In a study involving mice and human autopsy tissue, researchers at the National Institutes of Health (NIH) and Cambridge University have shown that some of these immune cells in our brains 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, PhD, Senior Investigator at the National institute of Neurological Disorders and Stroke (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 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, McGavern's team worked with researchers in a lab led by Menna R. Clatworthy, MD, PhD, at the University of Cambridge 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 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.
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.
