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Immune cells trained in the gut protect the brain
Researchers found that the brain's protective membranes are guarded against microbes by immune cells that are trained in the gut.
These cells produce protective antibodies whether or not an infectious threat to the brain currently exists.
Giving mice a drug that weakened their intestinal barrier boosted the number of IgA cells (red) and other antibody-making cells (green) around the dural venus sinuses. McGavern lab, Nature
A structure called the blood-brain barrier helps protect much of the brain from infections. Membranes surrounding the brain—called the meninges—provide an additional layer of defense. The meninges host immune cells that can kill invading pathogens.
But this part of the brain also contains a vulnerability. The outer layer of the meninges, the dura mater, contains channels, called dural venus sinuses, that aren't sealed by the blood-brain barrier. These allow slow-moving blood to drain from the brain back toward the heart. But this slow movement creates an opportunity for pathogens to get into the brain. Infections in the brain—whether by bacteria, viruses, or fungi—can be deadly.
The role of antibodies in this part of the brain hasn't been well understood. Antibodies, which are produced by the immune system, circulate in the blood, recognize foreign substances like bacteria and viruses, and neutralize them. They are thought to enter the meninges only when the blood-brain barrier is damaged.
A research team led by Dr. Dorian McGavern from NIH's National Institute of Neurological Disorders and Stroke (NINDS) and Dr. Menna Clatworthy from the University of Cambridge used mice and samples from human brain tissue to study immune cells in the meninges. Their results were published on November 4, 2020, in Nature.
The team found that the meninges in healthy mice already contain antibody-producing cells called IgA cells. These are typically found in other barriers such as the mucous membranes of the gut. Older mice had more IgA cells, suggesting they accumulated with age. Similar cells were found in samples taken from human brains.
The IgA cells appeared to have a link with the gut. When the researchers reduced the normal gut microbes in mice with antibiotics, fewer IgA cells were found in the brain. When they restored normal gut bacteria, the IgA cells in the brain bounced back. There was no similar link when microbes were altered on the skin of mice.
Illustration showing how IgA cells reside in the dura mater along venous sinuses that drain blood from the brain. The immune cells protect the brain by producing antibodies against microbes that they first encountered in the gut.McGavern lab, NINDS
By comparing DNA sequences from IgA cells found in the gut with those in the brain, the team found a large overlap. This suggests that the IgA cells in the brain learned to identify specific pathogens in the gut. They then traveled through the bloodstream to the brain to produce antibodies locally.
In the gut, IgA antibodies are known to play an important role in trapping microbes and preventing them from interacting with the gut lining. When the researchers injected mice with a fungus that can cause a deadly brain condition called encephalitis, they found that the antibodies similarly trapped the fungus in the dural venus sinuses. Further experiments showed that local IgA cells—not those from elsewhere in the body—were making the antibodies protecting the brain.
"The venous sinuses within the dura act like drainage bins, and, consequently, are a place where pathogens can accumulate and potentially enter the brain," McGavern says. "It makes sense that the immune system would set up camp in this vulnerable area,"
The researchers plan to focus on the mechanisms that allow IgA cells to be educated in the gut to potential dangers and then defend the regions surrounding the brain and central nervous system.
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References: Gut-educated IgA plasma cells defend the meningeal venous sinuses. Fitzpatrick Z, Frazer G, Ferro A, Clare S, Bouladoux N, Ferdinand J, Tuong ZK, Negro-Demontel ML, Kumar N, Suchanek O, Tajsic T, Harcourt K, Scott K, Bashford-Rogers R, Helmy A, Reich DS, Belkaid Y, Lawley TD, McGavern DB, Clatworthy MR. Nature. 2020 Nov 4. doi: 10.1038/s41586-020-2886-4. Online ahead of print. PMID: 33149302.
Funding: NIH's National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Allergy and Infectious Diseases (NIAID); UK National Institute of Health Research; UK Medical Research Council; Chan-Zuckerburg Initiative; Versus Arthritis.
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