In the MS Physiology 101 series we explore the fundamental concepts of physiology as they pertain to multiple sclerosis. It is my hope that through this series you will gain a better understanding of what happens in MS at the cellular level as well as be able to identify ways to improve the outcome of your condition.
In this article, we focus on the Central Nervous System, which is the principal area of damage in MS.
The CNS and the PNS
Your nervous system is divided into two parts: the CNS (central nervous system) and the PNS (peripheral nervous system).
The CNS consists of the brain and the spinal cord, and the PNS is the network of nerves within your body that connects with the spinal cord.
The spinal cord is a long bundle of nerves that extends from the brain and down through the spine. Both the spinal cord are the brain are protected by CSF (cerebrospinal fluid), which is sandwiched between three layers of meninges (heard of meningitis?).
A layer of bone surrounds the meninges. In case of the spine, the layer of bone consists of vertebrae; in the case of the brain, the layer of bone is the skull.
Your brain controls your limbs by producing electrical signals, which are first relayed down through the spinal cord, then through the PNS, until it reaches your limbs.
Neurons (also known as nerve cells) are cells that facilitate the relaying of signals throughout your nervous system.
Neurons typically consist of the cell body (also known as the soma), dendrites, an axon, synapses, and a segmented layer of fat called the myelin sheath.
How Signals Travel
When stimulated, an electrical charge within the neuron builds.
When the charge has reached a certain point, it becomes an "action potential" (electrical signal), at which points it fires through the length of the axon (the nerve fiber).
When the action potential reaches the end of the axon, the synapses release a signal in the form of either chemicals (called neurotransmitters) or electricity (ions).
The signal is received by nearby neurons via their dendrites, and the neurons may continue the transmission of the signal across your body.
The Myelin Sheath of the Neuron
The myelin sheath (pronounced "MY-uh-lin SHEETH") is the segmented layer of (mostly) fat that insulates the nerve cells in the CNS and almost all nerve cells in the PNS.
Myelin consists of:
- Lipids (fatty acids) such as cholesterol and sphingomyelin (e.g., galactocerebroside/galactosylceramide, phosphocholine, and ceramide)
- Proteins; specifically, MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin-associated glycoprotein), and PLP (proteolipid protein)
The segmented arrangement of the myelin sheath makes the conduction of the action potential more efficient.
Oligodendrocytes (pronounced "ALL-iggo-dendra-sites" and abbreviated as OLGs) are cells found only in the CNS and whose main function is to produce the myelin sheath that protects neurons (although not all OLGs do).
OLGs originate from oligodendrocyte precursor cells (also known as OPCs or oligodendrocyte progenitor cells).
OPCs move by crawling along blood vessels. Once they reach their destination, they multiply and mature into myelinating OLGs.
Each myelinating OLG can form a segment of myelin for up to 50 adjacent neurons, OLGs are critical to restoring your damaged myelin.
Because the brain and the spinal cord are so vital, access to the CNS by substances in the PNS is tightly controlled by selectively permeable barriers.
While some substances can enter the CNS with relative ease (e.g., curcumin, uridine, lipopolysaccharide), other substances (such as blood-borne pathogens) can pass through only under special circumstances, thanks to the Blood-Brain Barrier and the Blood-CSF Barrier.
Although there are exceptions (namely the blood vessels in the choroid plexus and the circumventricular organs), blood vessels within the brain are generally fortified with what's called the blood-brain barrier (BBB).
Although the exact composition of the BBB may vary, it typically consists of:
- Cells (endothelial cells, pericytes)
- Cell junctions
- Basement membrane
- The feet of an immune cell called an astrocyte
The Blood-CSF Barrier (BCSFB) separates the blood from the the CSF.
The BCSFB lines the brain's four ventricles, which are chambers in which the CSF is produced.
The BCSFB is made up of ependymal cells and choroid plexus cells. As with the endothelial cells of the BBB, BCSFB cells are secured together with tight junction molecules as well as a basement membrane.
Passing Through The Barriers
In order for a substance to pass through the BBB or BCSFB, it has to pass through two key constituents of the barriers: the basement membrane and the cell junctions.
The basement membrane, which is composed of several layers, is a porous physical barrier that envelopes much of the BBB and the BCSFB, and it includes the basal lamina.
Cell junctions are the bonds between adjacent cells that comprise a barrier.
Within the BBB, cell junctions are composed of various molecules categorized as tight junctions (TJs), junctional adhesion molecules, gap junction molecules, and adherens molecules.
The junctions between the cells can be modulated through the expression (i.e., the production or surfacing) of the molecules that make up the junctions.
Modulation of the Cell Junctions
To better understand this mechanism, we can look at the the interplay between VEGF-A (vascular endothelial growth factor A) and TJ proteins.
Endothelial cells in the BBB produce a couple of TJ proteins called claudin-5 and occludin. Under certain conditions of cellular stress (e.g., when a cell is deprived of oxygen), cells produce VEGF-A (another protein).
When VEGF-A binds to the VEGF receptors that are expressed on the surface of the endothelial cells, the cells produce less claudin-5 and occludin.
As a result, the junction between the two adjacent cells becomes weaker, and so does the BBB overall.
What May Happen in Multiple Sclerosis
Now that we have a basic understanding of the CNS, let's take a look at what happens in MS.
Leukocyte Infiltration of the CNS
In MS, immune cells attack cells (usually nerve cells) within the CNS. In order for that to happen, the immune cells (also called leukocytes or white blood cells) must infiltrate the CNS.
Although the exact details of that process aren't fully known (partly because of all the variability in the nature of autoimmunity in individuals), we do have a pretty good understanding of how it might happen in certain cases.
To that end, here's a possible scenario centered on pathogenic T cells:
- In the PNS, T cells are "primed" for autoimmunity. You can think of these immune cells to be like bloodhounds that have been given a shirt to sniff. The reasons for this "priming" varies, but has to do with the breakdown of immune tolerance.
- Under situations of cellular stress, your body may produce proinflammatory cytokines such as IL-1β (interleukin-1 beta) and TNFα (tumor necrosis factor alpha). In response to that, endothelial cells in the blood-brain barrier secrete chemokines (chemical attractants) such as CCL20 as well as VEGF-A.
- As CCL20 is a ligand (a binder) to CCR6 receptors, CL20 attracts CCR6+ T cells (i.e., T cells with CCR6 receptors on their surface) toward the endothelial cells.
- Once that happens, the T cell rolls along the endothelial cells of the BBB, slowing down and then finally coming to a stop when its integrin receptors (such as VLA-4) bind with receptors on the surface of the endothelial cells such as VCAM-1.
- As shown earlier in this article, VEGF-A causes a weakening of the BBB by loosening the tight junctions.
- The T cell secretes proinflammatory cytokines such as osteopontin and MMP-9. Osteopontin contributes to cell adhesion and helps to shape inflammatory activity. MMP-9 (along with MMP-2) are known to facilitate the penetration of the astrocyte endfeet in the BBB (the yellowish component in the diagram of the BBB in this article) and are also known to chew up the basement membrane.
- Through a process called diapedesis, the T cell squeezes through the compromised BBB and enters the CNS, where it's able to attack nerves and other cells, leading to the neurological symptoms that are a hallmark of MS.
- Osteopontin (along with other things) inhibits the remyelination process; lesions form.
Identifying Therapeutic Targets
If we consider the sequence of events outlined, we can see that there are a few potential events we can target to prevent the damage from occurring:
- We may be able to take steps to prevent the priming of immune cells, and those steps may include restoring immune tolerance.
- We can aim to downregulate (reduce) IL-1β and TNFα.
- We can block the binding of CCL20 with CCR6 through the use of anti-CCL20 antibodies, anti-CC6 antibodies, CCR6 antagonists (ligands that block the activation of a receptor).
- We can neutralize VEGF-A via antibodies.
- We can neutralize VLA-4 on T cells to prevent cell adhesion.
- We can aim to downregulate osteopontin and MMP-9.
- We can interfere with the pathogenic T cell activity in the CNS.
Now that we have an idea of what happens during the infiltration of leukocytes into the CNS as well as what we can do to prevent it, let's take a look at the mechanism of action of the most popular MS medications: Tysabri.
How Natalizumab (Tysabri) Fits Into This Scenario
Natalizumab is an anti-VLA-4 antibody, meaning it diminishes a mechanism that T cells use for adhering to the blood-brain barrier, thereby reducing its ability to infiltrate the CNS and cause damage.
Because the body is so complex, natalizumab does lead to other effects as well--some good, some bad--but neutralizing the VLA-4 integrin receptors on T cells is its primary method of action.
Of course, this makes sense logically. But let's also consider that:
- Natalizumab does not directly address any of the other potential therapeutic targets; perhaps we would not need to neutralize VLA-4 if the T cell were never improperly primed or if CCL20 weren't overexpressed.
- Cell adhesion mediated by VLA-4 is normal behavior, so it shouldn't be surprising that outright blocking this behavior can prevent T cells from responding to infections (including PML).
So while neutralizing VLA-4 logically makes sense, we can see that not addressing the other factors makes for an incompletely therapy and that being too heavy-handed with a single therapeutic target can lead to imbalances.
This should also make it clear that you should not think of any of the MS medications to be a "cure" for MS in any sense.