may also be linked
to the immune system and neurodevelopmental problems such as autism.
When MIT neuroimmunologist Gloria Choi and her colleagues raised cytokine levels in pregnant mice, they saw brain changes and autism-like behavior in offspring [14].

Despite these fascinating insights, much of the research on how immune cells, especially in the border zones, operate in the brain, is still in
its infancy.
Kipnis said: "We are far from understanding what happens
in a healthy brain.
”

Two-way action

Communication between the immune system and the brain seems to have another direction: the brain can direct the immune system
.

Some of these insights were born decades ago
.
In the 70s of the 20th century, scientists guided rats to develop immunosuppression when they tasted saccharin by pairing an artificial sweetener with an immunosuppressive drug for several days [15].

In a more recent study, Asya Rolls, a neuroimmunologist at the Technion, and her team explored the link between
mood, immune status, and cancer in mice.
Their 2018 report [16] states that activating neurons in the ventral tegmental area, a brain region involved in positive emotions and motivation, can enhance the immune response, thereby slowing tumor growth
.

Then, in 2021, her team identified neurons in the insular cortex, a part of the brain involved in processing emotions and bodily sensations, among others, that is, active during colonic inflammation
, the onset of colitis.

By artificially activating these neurons, the researchers were able to reawaken the gut immune response [17].

Just as Pavlov's dogs learned to associate ringtones with food, making them drool when they hear sounds, these rodent neurons also capture an immune response "memory"
that can be restarted.
"This shows that there is a very strong interaction
between neurons and immune cells.
" Movahedi said he was not involved in the work
.

Rolls suspects that organisms evolved this immune "memory" because it benefits itself, speeding up the immune system
when the body may encounter pathogens.
In some cases, she added, they can be maladaptive — when the body anticipates infection and produces an unwanted immune response, leading to collateral damage
.
Rolls believes that this pathway may help explain how mental states affect immune responses, providing a potential mechanism
for many psychosomatic disorders.

The discovery of this immune "memory" also sheds light on
treatment options.
Rolls and her team found that blocking the activity of these inflammation-related neurons reduced inflammation
in mice with colitis.
Her team hopes to apply these findings to humans and is investigating whether using non-invasive brain stimulation to suppress neuronal activity could help alleviate symptoms in patients with Crohn's
disease and psoriasis, two diseases mediated by the immune system.
Rawls says it's still early days, "but it would be cool if it were useful.
"

Other research groups are exploring how the brain controls the immune system
.
Choi's team is tracking down specific neurons and circuits that modulate immune responses
.
She hopes to one day map the interaction between the brain and immune system, outline the cells, circuits and molecular messengers responsible for two-way communication, and link
these to behavioral or physiological data.

One of the biggest challenges today is teasing out which cell populations are involved in these diverse functions
.
To address this, some researchers have been exploring the differences
at the molecular level in single cells by sequencing genes in these cells.
For example, subsets
of microglia associated with neurodegenerative diseases have been identified.
Understanding the functional differences between these microglia and healthy microglia will help develop treatments
, Stevens said.
They can also be used as markers to track disease progression or treatment effects
, she added.

Researchers have begun using these insights to study the immune ecosystem
in and around the brain.
Schwartz's team, for example, is rejuvenating the immune system in hopes of fighting Alzheimer's disease
.
Schwartz said the work opens up new avenues for treatment, particularly for neurodegenerative diseases
.
"This is an exciting time
in the history of brain research.
"

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The original article was published in the June 1, 2022 news feature section of Nature as Guardians of the brain: how a special immune system protects our grey matter

© nature

doi: 10.
1038/d41586-022-01502-8

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