How does the immune system even know what’s happening in the brain?

The study finds a site of immune surveillance of the brain, points to new ways to target brain inflammation.

Many neurological and psychiatric conditions are associated with inflammation in the brain. Many studies have had suggested that immune cells and molecules play a significant role in brain development and function.

Yet, how the immune system keeps tabs on the brain remains obscure.

Scientists from Washington University School of Medicine in St. Louis have found the answer to the question. 

Immune cells are positioned in the meninges, where they test liquid as it cleans out of the brain. If the cells detect signs of infection, disease, or injury, they are set up to start an immune response to face the issue.

According to scientists, the study prompts the possibility of targeting immune cells at such surveillance sites to treat conditions driven by brain inflammation.

Senior author Jonathan Kipnis, the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology said, “Every organ in the body is being surveilled by the immune system. If there’s a tumor, an injury, an infection anywhere in the body, the immune system must know about it. But people say the exception is the brain; if you have a brain problem, the immune system lets it happen. That never made sense to me. We’ve found that there is indeed immune surveillance of the brain — its just happening outside the brain. Now that we know where it’s happening, that opens up lots of new possibilities for modulating the immune system.”

In 2015, scientists discovered a network of vessels that drains liquid and small molecules from the brain into the lymph nodes, where immune responses are initiated. The disclosure showed a direct physical association between the brain and the immune system. Be that as it may, the network of vessels represented an exit from the brain. It remained unclear where immune cells entered or surveilled the brain.

In this new study, scientists set out to find the immune system’s gateway to the brain. They found a clue that the vessels containing fluid leaving the brain run alongside sinuses in the dura mater, the tough outer layer of the meninges just underneath the skull.

Dural sinuses, which contain blood that carries immune cells, lack the tight barrier that keeps blood separate from the brain.

During experiments, scientists found that the dural sinuses were packed with molecules from the brain and immune cells carried in with blood. Several types of immune cells were represented, including some that pick up and display suspect molecules from the blood and others that scan the suspect molecules and respond to them by mounting a defense.

Kipnis said, “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’s 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’s a problem. They will take that evidence to immune headquarters, which is the lymph nodes, and initiate an immune response.”

The discoveries recommend that the immune system keeps an eye on the mind from a distance and possibly enters when it finds a problem. This could clarify why the brain was taught for such a long time to be immune-privileged.

Justin Rustenhoven, a postdoctoral researcher and the first author on the new paper, said, “Immune activity in the brain can be highly detrimental. It can kill neurons and cause swelling. The brain can’t 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 don’t risk damaging it.”

In their study, scientists also used a mouse model of multiple sclerosis (MS). They showed that the MS’s emergence triggered a massive accumulation of activated immune cells in the dural sinuses, suggesting that harmful immune responses may begin in the dura mater and spread to the brain.

However, future studies are required to verify the role of dural sinuses in neuroinflammatory conditions. But the location of the sinuses just on the inside of the skull on the accessible side of the blood-brain barrier suggests possibilities for targeting the immune system in that area.

Senior author Jonathan Kipnis said“If this is a gateway to the brain, we can attempt to manipulate the area with therapies aimed at preventing over-activated immune cells from entering the brain. The dura is close to the surface, so we may even be able to deliver drugs through the skull. In theory, you could develop an ointment that diffuses through the skull bone and reaches the dura. We might have found where inflammatory responses for many neuroimmunological conditions start, and there’s so much we can do with that.”

Journal Reference:
  1. Rustenhoven J et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. Jan. 27, 2020. DOI: 10.1016/j.cell.2020.12.040

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