White blood cells (or leukocytes) are the unsung superheroes in this battle- targeting pathogens, fighting infection, and aiding in immune response.

​

However, this isn’t a story about their accomplishments; it’s clear enough how important their function is to us after we emerge from a bad cold or witness the clotting of blood after an injury.

​

This is a tale of a superhero gone rogue.

​

The trouble begins when leukocytes accumulate in the brain. Unfortunately, too much of a good thing can be harmful to your health. Multiple studies show that uninhibited leukocyte migration to the brain is commonly seen in patients with neurological problems like multiple sclerosis, cerebral infection, stroke, and trauma.

​

But before we get too ahead of ourselves, we need to figure out exactly how leukocytes are travelling to the brain in the first place.  

​

 

 

The Blood Brain Barrier

​

Reaching the brain isn’t easy. As the seat of the central nervous system, the brain plays a crucial role in the rest of the body’s functioning. Here is where decisions are made (either consciously or subconsciously), nervous signals are sent out, and neurotransmitters are directed to their final destinations. 

​

The brain can’t be affected by the countless hormones and harmful pathogens rocketing around through the rest of the body- it would be disastrous for the organism.   

​

This is where the blood brain barrier (BBB) comes in.

 

As the name suggests, it’s a barricade that protects the brain from toxic substances in the blood. A web of blood vessels called capillaries (importantly, the smallest type of blood vessels) sheaths the brain.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

These capillaries are lined with a special type of cell that lines the inside of all blood vessels: endothelial cells, which have slight gaps in between to allow entry of molecules that are important to the brain. 

 

These slight gaps between the endothelial cells are traversed by thin fibers of protein called tight junctions (made up of claudin-3 and claudin-5), which keep unwanted molecules from slipping past the cells.

​

​

​

​

​

​

​

​

​

​

​

​

​

​

​

​

​

​

The end result is a brain that’s protected from most molecules except very small ones and ones important to it in some way. 

​

 

 

 

Leukocyte Migration Pathway

​

How leukocytes cross the blood brain barrier has long been a mystery. It’s accepted that they take the path of least resistance, which should be right between the gaps of the endothelial cells (and, somehow, bypassing the tight junctions). This method of travel is known as paracellular migration (para meaning parallel to the borders of the cells, fittingly).

 

Bizarrely, leukocytes have also been witnessed barreling straight through the middle of the endothelial cells themselves in what is known as transcellular migration (trans meaning through the cell).

​

So what is it? Do leukocytes slip in between EC cells and into the brain, or do they stroll right through the cell body itself? Winger and Koblinski hypothesized that leukocyte travel to the brain, or transendothelial migration (TEM), depends on how tightly packed together the endothelial cells in question are.

 

The smaller the gaps, the more likely leukocytes would find it easier to travel through the cells rather than in between them. In the tightly packed cells of the blood brain barrier, this should mean a high percentage of TEM would be transcellular- right through the cell bodies. This hypothesis could also potentially solve the problem of what happens to tight junctions as leukocytes travel through the cells, as they would be undisturbed by transcellular migration.

​

​

​

Knowing how exactly leukocytes travel to the brain can be the first step towards preventing their accumulation in the brain and learning more about the blood brain barrier.

​

​