The brain has long been viewed as being very unique. It’s special. It’s what sets humans apart from other mammals and what has allowed us to imagine, design, create, and build the world that we live in today. On a biological level, the brain has similarly been viewed as being quite special. Unlike most organs, which are easily accessible to other type of cells via the circulatory system, the brain was thought to be sealed off, or isolated, by a thick layer of cells known as the blood-brain barrier. Recently, though, contradictory evidence has emerged, indicating that the brain is in fact permeable to a variety of other cells, including both immune cells and pathogens.

The blood-brain barrier

A variety of cells, including ‘foreign’ cells (bacterial or viral pathogens) and some of the body’s own immune cells, travel throughout the body via the bloodstream. From the bloodstream, these cells can take up residence in a variety of tissues, like the gut or the skin. Some tissues, though, are more difficult to gain entry to than others, with the brain being the prototypical example of an impenetrable organ. Reasons for this difficulty are cellular layers that control what enters or exits those tissues. For the brain, this layer of cells (called endothelial cells) are tightly linked, creating what’s called the blood-brain barrier (BBB).

Although the brain is largely protected with this barrier, research has emerged that indicates that some cells, including immune cells and pathogens, might be able to sneak across the BBB in one way or another. For example, in the neurodegenerative disease multiple sclerosis (MS), some types of immune cells from the gut have been found in brain, indicating that these cells have devised a mechanism to traverse the BBB. Similarly, some infections encountered early childhood may increase the chance of mental illnesses like depression and anxiety, indicating a link between pathogens and brain function and suggesting that pathogens, too, may possess the ability to infiltrate the brain

Given what we know about the BBB, it’s particularly puzzling that a lot of new research shows evidence of cellular infiltration of the brain. How can immune cells from the gut make their way into the brain in MS? In the study linking childhood infections to the increased likelihood of mental illness, how can a bacterial infection affect the brain if the bacterium doesn’t easily cross the BBB? Do these cells (immune cells and pathogens) somehow slip between the BBB cells? Do they find a route into the brain where the BBB is weak?

Cellular infiltration of the brain

To understand this puzzle, a recent review explains how some cells, with a focus on pathogens, can enter the brain. In one mechanisms called ‘transcellular entry’, a pathogen passes directly through the endothelial cells of the BBB (Figure 1A). From the blood, the pathogen binds to receptors on the surface of the BBB endothelial cells, the pathogen fully enters the endothelial cell, then exits the opposite side of the endothelial cell into the brain. This leaves the BBB undamaged but allows the pathogen to move from the blood into the brain. The mosquito-borne viruses, West Nile virus and Zika Virus, are thought to follow the transcellular path.  

A number of additional routes are described, including the ‘Trojan horse route’ or the ‘Paracellular’ (between-cell route). In the ‘Trojan horse route’, a pathogen first infects the host’s own immune cell (monocyte) then the immune cell enters the endothelial cell of the BBB. The BBB recognizes the monocyte as a host cell, effectively concealing the pathogen. The infected monocyte then passes into the brain (Figure 1B). The ‘Paracellular’ route is relatively simpler. For this ‘between-cell’ route, the pathogen cuts the proteins that act as the glue between the BBB endothelial cells (Figure 1C). This weakens the association between the BBB cells giving enough space for the pathogen to squeeze through these newly-created gaps to enter the brain.  

Immunity, the brain, and where we go from here

Elucidating the mechanism for cellular-entry into the brain can help us start to understand the intricacies of how (and why) immunity and neurological conditions are tightly coupled. Each new study conclusion often raises more questions than it answers. For instance, how do these gut immune cells first travel to the brain in Multiple Sclerosis? Do they receive some external signal that says “initiate gut-to-brain travel now!” and if so, what is this signal? Once at the BBB, are they specifically recognized and ‘captured’ by receptors on the BBB endothelial cells? Perhaps the BBB cells in people with higher risk of MS have more receptors to capture these circulating immune cells? Once in the brain, do these cells harm or try to help the brain?

The idea that the immune system is implicated in  various neurological conditions isn’t necessarily a new idea. However, knowing that the brain is relatively-permeable to ‘outside’ cells has opened new avenues of research that strive to answer questions like those posed above. More and more, studies of neurological conditions are integrating this new information about BBB traversal and using it to inform novel research endeavors. Undoubtedly, many questions still remain to be addressed and answered, but the hope is that,  by knowing that the brain is accessible to the immune system and harmful pathogens, the causes of neurological illness may be understood in greater detail. This, in turn, may lead to preventative measures and treatment options for people currently diagnosed with these often-debilitating diseases and illness.