Why the blood brain barrier bars entry of immune cells and antibodies
What is it about how the brain works that makes it an advantage for the brain to bypass the primary defense system used by the rest of the body? The blood brain barrier is designed to exclude both pathogens and the cells of the immune system. It also excludes large proteins including immune system antibodies. It is only after viruses and bacteria are able to trigger a breakdown of the blood brain barrier that immune system responders gain entrance. And, when it occurs, it seldom turns out well.
One feature that prevents the brain from easily managing a classic immune response is that there is very little room for its expansion within the skull. The classical inflammation response to injury and pathogens includes swelling (edema), heat in the tissue, and loss of function in the area affected.
A second feature of the brain that makes expansion a problem is that its cells are very tightly packed together. The geometry of the extracellular space around brain cells has been modeled to be an interconnected network of pores and tunnels that are less than 100 nm across. It is estimated that there are about 100 billion neurons and 10 times that many glia cells in the brain. The microvasculature itself further crowds the space with a surface area of 15-25 square meters.
When inflammation persists outside the brain there is increased blood flow, increased capillary permeability, and increased macrophages and lymphocytes in the tissue. Peripheral macrophages allowed into the brain cause a great deal of damage to neurons. Because neural circuits are so well integrated with each other, damage to neurons even in a small area may cause widespread disturbance in brain function.
A previous post described the brain’s own version of macrophages, the microglia. When damage occurs within the healthy brain microglia are the first responders. They are able to clear away the destruction and repair neurons without edema and extra heat in the tissue. If the job becomes too much for the microglia, they are able to present antigen to surveillance T-cells that are found in the cerebrospinal fluid. Such antigen presentation in extreme situations leads to changes in permeability of the blood brain barrier that allows entrance of the adaptive immune system.
What precisely is the blood brain barrier?
Transport of blood borne molecules into the brain is tightly controlled by an unusual arrangement at brain capillaries. The concentration of water, hormones, amino acids, neurotransmitters and other metabolites fluctuate in blood to a great degree.
Such fluctuations in brain tissue would cause unacceptable instability in neural activity. Almost no large molecules and 98% of blood’s small molecules do not cross the capillary barrier named the blood brain barrier. Click the images for a better view of the details in a new tab.
The blood brain barrier is created by tight lacing together of capillary endothelial cells with protein formations called tight junctions and adherens junctions. These junctions set up a situation where all molecules must be transported from the capillaries through, instead of around, the endothelial cells. An additional layer of physical and functional support for the blood brain barrier comes from pericytes, cells that wrap around the capillaries, and projections of astrocyte glial cells that make direct contact with capillary cells. Between these two cell types they virtually enclose the entire capillary bed.
The blood brain barrier does not block exchange of oxygen for carbon dioxide. Both gases are lipid soluble and pass through the cell membranes of the barrier. Other small lipid molecules also pass through the blood brain barrier, but many of them are subsequently transported back to the vascular system by efflux pumps.
It has been estimated that 10-15% of all proteins in the brain’s vascular system are transporters that move substances across the cells. Glucose the main energy substrate of the brain is transported in by the GLUT1 capillary endothelial cell transporter. There are also transporters for essential amino acids from which neurotransmitters are made including norepinephrine, dopamine, and serotonin.
Entry of water and molecules necessary for brain health occurs primarily through the capillaries of the choroid plexus in the brain’s central chambers. Each of the four ventricles has a choroid plexus that produces cerebrospinal fluid. There exists a complex communication, orchestrated by ependymal cells of the ventricles, between interstitial fluid around neurons and the cerebrospinal fluid. Nutrients are supplied to the interstitial fluid by cerebrospinal fluid taken up by ependymal cells. In turn, ependymal cells remove metabolic waste from the interstitial fluid and deliver it into the cerebrospinal fluid and ultimately into blood returning to the heart.
The Virchow-Robin space – another barrier between neurons and the immune system
There is a layer of thin membrane that covers the surface of the brain called pia mater. The name comes from Medieval Latin and it translates to ‘tender mother’. Pia mater also dips into the substance of the brain and forms a sheath around the brain’s arteries and arterioles.
Large arteries supplying the brain are branches of the internal carotid arteries of the neck and the vertebral arteries. The pia mater sheath around the larger arteries entering the brain through the subarachnoid space is continuous with that of the smaller penetrating arteries and arterioles of brain tissue.
The space between the pia mater sheath and arteries is called the Virchow-Robin space. The Virchow-Robin space is filled with interstitial fluid and it has important connections with the lymphatic drainage of the head. In normal brain, any pathogen or immune cell that manages to escape the arteries or arterioles of the brain is quickly removed by the Virchow-Robin space. The Virchow-Robin space ends where blood capillaries and the blood brain barrier begin.
If you would like to learn more about the importance of the blood brain barrier to brain metabolism and inflammation check out my book “Inside the Closed World of the Brain, How brain cells connect, share and disengage–and why this holds he key to Alzheimer’s disease.”
More information on the support cells of the brain can also be found in the following posts.
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Margaret Thompson Reece PhD, physiologist, former Senior Scientist and Laboratory Director at academic medical centers in California, New York and Massachusetts and CSO at Serometrix LLC is now CEO at Reece Biomedical Consulting LLC.
Dr. Reece is passionate about helping students, online and in person, pursue careers in life sciences. Her books “Physiology: Custom-Designed Chemistry” (2012), “Inside the Closed World of the Brain” (2015) and the workbook (2017) companion to her online course “30-Day Challenge: Craft Your Plan for Learning Physiology” are written for those new to life science. More about her books can be found at amazon/author/margaretreece.
Dr. Reece offers a free 30 minute “how-to-get-started” phone conference to students struggling with human anatomy and physiology. Schedule an appointment by email at DrReece@MedicalScienceNavigator.com.by