Autoimmune Diseases Linked To Genomic Switches

First Posted: Feb 16, 2015 09:06 PM EST

Researchers at the National Institutes of Health have now discovered certain genomic switches in blood cells that may be key to regulating the human immune system.

Senior study author John J. O'Shea, M.D., and the scientific director at NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases studied how the immune system can mistakenly attack its own cells, resulting in inflammation.

"We now know more about the genetics of autoimmune diseases," said NIAMS Director Stephen I. Katz, M.D., Ph.D., in a news release. "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."

Many autoimmune diseases occur when the immune system mistakenly attacks its own cells, resulting in inflammation that can result in different health problems. Though the causes of many autoimmune diseases are not well understood, scientists believe that they have a genetic component because they often run in families.

However, identifying an autoimmune disease isn't always so simple. Some genes have been found in regions of DNA that the genes do not carry. Furthermore, scientists have suspected that the variants are in DNA elements called enhancers that act as switches to help control various gene activities.

Researchers began searching for super-enhancers (SEs) in T cells, otherwise known as immune cells that play a critical role in rheumatoid arthritis. SEs could serve as signposts to steer them toward potential genetic risk factors for the disease, according to the study. 

"Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach," the researchers concluded. "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."

Reserachers then compared T-cell genomes for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. Several hundred were identified with further analysis, which showed that they largely control the activities of genes that encode cytokine and cytokine receptors.

Researchers found a striking observation via a large fraction of previously identified alterations linking rheumatoid arthritis and other autoimmune diseases with localization in the T cell SEs. For instance, when human T cells were exposed to the drug tofacitinib, the acities controlled by SEs were compared to genes without SEs. 

Findings showed that tofacitinib may bring therapeutic effects in part by acting on SEs that alter the important T cell genes. 

"Three types of data--the genetics of rheumatoid arthritis, a genomic feature of T cells, and the concluded Dr. Vahedi. "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."

More informaiton regarding the findings can be seen via the journal Nature

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