Immune Privilege in the Brain

The blood-brain barrier, in the form of a pillow fort.
Family Guy, 20th Century Fox.
During inflammation, immune cells have two jobs: tissue defense and restoring homeostasis. When there is an injury to a tissue, immune cells can become activated, releasing cytokines and chemokines to recruit other immune cells with the goal of removing the source of injury and returning the tissue to a state of homeostasis. Many different cells are involved in this complex process, which depend on the ability of immune cells to move between the circulation and the injured tissue. However, certain tissues can have specialized immune environments. This blog is about one particular tissue that was thought for a century to be completely separated from the peripheral immune system: the brain.
The protective barrier around this brain seems to have been compromised.
Super Metroid, Nintendo.
In 1885, Paul Ehrlich discovered that injecting a dye into the systemic circulation of rats stained most tissues, but did not seem to ever reach the brain1. Though he initially attributed this to low affinity of nervous tissue to the dye, his student, Edwin Goldmann, later showed that the opposite experiment, injecting the dye into cerebrospinal fluid (CSF), actually stained brain tissue quite readily but not any peripheral tissues. They surmised that a barrier, called the blood-brain barrier (BBB), existed between the brain and the circulation such that certain substances, such as the soluble dyes they used, could not pass. Though this was later complicated by the existence of certain dyes that actually were able to cross the BBB, it eventually became well established that solutes had to have specific properties in order for it to penetrate the barrier.

The substances that can cross the blood-brain barrier are limited to water, some gases, certain lipid-soluble molecules, glucose, and amino acids.
The BBB is comprised of cerebral endothelial cells whose opposing membranes form tight junctions surrounded by the basal lamina, a basement membrane supported by the end-feet of astrocytes. Each cellular component of the BBB contributes to the lack of permeability of the blood-brain barrier, providing added protection of the brain and central nervous system (CNS) from external agents while also creating an obstacle for elements that may be beneficial to the brain, such as therapeutics.
Cross section of a cerebral capillary.
However, certain events can cause significant alterations to the BBB, such that BBB permeability is increased. A compromised BBB can both be the causation and consequence of particular neuropathologies. Injuries to the BBB that may increase permeability include infections, hypoxia/ischemia, trauma, metastatic tumors, and inflammation through autoimmune disorders2. After the BBB barrier has been compromised, injured neurons and activated glial cells release inflammatory factors, such as cytokines, chemokines, and eicosanoids, which can recruit circulating peripheral leukocytes that were previously kept out by the BBB.

After certain types of insults, the blood-brain barrier can be compromised and immune cells can infiltrate the CNS.
Infiltrating immune cells propagate an immune response in the CNS, causing further glial cell activation and neuronal damage. This completes a positive feedback loop that can lead to chronic neuroinflammation, which can lead to neurodegeneration and potentially contribute to a number of age-related dementias, such as Alzheimer's disease. Make sure to learn more about glial cell activation and Alzheimer's disease by reading some of our previous blog posts.

Deadpool, Marvel Comics.
As you may suspect, the immune system of the brain is a little bit more complex than a barrier of endothelial cells keeping bad things out and the good things in. In fact, some recent discoveries have shown that the brain may be communicating with the peripheral immune system in several ways, including a lymphatic system in the brain, something that we will be covering in an upcoming blog. Listen to our podcast discussion on this topic: Neuroinflammation with Kenya Cohane. Also, please check out our Neuroinflammation Areas of Biology page to learn more about the inflammation in the CNS.
  1. The Blood-Brain Barrier in Neuroinflammatory Diseases, Pharma Reviews
  2. The Blood-Brain Barrier/Neurovascular Unit in Health and Disease, Pharma Reviews

The brain-blood barrier is no match for mind-sucking brain slugs, apparently.
Futurama, 20th Century Fox
Contributed by Ed Chen, PhD.
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