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.Ā The ground-breaking work, published in the journalĀ Nature,Ā may be useful for developing treatments forĀ 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.Ā 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.

ā€œWe now know more about the genetics of autoimmune diseases,ā€ statedĀ NIAMS Director Stephen I. Katz, M.D., Ph.D. ā€œKnowledge of the genetic risk factors helps us assess a personā€™s susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual.ā€

FindingĀ 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. Oā€™Shea, M.D., the scientific director at NIHā€™s National Institute of Arthritis and Musculoskeletal and Skin Diseases, the researchers decided to studyĀ a newly discovered type of enhancer called a super-enhancer (SE). SEs are powerful switches that control genes.Ā Dr. Oā€™Shea and his collaborators lookedĀ for SEs in T cells, immune cells that are important for contributing to the autoimmune diseaseĀ rheumatoid arthritis.

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ā€œRather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,ā€ remarkedĀ Dr. Oā€™Shea. ā€œFrom the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assetsā€”their key proteinsā€”and thereby where we are most likely to find genetic alterations that confer disease susceptibility.ā€

The researchersĀ searched the genetic material of T cells and found that manyĀ identified mutationsĀ associated with autoimmune diseases could be localized to T cell SEs. The scientists then treatedĀ human T cells withĀ a drug used for rheumatoid arthritis, called tofacitinib.Ā They discovered thatĀ genes controlled by SEs changed dramaticallyĀ compared to other genes without SEs. They concluded thatĀ tofacitinib may workĀ by acting on SEs to affectĀ T cell genes.

ā€œThree types of dataā€”the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drugā€”are all pointing to the importance of super-enhancers,ā€ said lead author, Golnaz Vahedi, Ph.D. ā€œThese 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.ā€