Researchers probing the mechanisms of nerve tissue damage in multiple sclerosis have identified two ways in which white blood cells overcome the blood-brain barrier to wreak havoc in the highly protected environment of the brain and spinal cord.
In a paper published in the journal Cell Reports, first study author Sarah Lutz, assistant professor of anatomy and cell biology at the University of Illinois at Chicago, and colleagues describe how they studied mechanisms of immune attack on the central nervous system (CNS) in a mouse model of multiple sclerosis (MS).
Prof. Lutz explains that in MS, immune cells are able cause damage because they can gain entry to the brain and spinal cord from the bloodstream. "A better understanding of how these cells cross the blood-brain barrier," she adds, "will aid our efforts to develop specific therapies to keep them out."
The bloodstream carries essential nutrients, oxygen, cells, and other substances to all parts of the body, including the CNS, which comprises the brain, spinal cord, and optic nerves.
The blood-brain barrier and 'tight junctions'
However, because of the delicate operations that go on in the CNS — such as the firing of neurons and passage of electrical signals that control movement and speech and carry information from the senses — it has a higher level of protection than the rest of the body.
One feature that can help the blood-brain barrier to restrict the movement of blood-borne cells, molecules, and ions into and out of the CNS is the close packaging of the endothelial cells that line the blood vessels that serve the CNS.
This close packing — which makes the blood vessels supplying the CNS virtually impermeable — comprises "tight junctions" of protein complexes that bolt the endothelial cells together.
In contrast, the junctions between endothelial cells in blood vessels that supply other organs and tissues are looser and can also be adjusted to allow a less restricted range of cells and other materials to pass through.
An autoimmune disease of the CNS
MS is a persistent autoimmune disease in which cells of the immune system attack the fatty layer of tissue that surround the nerve fibers, or axons, in the CNS, mistaking it for a disease agent or other threat.
The fatty layer of tissue is known as myelin, and it protects the electrical impulses that carry messages between the CNS and other parts of the body — such as movement muscles and the senses. In MS, however, the immune system degrades not only the myelin but can also damage the exposed axons.
The myelin damage occurs at multiple places in the CNS. These become lesions that harden into scar tissue, or sclerosis, hence the name of the disease.
MS has many different symptoms depending on which parts of the CNS are affected. They include, but are not limited to: impaired vision; blindness; difficulty remembering and concentrating; poor coordination; problems with balance; extreme fatigue; tremors; slurred speech; numbness; and paralysis.
Symptoms can flare up, go away, and then come back again, or they can stay and progressively worsen.
The disease is commonly diagnosed in people aged 20–50, but it can affect any person of any age. In the United States, there are thought to be around 1 million people living with MS.
Damaged 'tight junctions'
Scientists who are looking for MS's causes have discovered that two types of white blood cell, the lymphocytes Th1 and Th17, are involved in destroying the myelin sheath that protects the axons of the CNS. But until now, it was not clear how these immune cells managed to get across the blood-brain barrier into the CNS.
For their investigation, Prof. Lutz and her colleagues studied the blood-brain barrier of both healthy mice and mice with autoimmune encephalomyelitis (EAE). Mice with EAE are often used as animal models in the study of MS.
To find out how the Th1 and Th17 immune cells get across the blood-brain barrier in MS, the team genetically labeled the tight junctions in the blood vessels using a fluorescent protein.
The scientists found that the tight junctions in the blood-brain barrier of the MS mice were much more damaged when Th17 cells were present, and that this damage seemed to occur in the very early stages of the disease.
Traveling through endothelial cells
Around 3 days after observing the damage that occurred in the presence of the Th17 immune cells, the researchers saw that the Th1 cells were attacking the myelin and damaging neurons.
However, these cells did not gain access to the CNS through the damaged tight junctions, but did so through another mechanism that involved passing through the endothelial cells themselves.
It appeared that the Th1 cells were able to use small pits, or "caves," called "caveolae." These are found on the surfaces of cells — including endothelial cells — that are used to transport materials into and out of cells.
The researchers confirmed their findings by breeding MS mice without caveolae; they found hardly any Th1 immune cells in the CNS of these mice.
They concluded that the Th1 immune cells need the caveolae of the endothelial cells in the blood vessels that serve the CNS in order to cross the blood-brain barrier.
Prof. Lutz explains that that this was the first time that they had ever seen the different mechanisms through which the two types of immune cell got across the blood-brain barrier to reach the myelin and the axons "in live animals in real-time."
"Now that we know how these cells get to neurons, drugs or small molecules can be designed that interfere with or block each of these processes to help treat and possibly prevent multiple sclerosis."
Prof. Sarah Lutz