For decades, scientists have generally considered the brain’s immune system to be largely separate from the immune defenses operating in the rest of the body. The brain has its own specialized immune cells, along with the blood-brain barrier, which prevents many substances and cells from entering the brain tissue.
New research from Stanford challenges that image. Scientists have found that a large number of immune cells from other parts of the body enter the human brain as people age. The discovery could reshape scientists’ understanding of brain aging and eventually create new possibilities for treating neurological diseases. The work, supported in part by the Knight Brain Resilience Initiative at the Wu Tsai Neuroscience Institute, was recently published in the journal Nature.
“We typically think of the brain as a closed system,” said Julia Belk, a postdoctoral researcher in pathology at Stanford Medicine and first author of the new study. “What we found is that actually a lot of immune cells enter the human brain during aging.”
An unexpected path to brain research
Belk’s interest in neuroscience began when he was a graduate student in Stanford’s Department of Computer Science, Humanities and Sciences. During that time, he also trained through the Sarafan ChEM-H Chemistry/Biology Interface Predoctoral Training Program. She has described that experience as important in shaping an interdisciplinary approach that combines basic science, computer science and medicine.
That training eventually led to a collaboration with Siddhartha Jaiswal, senior author of the new study, an associate professor of pathology at Stanford Medicine and a member of the Institute for Stem Cell Biology and Regenerative Medicine.
In previous work, researchers examined genetic information from thousands of people, including some who had been followed for decades. The team showed that people who carried certain clones of immune cells produced by mutated blood stem cells were much less likely to develop Alzheimer’s. That result raised the possibility that these unusual immune cells could be interacting with the brain in some way.
The researchers later found evidence that some of the mutant cells could enter the brain itself. The mutations involved are associated with clonal hematopoiesis of undetermined potential, a condition found in only a minority of people. Still, the discovery led the team to ask a broader question: Could immune cells from the blood routinely enter people’s brains as they age?
“Unlike most immune cells, which are continually replenished by blood stem cells from the bone marrow, immune cells in the brain were supposed to be renewed throughout life without external contribution to the brain,” Jaiswal said. “Our first study showed that this may not always be the case.”
Challenging an old view of microglia
For years, many researchers believed that specialized immune cells in the brain, known as microglia, were established at birth and remained a self-sustaining population throughout life. Under that model, immune cells from other parts of the body were not expected to migrate to the brain and become part of this population.
Belk and his colleagues began to consider a different possibility. If external immune cells could enter the brains of some people, perhaps the process would not be unusual at all. Rather, it could be a common feature of human aging.
The idea that immune cells in the blood could play a role in Alzheimer’s was both unusual and controversial. In 2022, Jaiswal and his colleagues sought support from the Knight Initiative for Brain Resilience, which funds research aimed at rethinking how scientists study brain resilience and neurodegenerative diseases.
Supported in part by the Knight Initiative Innovation Award, Belk, Jaiswal and co-senior author Howard Chang, Virginia and DK Ludwig Professor of Cancer Research and professor of genetics at Stanford Medicine, began investigating why peripheral immune cells appeared to increase resistance to Alzheimer’s. However, before addressing that question, they first needed to determine whether immune cells from the blood could actually replenish microglia in the brain.
Tracing immune cells from blood to brain
To investigate this, the researchers studied human brain tissue. They used samples from the Stanford Rapid Autopsy Center, led by co-author Jody Hooper, a professor of pathology at Stanford Medicine, as well as samples from the University of Washington’s Alzheimer’s Disease Sequencing Project.
These programs collect post-mortem blood and brain tissue from people with and without Alzheimer’s. That combination gave the team a rare opportunity to directly compare immune cells found in the bloodstream with those present in brain tissue after death.
The challenge was to determine exactly where the immune cells had originated within the brain. Because immune cells divide continually, scientists needed to trace their cellular family trees. Their goal was to distinguish cells descended from the original population of microglia that had been present since birth from cells descended from blood stem cells in the bone marrow later in life.
Researchers found a way to do this by comparing the DNA of immune cells in the blood with the DNA of immune cells in the brain. They used shared mutations as biological markers of ancestry, somewhat like a consumer ancestry testing service.
Random mutations gradually accumulate in blood stem cells as people age. The immune cells produced by those stem cells inherit the same mutations. As a result, if two groups of immune cells carry matching mutations, it is highly likely that they share the same origin.
“If we see the same mutations in the blood and in the microglia of the brain, then we can be very confident that the immune cells in the brain are descendants of those immune cells in the blood,” he said.
Using that approach and techniques developed during their 2023 research, Belk and his colleagues compared immune cells from paired blood and brain samples. The genetic signatures matched. The results showed that the body’s immune cells had entered the brain and the process occurred as early as middle age.
Further experiments revealed another surprising development. Once peripheral immune cells entered the brain, they transformed into specialized microglia. The researchers noted that this process does not appear to occur in other species such as mice or non-human primates.
A possible new route for brain immunotherapy
Beyond challenging established ideas about brain immunity, the finding could eventually provide a new strategy for developing brain-targeted treatments.
“Now that we know that these immune cells can actually enter the brain, we can think of all kinds of new engineering strategies to get those peripheral immune cells to do useful things.”
One possibility would be to engineer immune cells so that they could attack and break down the amyloid and tau aggregates associated with neurodegenerative diseases. Over time, these cells could be given to people preventatively, before those harmful aggregates start to build up.
The discovery could also expand research into how the health and history of blood stem cells affects the brain. Because many microglia in aging humans appear to originate from blood stem cells, anything that changes blood or bone marrow cells could also influence the brain.
“Our findings suggest that the life history of blood stem cells could influence the risk of brain diseases by altering microglia,” Jaiswal said.
For Belk, the results are also notable because they reveal an aspect of brain aging that appears to be distinctly human.
“I think this is exciting because it’s also a uniquely human characteristic of aging that we had no idea about.”