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Protecting the brain from infection can start with an intestinal reaction

Some immune defenses of the brain may have their roots in the gut.

A new study in mice finds that immune cells are first trained in the gut to recognize and launch attacks on pathogens and then migrate to the surface of the brain to protect it, researchers report Nov. 4 in Nature. These cells have also been found in surgically removed parts of human brains.

Every minute, about 750 milliliters of blood flow through the brain, giving bacteria, viruses or other blood-borne pathogens the opportunity to infect the organ. For the most part, invaders are held out by three layers of membrane, called meninges, that wrap around the brain and spinal cord and act as a physical barrier. If a pathogen manages to break that barrier, the researchers say, trained immune cells in the gut are ready to attack by producing a battalion of antibodies.

The most common way for a pathogen to end up in the bloodstream is from the gut. “So it makes perfect sense for these (immune cells) to be educated, trained, and selected to recognize the things that are present in the gut,” says Menna Clatworthy, an immunologist at Cambridge University.

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Clatworthy's team found antibody-producing plasma cells in the leathery meninges, which lie between the brain and the skull, in both mice and humans. These immune cells have produced a class of antibodies called immunoglobulin A or IgA.

These cells and antibodies are found primarily in the inner lining of the gut and lungs, so scientists wondered if brain cells had any link to the gut. It turned out that there were: Mice without germs, which had no microbes in the intestines, also had no plasma cells in the meninges. However, when bacteria from poop from other mice and humans were transplanted into the intestines of mice, their intestinal microbiomes were restored and plasma cells appeared in the meninges.

“This was a powerful demonstration of how important the gut could be in determining what is in the meninges,” Clatworthy says.

The researchers captured microscopic images of an attack on the meninges of mice directed by plasma cells that had probably been trained in the gut. When the team implanted a pathogenic fungus, which is normally found in the gut, in the bloodstream of mice, the fungus attempted to enter the brain through the walls of the blood vessels in the meninges. However, plasma cells in the membranes formed a mesh made of IgA antibodies around the pathogen, blocking its entry. Plasma cells are found along blood vessels, Clatworthy says, where they can quickly launch an attack on pathogens.

"As far as I know, this is the first time that someone has demonstrated the presence of plasma cells in the meninges. The study rewrote the paradigm of what we know about these plasma cells and how they play a key role in keeping our brain healthy, "says Matthew Hepworth, an immunologist at the University of Manchester in England who did not participate in the study. More research is needed to classify how many of the plasma cells of the meninges come from the intestine, according to him.

The finding adds to growing evidence that intestinal microbes may play a role in brain diseases. A previous study, for example, suggested that in mice, potentiating a specific intestinal bacterium could help fight amyotrophic lateral sclerosis, or ALS, a fatal neurological disease that results in paralysis (SN: 22/07/19). And while the new study found plasma cells in the brains of healthy mice, previous research found other cells trained in the gut in the brains of mice with multiple sclerosis, an autoimmune disease of the brain and spinal cord.

For now, researchers want to understand what tracks plasma cells follow in the gut to know it’s time for them to embark on a journey to the brain.

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