Novel Switch for Autoimmune Diseases Could Play Role In MS

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Healthy human T cell.National Institutes of Health (NIH) scientists may have discovered a critical immune system switch that could affect genes involved in autoimmune diseases. The ground-breaking work, published in the journal Naturemay be useful for developing treatments for autoimmune disorders such as multiple sclerosis (MS).

MS is characterized by an immune system attack on the body’s own myelin, a fatty covering that surrounds nerve cells and allows them to communicate. When myelin is damaged, communication in the nervous system goes awry, and problems with movement, sensation, vision and pain can occur. The cause of MS is not known, but both environment and genes may play a role.

“We now know more about the genetics of autoimmune diseases,” stated NIAMS Director Stephen I. Katz, M.D., Ph.D. “Knowledge of the genetic risk factors helps us assess a person’s susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual.”

Finding autoimmune disease susceptibility genes, such as those involved in MS, is difficult due to environment-gene interactions that likely occur. Switches to control gene activities, known as enhancers, have been proposed to play a possible role.

Led by John J. O’Shea, M.D., the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, the researchers decided to study a newly discovered type of enhancer called a super-enhancer (SE). SEs are powerful switches that control genes. Dr. O’Shea and his collaborators looked for SEs in T cells, immune cells that are important for contributing to the autoimmune disease rheumatoid arthritis.

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“Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” remarked Dr. O’Shea. “From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets—their key proteins—and thereby where we are most likely to find genetic alterations that confer disease susceptibility.”

The researchers searched the genetic material of T cells and found that many identified mutations associated with autoimmune diseases could be localized to T cell SEs. The scientists then treated human T cells with a drug used for rheumatoid arthritis, called tofacitinib. They discovered that genes controlled by SEs changed dramatically compared to other genes without SEs. They concluded that tofacitinib may work by acting on SEs to affect T cell genes.

“Three types of data—the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug—are all pointing to the importance of super-enhancers,” said lead author, Golnaz Vahedi, Ph.D. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”

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