Researchers with the National Institutes of Health have identified the genomic changes of a blood cell important to regulating the human immune system. The results, reported in Nature today, open the door to new investigation in drugs and personalized medicine to assist those with autoimmune problems like as inflammatory bowel disease or rheumatoid arthritis.
The senior author of the research, John J. O’Shea, M.D., is the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases. The led author, Golnaz Vahedi, Ph.D., is a postdoctoral fellow in Dr. O’Shea’s laboratory in the Molecular Immunology and Inflammation Branch. The research was conducted in alliance with investigators lead by NIH Director, Francis S. Collins, in the Medical Genomics and Metabolic Genetics.
Autoimmune diseases take place when the immune system wrongly attacks its own cells, resulting in inflammation. Various tissues are impacted in various diseases, for instance, the joints turn into swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The reasons for these conditions are not well recognized, but researchers feel that they have a genetic aspect because they generally run in families.
“We now know more about the genetics of autoimmune diseases,” stated NIAMS Director Stephen I. Katz. “Understanding of the genetic risk aspects allows us to evaluate a person’s vulnerability to disease. With additional study on the related biological mechanisms, it could gradually allow doctors to tailor therapies to each individual.”
Figuring out autoimmune disease susceptibility genes can be a concern because in most of the cases a complex mix of genetic and environmental aspects are involved. Genetic research have proven that individuals with autoimmune diseases have unique genetic variants, but most of the modifications are identified in areas of the DNA that do not carry genes. Researchers have suspected that the variants are in DNA components known as enhancers, which act like switches to manage gene activities.
Dr. O’Shea’s team wondered if the changes may lie in a recently identified type of enhancer known as a super enhancer (SE). Previously work in the lab of Dr. Collins and others had proven that super enhancers are particularly powerful switches, and that they manage genes essential for the function and identity of each individual cell type. In add-on, a huge number of disease-connected genetic changes were identified to fall within super enhancers, indicating that disease takes place when these switches malfunction.
Dr. O’Shea’s team started by searching for super enhancers in T cells, immune cells identified to play an essential role in rheumatoid arthritis. They reasoned that super enhancers could serve as signposts to guide them toward possible genetic risk factors for the disease.
“Instead of beginning off by searching at genes that we previously knew were essential in T cells, we took an unbiased method,” said Dr. O’Shea. “From the locations of their super-enhancers, T cells are informing us where in the genome these cells invest their assets, key proteins and thereby where we are most probably to find genetic modifications that confer disease susceptibility.”
Making use of genomic methods, the investigators combed the T cell genome for areas that are especially available to proteins, a hallmark of DNA segments that carry super enhancers. They recognized several hundred, and additional analysis demonstrated that they mostly control the activities of genes that encode cytokine and cytokine receptors. These kinds of molecules are essential for T cell function due to the fact they allow them to connect with other cells and to mount an immune reaction.
But the investigators most stunning observation was that a large portion of earlier recognized modifications connected with rheumatoid arthritis and other autoimmune problems localized to these T cell super enhancers. Further studies offered even more proof for a central role for super enhancers in rheumatoid arthritis. When the researchers revealed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes managed by super enhancers were significantly impacted in comparison to other genes without super enhancers. This outcome recommends that tofacitinib may bring about its therapeutic effects in part by acting on super enhancers to modify the activities of essential T cell genes.
“Three kinds of data, the genetics of rheumatoid arthritis, a genomic function of T cells, and the pharmacological outcomes of a rheumatoid arthritis medicine are all directing to the significance of super-enhancers,” stated Dr. Vahedi. “These areas are where we prepare to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune problems, and for new therapeutic targets for these problems.”