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Protecting the Brain through Gut-Trained Immune Cells
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 infections in the brain by first spending time in the gut.

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.

In a study published in Nature, by researchers from the National Institutes of Health and Cambridge University found that immune cells that were originally from the gut could provide a fighting chance against such infections in the brain.

“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.

“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.” Added Dr McGavern.

In this study, Dr McGavern's team worked with researchers in a laboratory 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. They discovered that there were many immune cells previously conditioned 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.

Dr McGavern shared that prior to this 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.

To confirm the gut origin of cells in the meninges the researchers looked at the IgA DNA sequences. Upon, comparing the DNA sequences from IgA cells found in the meninges to those taken from a very short segment of the intestine, they found more than 20 percent overlap between the two--much greater than would be possible through random chance.

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.

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