Cells to protect the brain
The brain sits cocooned inside a series of protective layers called the meninges. These, together with a structure called the blood brain barrier, keep out unwanted infections that could otherwise be lethal. But how exactly the brain’s defense systems work isn't known. Now, a new discovery has added an important piece to the puzzle: specialised plasma cells, these are blood cells that make antibodies, learn to recognise important, potentially harmful bacteria in the intestine and then make their way to the outer part of the meninges, called the dura, where they churn out antibody to keep the brain bug free. Menna Clatworthy from the University of Cambridge, spoke to Chris Smith about this work, published in Nature...
Menna - The thing that really got me interested in thinking about the brain, is that there's increasing evidence, that the immune system plays a role in a number of brain disorders. So things like depression and anxiety, and even the progression of neurodegenerative diseases like Parkinson's disease. As well as that, we know that the immune system is required to defend parts of the body from infection. So this could be important for defense against infections in the brain and in the meninges. So things like meningitis.
Chris - How did you pursue this to try and work out how the brain was actually fending off infections?
Menna - As with many studies in immunology, we use the mouse as a model. And so the first thing that we did was to take meninges and look at them under the microscope. And there were plasma cells in the dura, and they were not just scattered anywhere. They were actually lined up along the border of large blood vessels that run through the dura. These blood vessels are called venous sinuses. The next question, when we found these plasma cells, was what antibody they were producing. To our surprise, we found that rather than producing IgG, what's normally found in the body, they were actually producing IgA, an antibody that's normally found in the gut.
Chris - So you've got this interesting observation, sort of anatomically in the first instance, of blood vessels running through the meninges, they've got cells that make antibody, lining up along them. But the antibody they're making is one that you would not normally associate with the bloodstream. It's one that you would find in the intestine.
Menna - Yes. So that was surprising. And I guess the next question was, well, do these cells actually originate in the gut or are they influenced by the gut? So to answer that we were able to use mice that have never seen any sort of bug. They have no bacteria or any microbes in their intestine. And when we looked at the dura from these animals, there were no IgA cells whatsoever. But when we added bacteria back into their gut, suddenly again, the antibody producing cells reappeared in the dura. And even if we only put one type of bacteria into these mice, a type of bacteria that couldn't go anywhere, other than the gut, we still saw the cells reappear in the dura. So that told us that those cells originated in the intestine.
Chris - The sort of hypothesis then, is that the bacteria go in the intestine, they educate the immune system and immune cells in the intestine, and what, the cells then migrate from the intestine with the knowledge of how to make antibodies against those specific microbes, up to the brain and take up residence in the meninges around the brain.
Menna - Exactly. And they specifically take up residence at the border of these dural venous sinuses. And I guess then the obvious question, well, why, why would that happen? Why is the system being set up? And the obvious answer would be, well, maybe those cells are there to protect the brain from microbes, bacteria that originate in the gut, but get into the bloodstream. And when they're flowing through those venous sinuses, where blood flow is quite slow, it's an opportunity for the bugs to get out into the brain. So to test that what we did was to remove all of the antibody producing cells, and then we challenged mice with microbes into their bloodstream. And what we found was the bugs were able to get across into the brain. So it told us that really we'd found a whole new defense system for the brain.
Chris - What are you going to do next?
Menna - We're interested in the signals that might take the plasma cells from the gut to the meninges. And then the other thing I'm really interested in is whether this has implications for how we try and protect people from meningitis. At the moment, if we vaccinate against meningitis, we give that vaccine into the muscle, but our study would suggest that actually, if you want to make cells to defend the brain, the route that you should give that vaccine is actually via the gut. And so that's something that we're looking into.