The researchers also found evidence of similar immune cells in human skull marrow, suggesting that this local defense system may not be limited to mice.

Scientists once believed that the brain was largely separate from the immune system. That view has changed dramatically in recent years. New findings suggest that the brain communicates with immune cells and may also have specialized immune “security stations” located unusually close to it.

Published in Nature, the study is the first to identify this type of immune hub in bone.

“This study reveals that the cranial marrow is much more than just a structural framework; it harbors a previously unrecognized site of brain-specific immune responses,” said lead author Jonathan Kipnis, Ph.D., the Alan A. Wolf and Edith L. Wolf Distinguished Professor of Pathology and Immunology and a BJC investigator at WashU Medicine. “Uncovering this local immune niche changes our view of neuroimmune interactions and opens exciting new avenues for the treatment of brain tumors and other neurological diseases.”

How skull marrow supports the brain’s immune defenses

Early research in Kipnis’ lab helped overturn the long-held idea that the brain is separate from the immune system. The group discovered lymphatic vessels in the dura mater, the protective outer layer of tissue that surrounds the brain just below the skull.

More recently, researchers discovered a small physical channel connecting the skull, dura mater and brain tissue. These channels provide a direct route through which immune cells and cellular waste products can travel between the brain and nearby cranial marrow.

In the new mouse study, scientists tracked proteins as they left the brain and traveled along these pathways into the skull marrow. There, they discovered organized immune structures similar to those normally found in lymph nodes.

Lymph nodes serve as important regulatory centers for immune activity. Among the cells found in these structures are follicular helper T cells, which support B cells and help produce large amounts of antibodies that fight infections and disease. Finding comparable structures in healthy bone marrow was unexpected.

“We have never seen structures like this in healthy bone marrow before,” said the study’s lead author, Dr. Jang Hyun Park, a postdoctoral fellow in the Kipnis lab who will start his own lab at the Korea Advanced Institute of Science and Technology this fall. “This is an exciting discovery that points out that the complex brain requires its own specialized immune structures to protect it.”

Skull immune hubs respond to brain tumors

The researchers then investigated whether these newly identified immune centers help protect the brain from disease.

They used a mouse model of glioblastoma, a highly malignant brain tumor, and used drugs to interfere with the immune hub in the skull. In mice whose immune hubs were destroyed, tumors grew faster than in mice whose immune hubs remained intact.

Mice with compromised cranial immune defenses also had shorter survival times. These findings provide evidence that the local immune structures play an active role in the body’s response to brain tumors.

Strengthening the immune response in the skull

Next, the research team examined whether the immune hubs could be intentionally strengthened.

The researchers developed a targeted treatment designed to increase antibody production within the skull marrow. They mixed three immune-boosting proteins into a gel and placed it directly under the scalp.

The treatment triggered a surge of immune activity against the tumor. Importantly, the response first appeared in immune hubs within the skull marrow and only later in nearby lymph nodes outside the skull.

Mice treated with the gel rejected tumors more effectively and survived longer than control animals.

Potential treatments for neurological diseases

The discovery may have implications beyond brain tumors. Because these immune hubs are located next to the brain, researchers believe they may eventually provide a way to influence immune activation in neurological diseases without broadly affecting other parts of the body.

“This discovery fundamentally changes our current understanding of neuroimmunology,” Kipnis said. “Knowing that the brain relies on first responders in the surrounding skull for protection could change the way we think about developing treatments for many neurological conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, long-term COVID-19 infections, and other neurological conditions that have an immune component. Such treatments could access these immune hubs directly through the skull without significant peripheral side effects.”