Brain Protected from Infection by Gut-Trained Immune Cells

A study published in Nature today has shown that some immune cells are trained to protect the brain from 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.

The central nervous system is protected from pathogens both by 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 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 this study, Dr. McGavern's team looked at what immune cell types reside in the outer layers of the meninges of mice and humans. They found that 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.

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.

"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."