How do bad antibodies get into the brain, anyway?
In my post on anti-NMDA receptor encephalitis, I wrote that the blood-brain-barrier or BBB should prevent big and bulky antibodies from passing into the brain, but for reasons that are just beginning to be explored and understood, the BBB fails at its job. A reader, Bruce, asked , ” Is the ‘upshot’ of this that ‘we’ don’t really know how the BBB does what it does? And are you going to post about the ‘reasons’ for the ‘failure’?” This is a really good question and I was in the process of answering in a short reply to Bruce, when I decided that this piece of biology is too super cool not to share with all of you. This blog is, after all, about the sooooo cool brain!
It turns out that leukocytes, immune cells such as antibody-producing cells, check on the health of tissues by accessing these tissues. They do this regularly and all the time and for all tissues. The immune cells gain access to tissues when leukocytes pass from the circulatory system (blood vessels) through the endothelial wall of the blood vessel. They do this through diapedesis, which essentially means passing through an endothelial cell barrier. The invasion is accomplished either by passing between cells (paracellular dipedesis) or through cells (transcellular dipedesis). As you may imagine this is a remarkable cell biological feat!! One cell invades and goes through, in the transcellular case, another cell. Biological truth is indeed strange and fantastic.
So how does this work? Remember that the BBB is a barrier made up of tight junctions between the epithelial cells lining brain capillaries. This would, as you may imagine, greatly deter paracellular dipedesis and indeed it does. It is now thought that diapedesis across the BBB occurs predominantly via the transcellular route. Amazing!
Now let’s return to the original question; how do we go from a normal check-on-and-maintain-immune-health state of affairs to a come-on-in-and-wreak-havoc disease state? Well, in some diseases including the autoimmune encephalitis diseases, diapedesis into the brain is up-regulated. Does this happen before the disease starts and is the upregulation the cause of the disease? Maybe. Alternatively it may be that the disease starts with a few invading (via normal diapedesis) immune cells which then start to make antibodies against the self (=autoimmune) and that only after the disease begins, does diapedesis get up regulated. I don’t know which of these is correct and I suspect that more work is needed to determine which scenario occurs in various CNS diseases. And the answer need not be the same for all diseases.
An upregulation in transcellular diapedesis is synonymous with a breakdown in the BBB. I imagine that such a BBB breakdown is critical to immune diseases including the autoimmune encephalitis diseases, stiff-person syndrome, and multiple sclerosis. But beyond these obvious suspects, neurodegenerative diseases such as Alzheimers and Parkinsons are now thought to involve a breakdown in the BBB. Again, whether this breakdown represents the chicken or the egg is not clear to me. Inflammation, which occurs for many reasons including as a result of an ischemic or hemorrhagic stroke, leads to an upregulation in diapedesis. As tissue swells, the spaces between cells become are stretched and so at least some of this increase may occur through an increase in paracellular diapedesis. Much more work in this exciting field is warranted.
There is a terrific commentary (a type of review) in Journal of Cell Science by Christopher V Carman on diapedesis that I highly recommend for those interested in learning more.