How new insights into skull-based immune cells could inspire treatments for brain disease

B cells that migrate from the skull to the brain via channels other than blood learn how to tell the difference between normal proteins and those that indicate the presence of disease, according to a new study. (CC0 Creative Commons)

Some immune cells in the brain protect against disease, while others cause inflammation and other problems that can actually lead to disease. Researchers at Washington University School of Medicine in St. Louis are shedding light on the differences between these immune cell populations in two new studies.

The researchers discovered that some immune cells originate in the skull and migrate to the meninges—the tissues that line the brain and spinal cord—without passing through the bloodstream. The sole job of those skull-based immune cells is to shield the brain from disease, they explained in the journal Science.

The discovery could boost drug development for a wide range of brain diseases, the researchers believe.

"There has been this gap in our knowledge that applies to almost every neurological disease: neuro-COVID, Alzheimer's disease, multiple sclerosis, brain injury, you name it," said senior author Jonathan Kipnis, Ph.D., professor of pathology and immunology at Washington University, in a statement. "We knew immune cells were involved in neurological conditions, but where were they coming from? What we've found is that there's a new source that hasn't been described before for these cells."

Kipnis and his team had previously demonstrated that immune cells in the meninges shield the brain from harmful invaders. For one of the two new studies, he and his colleagues focused on “innate” immune cells, which cause inflammation that can heal injuries and defend against disease. But these cells can also cause damage and contribute to diseases like Alzheimer’s.

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A second Washington University team zeroed in on “adaptive” immune cells, which can destroy viruses and cancer but sometimes mistakenly attack healthy tissues, causing diseases like multiple sclerosis. The researchers discovered that B cells in the adaptive immune system originate and mature in the skull’s bone marrow.

Those B cells learn how to tell the difference between normal proteins and those that indicate the presence of disease. Because they migrate from the skull to the brain via channels other than blood, they maintain that ability to patrol the central nervous system without attacking normal proteins, the researchers explained.

A separate set of B cells does travel into the meninges from the blood—and these cells are not as good at distinguishing normal from abnormal proteins, according to that team. Meanwhile, Kipnis and his colleagues discovered that innate meningeal myeloid cells, which flood injured brain tissues, are inflammatory when they travel from the blood.

The influence of immune cells in the brain on neurological diseases is an area of intense research, much of which has been focused on microglia, a subset of myeloid cells that remove debris. Last year, for example, researchers at Stanford University spun off a startup, Tranquis Therapeutics, to target dysfunctional microglia in neurologic disorders. Its lead asset is a drug that restores a downregulated metabolic pathway in myeloid cells.

The Washington University researchers believe their discoveries about the origins of immune cells in the brain could be used to design new therapies for inflammatory brain disorders. "The location of these cells in the skull makes them relatively accessible, and opens up the possibility of designing therapies to alter the behavior of these cells and treat neuro-immune conditions," Kipnis said.