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.
Categories: Brain anatomy, Brain Function
Thanks, but more questions get raised re anti-NMDA receptor encephalitis and leukocytes. Based on the linked article and this one:
it would seem- of course the caveat is my lack of knowledge other than reading- that it’s particular leukocytes that are the ‘suspicious characters’. Namely lymphocytes and monocytes.
The wiki entry indicates that lymphocytes circulate in memory cells for years; what ‘memory cells’ is it referring to?
Did Susannah Cahalan indicate any blood or spinal fluid test results in her case?
Off topic but maybe of interest: ” why aging appears to wreak such havoc on our circadian rhythm”; “Older adults with less activity in their ventrolateral preoptic nucleus (VLPO)—a group of neurons in the hypothalamus that controls wakefulness by releasing the neurotransmitters galanin and GABA—are far more likely to experience sleep troubles than those with more active VLPO regions, according to scientists who compared the number of neurons in an aging individual’s VLPO to the amount of time that person spent in restful sleep. Overall, adults who had 6,000 or more neurons enjoyed 10 percent more restorative snooze-time than those with 3,000 or fewer neurons.”
Not sure it makes sense to comment on this post from a year back, but this thing seems to belong here. I hope this comment will get noticed…
I came across this article http://www.hindawi.com/journals/cricc/2013/383125/
Case Report Ketamine Infusion Associated with Improved Neurology in a Patient with NMDA Receptor Encephalitis 2013 MacMahon et al.
This is a description of apparently the same anti-NMDA receptor encephalitis, but what is interesting here is that the treatment that saved Ms. Calahan (intravenous immunoglobulin) did not work. At all. And the titer for the anti-NMDAR antibodies was negative for the blood.
But it was positive for the CSF!
So this, rather Ms. Calahan’s seems to be the case for the real diapedesis of B-cells into the brain, don’t you think? The antibodies seem to have been produced only within the brain tissues, and not in the blood, so it must be by B-cells that made it through BBB and stayed there for some reason. Nothing was abnormal in the blood apparently.
And even more mind-boggling is the way the condition was finally treated successfully: ketamine! It’s actually quite humbling, you think that ketamine is an NMDAR antagonist, and here it miraculously works as an agonist, immediately and decisively reversing the symptoms…
This is so interesting on so many levels. First that the patient had antibodies in CSF but not blood, as you say. I am wondering whether diapedesis happened in both instances but in Ms Calahan’s case, the antibodies remained in the blood whereas in this case, they were cleared. If diapedesis ever happened that implies that the antibodies were in the blood at the time of that occurrence. So somehow they went away. The only other alternative is that the antibodies arose de novo within the BBB – hard to imagine.
Then as far as ketamine’s actions, I will say that the molecular structure that makes something a good competitive antagonist makes it a candidate agonist as well. It is common for receptor agonists and antagonists to have antagonist and agonist actions as well. Usually one predominates. But it is not clear that the ketamine was acting on the glutamate receptor and certainly not clear that it was acting there as an agonist.
In the end, medicine is about try it and see if it works, and hopefully do no harm in the trying. Science is about predicting what to try and then sometimes, as in this case, figuring out why something unexpectedly “worked.” Best example of this is the discovery of iproniazid as an antidepressant after it was tried as a treatment for TB. Those TB patients still had TB but they sure were happier….
Nice to hear from you.