The lining of the gut and the dura mater of the brain both serve as barriers against germs. But their commonality goes deeper than that. Both contain well-trained immune cells, specifically, immunoglobulin A (IgA)-secreting plasma cells. They acquire their germ-fighting capabilities in the gut, where many of these immune cells remain, but some are eventually stationed at the outermost layer of the meninges, where blood vessels are not sealed as they are in the deeper layers, leaving a gap in the brain’s defenses.

The gap has been known to be guarded by macrophages and T cells, but now, thanks to researchers at the National Institutes of Health (NIH) and Cambridge University, we can also appreciate how antibody-secreting cells help protect the brain. These scientists, led by the NIH’s Dorian McGavern, PhD, and Cambridge University’s Menna R. Clatworthy, MD, PhD, studied mice and human autopsy material to conduct a detailed analysis of meningeal humoral immunity.

“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.”

The scientists’ findings appeared November 4 in Nature, in a paper titled, “Gut-educated IgA plasma cells defend the meningeal venous sinuses.” The paper describes how the scientists focused on plasma cells, which are derived from B cells.

Normally, the antibodies found in the blood are a type known as immunoglobulin G (IgG), which are produced in the spleen and bone marrow. However, the antibodies found in the meninges were IgA, which are usually made in the gut lining or in the lining of the nose or lungs—these protect mucosal surfaces, the surfaces that interface with the outside environment.

“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. 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.”

IgA-secreting cells reside in the dura mater along venous sinuses that drain blood from the brain. These cells produce antibodies against microbes they first encountered in the gut. [McGavern Lab, NINDS]
The scientists were able to sequence the antibody genes in B cells and plasma cells in the gut and meninges and show that they were related. In other words, the cells that end up in the meninges are those that have been selectively expanded in the gut, where they have recognized particular pathogens.

“Here we show that, during homeostasis, the mouse and human meninges contain IgA-secreting plasma cells,” the authors of the Nature article wrote. “These cells are positioned adjacent to dural venous sinuses: regions of slow blood flow with fenestrations that can potentially permit blood-borne pathogens to access the brain. Peri-sinus IgA plasma cells increased with age and following a breach of the intestinal barrier. Conversely, they were scarce in germ-free mice, but their presence was restored by gut recolonization.”

Compared to normal control mice, the germ-free mice, which did not have their own microbiome, had almost no IgA cells in their meninges, the scientists observed. The scientists 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% overlap between the two—much greater than would be possible through random chance.

“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 McGavern. “These data provide more compelling evidence that the brain is protected by immune cells that are educated in the gut.”

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 McGavern. “This clearly shows the importance of the local immune response.”

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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