The Blood/Brain Barrier

The Blood/Brain Barrier (BBB)

The Central Vein and the BBB

The vast majority of MS lesions are centered on a post-capillary venule.  This vasocentric nature of MS lesions stands as one of the most consistent and important observations first made by pathologists of the late 19th century. While the vasocentric nature of lesions is well defined, it remains unclear why MS lesions are centered on a blood vessel.  Barnett and Prineas argue that when MS lesions first form, injury to the blood-brain barrier, along with oligodendrocyte death, constitute the earliest events in MS lesion formation.   The vasocentric nature of MS lesions coupled with this early blood-brain barrier injury supports the hypothesis that the blood-brain barrier itself is a primary target in the MS disease process.

The Inflammatory Lesion

The fate of the earliest or newly forming lesion is at least twofold.  The lesion can resolve with removal of the dead oligodendrocytes and degenerated myelin, followed by robust regeneration of myelin by resident multipotent stem cells termed oligodendrocyte progenitor cells (OPCs).  Alternatively, the lesion can evolve into a highly inflammatory lesion with B and T lymphocytes (B-cells and T-cells) surrounding the blood vessel and many macrophages within the lesion digesting degraded myelin.  We currently term this latter lesion an “active lesion”. MRI can identify these new “active lesions” when intravenous contrast dye is administered, since the dye passes through an extremely damaged blood brain barrier and stays within the brain for enough time to be detected by the MRI.

As the inflammation within an active lesion resolves, the blood-brain barrier begins to repair itself.  Within a few weeks, the intravenous contrast dye cannot penetrate the repaired barrier to enter the CNS.  The inability to visualize contrast dye within an MS lesion often leads patients, physicians and even scientists to conclude erroneously that the BBB is fully repaired and the lesion no longer active.

However, we think that the BBB never fully repairs itself in MS unless the brain tissue within the lesion has returned to normal.  Instead, we think there is a chronic (long-term) opening of the BBB that is not as severe as when contrast-enhancing lesions can be observed on MRI yet open enough that molecules from the blood seep into the lesions.   Molecules that seep into the brain through a leaky BBB fall into the category of DAMPs and function to impede remyelination.

What is the blood brain barrier?

Central Nervous System blood vessels have special characteristics designed to provide critical nutrients while limiting the transfer of potentially toxic molecules from blood into the brain, spinal cord and retina.  The power of this CNS barrier can be simply realized by considering the appearance of blood, which all of us have seen, to the appearance of cerebrospinal fluid (CSF), which is a clear colorless liquid that looks like water.  From the complex composition of blood, the BBB generates the highly specialized CSF for CNS function.

To create the very specific milieu optimal for CNS function the BBB has acquired specialized functions.  These include: a zipper-like structure between the cells that line blood vessels termed tight junctions; tight regulation of vesicle traffic between the blood side and the brain side of the blood vessel; specialized transporters that actively move necessary molecules into the brain (like glucose) and transport toxic molecules out of the brain; and enzymes that degrade molecules potentially hazardous to CNS function.  This complex interaction between brain cells and blood vessels is termed the neurovascular unit.