Researchers have a new clue to what causes multiple sclerosis (MS), a disease in which the immune system destroys the protective sheath around nerve cells. A study in the January Nature Medicine suggests that in MS, immune cells never properly learn to avoid a certain protein in the sheath. The findings may help pave the way for a better treatment strategy.
In MS, which affects about 1 million people worldwide, the immune system eats away at the fatty myelin that insulates nerves and helps signal transmission. Victims cope with bouts of muscle weakness and numbness; in severe cases, MS can lead to paralysis and death.
Most of the time, the immune system learns to distinguish between "self" and "nonself" proteins: T cells, for instance, go to school in the thymus, where they are baited with the body's own proteins. Those T cells that attack are eliminated. Flaws in this educational program could be one way in which autoimmune disorders like MS might arise, thought immunologists Ludger Klein and Bruno Kyewski of the German Cancer Research Center in Heidelberg. For instance, if there isn't enough of a particular protein in the thymus, T cells that would be prone to attack it would not be weeded out. To test this hypothesis, the researchers looked at the activity of the gene for a protein called PLP--a major component of myelin and one of the main targets of renegade T cells in MS--in the thymus of two different mouse strains, one susceptible and the other resistant to an MS-like disease. They found that both strains had about the same amounts of PLP in their thymuses--although the version in the thymus was a bit shorter than the one produced in the central nervous system (CNS).
When the team took a closer look at the parts of the protein that the T cells latched onto during their attack, they were in for a surprise: In the MS-resistant strain, the four main target regions all lay within the short version of PLP present in the thymus, but in the susceptible mice, one target region fell within the short stretch absent in the thymus but present in the CNS. Like mice, humans make only the shorter PLP version in the thymus.
To exploit this in a therapy for MS, "one would have to restore tolerance against [protein snippets] that are not expressed in the thymus" early in the course of the disease, says Stanford immunologist Lawrence Steinman. If early results in animals work in humans as well, he adds, it might one day be possible to give T cells of MS sufferers some remedial schooling by injecting artificial protein fragments.
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