Two receptors explain MS?

Rare, dual-receptor T-cells may be at the root of multiple sclerosis, according to an article published online today (June 6th) in __Nature Immunology,__ providing a possible explanation for other autoimmune diseases. Spinal MRI showing multiple sclerosisImage: National Institutes of Health"It has been thought for a while that these dual receptor T-cells are involved in autoimmunity," said Nitin Karandikar from The University of Texas Southwestern Medical Center, who was not involved in the st

Written byEdyta Zielinska

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Spinal MRI showing multiple sclerosis
Image: National Institutes of Health

"It has been thought for a while that these dual receptor T-cells are involved in autoimmunity," said Nitin Karandikar from The University of Texas Southwestern Medical Center, who was not involved in the study. "This [study] is the first formal proof of that." In multiple sclerosis, T-cells attack the myelin covering nerve cells in the central nervous system, slowing the transmission of signals between nerve cells, and leading to cognitive and physical decline. Scientists believe that the disease is caused by several factors. First, genetic mutations that predispose an individual's immune system to attack its own tissue are likely to play a role. The disease is also thought to require a second hit with an environmental trigger such as a viral infection, which can stimulate the activation of T-cells that bind to proteins such as myelin basic protein (MBP). But even genetic and environmental factors combined explain only a small percentage of MS cases, suggesting that a third mechanism is likely involved in the onset of MS. Joan Goverman and colleagues at the University of Washington attacked the question by creating a new animal model that more closely resembled the disease than currently used models. The team engineered mice to express CD8 T-cells that can recognize MBP -- genetically predisposing the mice to MS. By infecting the mice with a virus that also expressed the MBP protein, the researchers could then activate the MBP-binding T-cells. As Goverman expected, the mice developed the disease, but surprisingly, so did the control mice that were infected with a virus lacking the MBP trigger. This suggested that the T-cells engineered to bind MBP could also recognize other parts of the viral particles, and were thus activated by viruses lacking MBP. Goverman knew, however, that the receptors that bound MBP did not also bind the virus, and through cross-breeding experiments, she showed that that there was a second, virus-specific receptor being produced on these MBP-engineered T-cells. Indeed, she showed that, by chance, a few T-cells with the engineered specificity for MBP had also built their own virus-binding receptors. When exposed to a virus lacking MBP, the dual-receptor T-cells were activated by these self-constructed receptors, which bound to and killed the virus. The activated T-cells could also start attacking neurons with their MBP-specific receptor, triggering the onset of MS. The study "is extremely interesting, clever, and technical in the way it's carried out," said Richard Ransohoff, from the Cleveland Clinic, who wrote an accompanying review article. "The bottom line" -- that T-cells with dual-specificity can initiate autoimmune disease -- "is simple and profound, and that's very appealing." But how common such dual-receptor T-cells really are is still unclear. While the study demonstrates the possibility that dual-receptor T-cells can cause disease in an experimental model, "we still don' know what happens in the wildtype," said Karandikar. Nor does it preclude the possibility that another mechanism is at play in humans, such as a single T-cell receptor with the flexibility to recognize peptides from both MBP and from a virus. The result "does not increase the likelihood much in my mind," that this occurs in the natural system, said Bill Heath from the University of Melbourne in Australia. Testing for the evidence in humans, says Goverman, is "the next step." She plans to test samples from patients with MS and investigate just "how many have dual T-cells." J. Qingyong et al., "Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs," __Nature Immunology,__ published online June 6th, 2010, Doi:10.1038/ni.1888
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