The membranes surrounding our brains are in a never-ending battle against deadly infections, as germs constantly try to elude watchful immune cells and sneak past a special protective barrier called the meninges. In a study involving mice and human autopsy tissue, researchers at the National Institutes of Health and Cambridge University have shown that some of these immune cells are trained to fight these infections by first spending time in the gut.
"This finding opens a new area of neuroimmunology, showing that gut-educated antibody-producing cells inhabit and defend regions that surround the central nervous system," said Dorian McGavern, Ph.D., senior investigator at NINDS and co-senior author of the study, which was published in Nature.
The central nervous system (CNS) is protected from pathogens both by a three-membrane barrier called the meninges and by immune cells within those membranes. The CNS is also walled off from the rest of the body by specialized blood vessels that are tightly sealed by the blood brain barrier. This is not the case, however, in the dura mater, the outermost layer of the meninges. Blood vessels in this compartment are not sealed, and large venous structures, referred to as the sinuses, carry slow moving blood back to the heart. The combination of slow blood flow and proximity to the brain requires strong immune protection to stop potential infections in their tracks.
"The immune system has invested heavily in the dura mater," said Dr. McGavern. "The venous sinuses within the dura act like drainage bins, and, consequently, are a place where pathogens can accumulate and potentially enter the brain. It makes sense that the immune system would set up camp in this vulnerable area."
In this study, Dr. McGavern's team worked with researchers in a lab led by Menna R. Clatworthy, M.D., Ph.D., University of Cambridge, UK to look at what immune cell types reside in the outer layers of the meninges of mice and humans. What they discovered was rather surprising: there were many immune cells previously educated to make antibodies against specific microbes. These antibody-producing cells, called IgA cells, are typically found in other barriers such as the mucous membranes of the bronchial tree of the lungs and gut.
"This finding was completely unexpected," said Dr. McGavern. "Prior to our study, IgA cells had not been shown to reside in the dura mater under steady state conditions."
When compared to normal control mice, researchers observed that germ-free mice, which do not have their own microbiome, had almost no IgA cells in their meninges. They then reconstituted the gut of these mice with microbes that could not move elsewhere and demonstrated that the network of meningeal IgA cells was fully restored. This did not occur when the skin of germ-free mice was reconstituted with different microbes, suggesting that bacteria in the gut were important in educating meningeal IgA cells.
The next step was to further confirm the gut origin of cells in the meninges by looking at the IgA DNA sequences. There are likely millions of different sequences of IgA throughout the body ready to detect a wide range of threats. When two of these sequences match, it suggests that the two cells being compared originated from the same source.
When the researchers compared DNA sequences from IgA cells found in the meninges to those taken from a very short segment of the intestine, they found a more than 20 percent overlap between the two--much greater than would be possible through random chance.
"It's truly remarkable that in such a small piece of intestine we would see this large an overlap with cells in the meninges," said Dr. McGavern. "These data provide more compelling evidence that the brain is protected by immune cells that are educated in the gut."
As in the brain, the lining of the gut is sealed to prevent leakage of its contents into the body. When the lining of the gut is breached, significant inflammation and activation of the immune system occurs. When the researchers intentionally breached the gut in this study, they saw a significant response in the meninges to defend against the presence of microbes in the blood.
The researchers also looked at the role IgA cells play in protecting the brain against known infections by injecting a fluorescent version of a fungus that, under normal conditions, leads to a strong response of IgA cells in the meninges that traps the fungus similarly to bacteria. However, in mice that no longer had IgA cells either due to genetic manipulation or the application of a depleting drug to the skull (so that only meningeal IgA cells were affected), the fungus found its way into brain tissue, which had fatal consequences in all of the treated mice.
"By simply removing the IgA cells from the meninges, and without affecting any other immune cells, this fungus went from being a controlled pathogen to causing a fatal brain infection," said Dr. McGavern. "This clearly shows the importance of the local immune response."
Dr. McGavern continued by explaining that the antibody-secreting cells in these sinuses do not wait for infection to become active, but rather they constantly pump out antibodies in anticipation of foreign pathogens. This "always on" process is another means by which this highly sensitive region is protected by the immune system.
When mice were treated with antibiotics, there was a decrease in the number of IgA cells in the meninges, suggesting that depleting microbes in the body, even for a short period of time, decreases the ability of the immune system to respond to infection. Likewise, changes in the microbiome--for example, due to a change in regional diet--would be expected to affect the composition of IgA cells as the system continuously adapts.
Future work in the McGavern lab will focus on mechanisms that allow for continual education and re-education of IgA cells in the meninges.
This study was supported by the NINDS Intramural Research Program, the Intramural Research Program of the National Institute of Allergy Infectious Diseases (NIAID), the National Institute of Health Research (United Kingdom), the Medical Research Council (United Kingdom), the Chan-Zuckerberg Initiative, and the Versus Arthritis Cure Challenge.
Fitzpatrick, Z et al. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature. November 4, 2020. DOI: 10.1038/s41586-020-2886-4
For more information:
- Meningitis and Encephalitis Information Page
- Meningitis and Encephalitis Fact Sheet
- NINDS Division of Intramural Research \
- NIH Intramural Research Program
NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
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