Turning immunity ON and OFF

in Reporting from the Lab by

Our immune system is a fortress with multiple layers of protection to keep invaders out of the body. But now and then, traitors arise within this fortress, turning the body against itself, causing what are called autoimmune diseases. Does the body have patrols to keep such traitors in check?

Scientists led by Dr. Jan Carette at Stanford University recently identified a new protein, DDX6 that controls the immune system. It makes sure that immune genes are turned OFF in a healthy person and  turned ON when the human body is attacked by microbes. Without this protein, the immune system would be continually active even without infection, turning the body against itself, destroying healthy cells and increasing the risk of developing autoimmune diseases. These findings were published recently in Cell Reports.

Harmful microorganisms trigger the immune cells in our body to release defense proteins called cytokines. Sixty years ago, the first cytokine, “interferon” was discovered. Today interferons are widely used for the treatment of Hepatitis C infection. Taking a closer look at interferons, they set off a cascade of events in infected cells, turning ON hundreds of other immune response genes to attack and kill invading microorganisms. But even after six decades of interferon research, very little is known about what keeps the interferon cascade in check and turned OFF in healthy cells when they are not challenged by foreign invaders.

Researchers in Jan Carette’s group selectively inactivated every gene in the human genome to find genes that turn OFF the interferon cascade. This led to the discovery of DDX6. When DDX6 was deleted, cells started producing large amounts of cytokines and were better at fighting many viruses like Dengue, Venezuelan equine encephalitis and vesicular stomatitis viruses. However, the cells did not know when to stop. The cytokine genes were turned ON even in the absence of infection resulting in a hyperactive, uncontrolled immune system. Hence, while the absence of DDX6 helped the cells fight against viral infection more robustly, it also triggered an inappropriate activation of the immune system.

Overall, the paper highlights the importance of DDX6 as an immune suppressor. This discovery puts many previous unexplained findings into perspective. Earlier scientists had noticed that there were many mutations near the DDX6 gene in people with autoimmune diseases such as rheumatoid arthritis and lupus. From this study, we know that DDX6 keeps the immune genes under control and thus can suppress autoimmune responses. Any mutations near the gene can disrupt its function and cause the body to attack itself. Exploring the link between DDX6 and autoimmunity is important in understanding the emergence of autoimmunity and could help in developing new therapeutics.

Article in spotlight : 

DDX6 Represses Aberrant Activation of InterferonStimulated Genes. Lumb JH et al. Cell Reports 2017 Jul 25;20(4):819-831.

Image source: flickr.com

About the author:

Shwetha Shivaprasad is a postdoctoral fellow in the Department of Microbiology and Immunology at Stanford University. She is a virologist by training and loves to learn something new everyday, expanding her knowledge base and skill set. She is currently in a phase of career exploration and trying her hand at science writing and reviewing. But nevertheless, she is irreversibly drawn towards the charm of a career in academia.

Editors : 

Radhika Raheja, PhD

Sushama Sivakumar, PhD

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