New insights into autoimmune disease mechanisms

18 February 2015

A new genomic study reveals a link between powerful gene regulatory elements and autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.

Autoimmune disorders result when the body’s immune system mistakenly attacks and destroys healthy body tissue; different tissues are affected in different diseases; about 80 have been recognised. The causes of these diseases are not well understood, but scientists believe there is a genetic component as they often run in families. 

It can be challenging to identify specific genetic risk factors for autoimmune disease, since in most cases they are the result of a complex mix of genetic and environmental factors. However, it is useful; Stephen Katz, Director of the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) explained: “Knowledge of the genetic risk factors helps us to 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”. 

Published in Nature, the new National Institutes of Health (NIH) study looked see whether genetic risk factors lay within a group of DNA elements called enhancers, which act like switches to control gene activation. Within these enhancers, super-enhancers (SE) are especially powerful switches that control genes important for function and identity of each different cell type. 

Using genomic techniques the researchers searched for SE in T-cells, immune cells thought to play an important role in rheumatoid arthritis. The researchers reasoned that as the locations of the SEs effectively show key genes for T-cells, they would signpost potential genetic risk factors for the disease.

The headline finding from the study was that a large fraction of previously identified genetic alterations associated with autoimmune diseases were indeed localised in the T-cells SEs. Further, when human T- cells were exposed to the rheumatoid arthritis drug tofactinib, it disproportionally affected the expression of rheumatoid arthritis risk genes with SE structures. 

Lead author Dr Golnaz Vahedi said: “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”.

Looking to the future Vahedi said that they planned further investigation of these regions to learn more about the underlying mechanisms at play in rheumatoid arthritis, and to identify novel therapeutic targets for these conditions.

Meanwhile, researchers at Trinity College Dublin reported in Nature Medicine this week the discovery of what they term a ‘marvel’ molecule, MCC950, that blocks a key driver for inflammatory diseases, the NLRP3 inflammasome. According to the scientists, the findings mark a significant development in the effort to find treatments for inflammatory diseases and could inspire new non-invasive treatments for arthritis, multiple sclerosis and other inflammatory conditions. Further, the findings support the belief that inflammatory diseases all share a common underlying process. 

Dr, O’Neill, professor of biochemistry at Trinity said: “We believe this has real potential to benefit patients suffering from several highly debilitating diseases, where there is currently a dire need for new medicines”.

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