Study maps gene variants to DNA regions that regulate immune cells.


A person’s genetic makeup plays a role in autoimmune diseases such as multiple sclerosis that develop when the body is attacked by its own immune system.  However, little is known about how immune cells are pushed into overdrive to cause these autoimmune diseases.  Now, a study from researchers at Washington University School of Medicine in St. Louis identifies genetic master switches that turn up, or down, the activity of specific types of immune cells.  The team state that the regions of DNA that make-up these master switches include numerous genetic variants linked to a range of autoimmune diseases that points to potential therapeutic targets.  The opensource study is published in the journal Cell.

Previous studies show that Innate lymphoid cells (ILCs), a recently discovered group of infection-fighting white blood cells, are among the first components of the immune system to confront certain pathogens. They have a critical function at mucosal barriers, such as the bowel or the lung, where the body comes in direct contact with the environment.  Specifically, innate lymphoid cells act quickly when a pathogen invades the body, responding to non-specific danger signals released by the cells at the site of infection. In contrast, T helper cells take days to respond, and only activate when they encounter a pathogen they recognize.  Despite being activated at different times and by different signals, innate lymphoid cells and T helper cells both serve as a kind of control tower for the immune response, sending out molecular signals to other immune cells.  The current study investigates the similarities and differences in the way gene expression in these two cell types is regulated.

The current study utilised cells from human tonsils to compare the patterns of gene activity in the two types of cells. Results show a set of super-enhancers, regions of DNA that serve as master control switches, for innate lymphoid cells and T helper cells that regulate genes which give each cell type its unique identity and function.  Data findings show that the super-enhancers contain many genetic variants associated with autoimmune diseases such as diabetes, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.

The group state that, to their knowledge, this is the first time that these sets of super-enhancers have been mapped for these cell types.  Results show that by looking at these super-enhancers, a number of genes were identified that are likely to be critical for eliminating pathogens.

The lab explain that these regions of DNA typically act like master dimmer switches on the activity of these immune cells and that in some cases, individual variations in a person’s DNA probably tweak the settings of these switches upward, leading to overactivation of the immune cells and autoimmune disease.  They go on to add that their observations could pave the way for more precise treatments in autoimmune diseases, where patients may be divided into groups based on the super-enhancer in which their genetic variant falls, with therapies targetting the genes regulated by each specific super-enhancer.

The team surmise that theirs is the first study to locate the variations in the landscape of innate lymphoid cell regulation. For the future, the researchers state that now it is known where the master switches are, it can be seen that those variants are associated with autoimmune disease because they affect the regulation of these immune cells.

Source: Washington University School of Medicine in St. Louis 

 

Cluster of dendritic cells (green) and innate lymphoid cells (red) in a small intestinal villous crypt. (Image via Columbia University).

Cluster of dendritic cells (green) and innate lymphoid cells (red) in a small intestinal villous crypt. (Image via Columbia University).

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