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An extremely brief but relevant overview of the nervous system 2

demylination

The nervous system is composed of a central and peripheral system. The peripheral nervous system is the part of the nervous system that consists of the nerves and bundles of nerve cells on the outside of the brain and spinal cord. A picture is worth a thousand words, look at the picture and let’s fast forward to myelin. Myelin is made of proteins, proteins are made up of amino acids. Groups of amino acids are called peptides, peptides can be as small as two amino acids.

Myelin insulates axons, the axon is a long threadlike part of a nerve cell along which impulses are conducted from the cell body to other cells. If myelin, made up of proteins, is damaged then messages are not transmitted to cells. Myelin proteins are highly similar, conserved, between species. And that is important to the study of polyneuritis equi (PNE).

When scientists (primarily the English and French) were investigating all manner of neurodegenerative diseases in people they got huge amounts of myelin from the spinal cords of cows because all animals have the same protein structure for myelin. This phenomenon is called conservation. Unfortunately, in 1984 an English cow developed strange signs that turned out to be the first recognition of Mad Cow disease.

Let’s digress, I like this part of history and what it gave us. The source of Mad Cow disease was animal feed. Specifically, animal feed contaminated with bits of protein called “prions”. First, disease was linked to sheep--but now some believe human bone might have gotten into the British animal feed. Doctors Alan and Nancy Colchester write that Indian and Pakistani peasants sometimes gather large bones from land and rivers to sell, and that "Hindus believe that it is essential for their remains after death to be disposed of in a river, preferably the Ganges. The ideal is for the body to be burned, but most people cannot afford enough wood for full cremation." During the 1960s and 1970s, the U.K. got a lot of raw material for fertilizers from Bangladesh, Pakistan, and India. Humans were known to have Creutzfeldt-Jakob disease, the infection passed to cows through ground-up bones in animal feed, and then the cows gave it back to people. Fearful of Mad Cow scientists turned to the horse as a source of tissue for their research. This vast body of knowledge gave us a leg up on polyneuritis equi.

There were some distinct differences in the equine protein and the bovine protein. It is molecularly heavier because it has 3 more amino acids. Ok big deal, I’m being thorough. But an unexpected result was horses have more, much more, basic myelin P2 protein (lets call it P2) in their central nervous system tissue. And P2 protein makes up 2-15% of the peripheral nervous system protein. The amount and distribution of P2 is a big deal because disease affecting this protein will be more apparent in horses. Myelin P2’s function is in lipid transport and storage in the cell responsible to myelinate nerves. The take home message here is that it was possible to test these myelin making cells (Schwann cells) for damage. If Schwann cells are damaged myelin production would decrease measurably.

Progressive neurological disease was induced in experimental animals by injecting myelin protein. This was important because a model using laboratory animals allowed controlled experiments. In the case of P2, an animal model for Guillian-Barre syndrome, a demyelinating disease of the human peripheral nervous system, was produced. If Schwann cells are damaged myelin production would decrease measurably in the model animals.

It wasn’t long before a connection was made to neuritis of the cauda equina, now called polyneuritis equi, a neurodegenerative disease in horses. Another similarity between Guillian-Barre and P2 neuritis was paralysis of the trigeminal and facial nerves. Cranial nerve involvement was also recognized in horses.

As an aside, this work was going on in 2005, some purified myelin protein became available. Horse neurologists got some purified spinal protein, injected it into a few horses, but didn’t get disease. Case closed. No more work on cauda equina induction by myelin protein. This small experiment closed the door to a model and produced a bias against this line of research that continues today. Did they use P2? And as you are going to see, different parts of myelin P2 can give different results in laboratory animals.

Back in Europe scientists purified equine myelin P2 and crystallized the protein giving them a highly refined molecule. There was another unexpected result of the P2 experiments that may relate to the small horse study. Myelin P2 was snipped (chemically) into peptides, different peptides and disease depended on the peptides that were used in the experiment. Some peptides did not cause disease whereas the whole purified protein did. The conclusion was that there must be a disease-inducing region of the protein. One peptide caused neuromuscular disease and weakness that would resolve, untreated. Another neuritogenic (disease causing) peptide consistently induced disease. Animals could become desensitized to disease-causing injections of the whole protein P2, but not to the neuritogenic peptide.

And, normal animals that were given blood cells (T-cells) from diseased animals (passive transfer) got disease! The disease was produced from immune cells from animals, not the protein itself. This raised several questions, but we’re going to cut to the chase. It wasn’t a malfunction of the cells that put myelin around axons. The myelinating cells did not change the proteins they made, nor did they change the capacity to remyelinate damaged axons in the face of disease.

What changed was the transfer of sensitized cells to a healthy animal. Researchers found that the sensitized cells induced the production of another protein, an immunoglobulin-binding protein on nerves that increased during the clinical deficit. The net result was now there was an increase in the ability of inflammatory cells to bind nerve cells. The nerve cells became the target of the body’s immune system.

What about that neuritogenic peptide? The neuritogenic peptide of P2, the myelin protein that wraps around axons, turned out to contain an inflammatory receptor that is recognized by the immune system. It participates in inflammatory reactions regulating cells that are involved in cell-to-cell signaling by molecules called cytokines.

In health, the neuritogenic peptide of P2 (and P2) are not exposed to the body’s immune system. When myelin is damaged and P2 is exposed disease ensues. Clinical signs manifest because the exposed peptides sensitize T-cells that stimulate a protein to bind immunoglobulin and make peripheral nerves a target of inflammation.