• Scientists have long puzzled over how the immune system surveils the brain when the blood-brain barrier prevents immune cells from entering.
• A study has now identified border “checkpoints” where the immune system monitors fluid leaving the brain for signs of infection.
• The discovery offers new possibilities for treating brain diseases, such as multiple sclerosis (MS).

Generations of students have learned that the central nervous system has “immune privilege.” This means that — to an extent — the immune system tolerates the presence of foreign proteins, or antigens, and tissue in the brain and spinal cord.

The immune system cannot respond in the usual way to infections, injuries, or tumors in the brain and spinal cord, because the blood-brain barrier prevents immune cells from entering or leaving.

Despite this, scientists know that inflammation plays a pivotal role in many neurological and psychiatric conditions, including Alzheimer’s disease, MS, autism, and schizophrenia.

So the question remains, if there is no exchange of information, how does the immune system respond to and influence the brain in such a broad range of conditions?

A team of scientists led by Washington University School of Medicine in St. Louis, MO, have discovered that immune cells are stationed in the dura mater, which is the tough outer membrane of the brain.

From this vantage point, they monitor the cerebrospinal fluid draining from the brain. If they detect the molecular calling cards of infection, cancer, or injury, they can mount an immune response.

The research appears in the journal Cell.

Immunity and the brain

“Every organ in the body is being surveilled by the immune system,” says senior author Dr. Jonathan Kipnis, Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology.

He explains:

“If there is a tumor, an injury, an infection anywhere in the body, the immune system has to know about it. But people say the exception is the brain; if you have a problem in the brain, the immune system just lets it happen. That never made sense to me. What we have found is that there is indeed immune surveillance of the brain — it is just happening outside the brain.”

In 2015, a study in mice revealed a network of vessels in the dura mater that drains cerebrospinal fluid from the brain into lymph nodes in the neck. Also in 2015, a study led by Dr. Kipnis recorded similar findings in both mice and humans.

Lymph nodes are part of an extensive network of fluid-filled vessels known as the lymphatic system. An accumulation of pathogens in lymph nodes can lead to the initiation of an immune response.

This suggested a more intimate connection between the brain and immune system than previously suspected. However, it remained unclear exactly where and how immune cells surveil the contents of the cerebrospinal fluid as it drains from the brain.

Dr. Kipnis and his colleagues knew that the lymph vessels that carry fluid from the brain run alongside blood-filled cavities, or sinuses, in the dura mater.

Crucially, the walls of these sinuses are more permeable than the blood vessels of the blood-brain barrier.

Following up this clue, the scientists showed in their experiments that small molecules from the brain and immune cells accumulate in the sinuses.

Some of the cells, known as antigen presenting cells, which include dendritic cells, pick up suspicious molecules and present them to other immune cells, called T cells, which patrol the body in the bloodstream.

When they bind to these suspect molecules, the T cells can initiate an immune response.

Special status

Dr. Justin Rustenhoven, a postdoctoral researcher and the first author of the new paper, says the brain must be shielded from the full force of the immune system.

“Immune activity in the brain can be highly detrimental,” he says. “It can kill neurons and cause swelling. The brain cannot tolerate much swelling, because the cranium is a fixed volume. So immune surveillance is pushed to the borders, where the cells can still monitor the brain but do not risk damaging it.”

Dr. Kipnis uses a metaphor to explain how immune cells in the dural sinuses monitor the contents of cerebrospinal fluid for unfamiliar proteins or antigens:

“Imagine if your neighbors went through your trash every day. If they start finding blood-stained towels in your trash, they know something is wrong. It is the same thing with the immune system. If patrolling immune cells see tumor antigens or signs of infection from the brain, the cells know there is a problem. They will take that evidence to immune headquarters, which is the lymph nodes, and initiate an immune response.”

The findings offer promising opportunities for treating brain disorders that involve autoimmune attacks on tissue.

In MS, for example, the immune system degrades the myelin sheath, which is the fatty insulating material that protects nerve cells.

Future treatments could target immune cells in the sinuses of the dura mater to prevent them from initiating certain immune responses in the brain.

“Now that we know where it is happening, that opens up lots of new possibilities for modulating the immune system,” says Dr. Kipnis.

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