The immune system is crucial to our health. It must sense pathogens and respond to these threats effectively. But the immune system also has to be carefully controlled. If it starts to attack healthy tissues, overreacts to an infection, or is constantly causing low-grade inflammation, serious problems can arise. Millions of people around the world suffer from autoimmune disorders like type 1 diabetes, lupus, or rheumatoid arthritis, for example. But understanding the causes of these disorders and how to stop them has remained elusive.
Researchers have now learned more about a major trigger of immune activity, and how it may relate to overactivity in the immune system. Reporting in Cell, scientists found that a protein called STING can cause a very rare autoimmune disorder known as STING-associated vasculopathy with onset in infancy (SAVI). In this disease, the immune system erroneously attacks lung and limb tissue, and typically leads to death before patients reach adulthood.
Usually, STING is an important monitor that surveils for foreign DNA in the host. When foreign DNA, such as from a virus is identified, STING triggers the production of immune molecules known as cytokines. These immune molecules can then direct immune cells to attack the viral pathogen. But this process is overly active in SAVI patients, and immune activity is constantly ongoing. This destroys healthy tissue.
STING does not only trigger the production of cytokines, this work showed that it also helps cells release these molecules. The researchers suggested that it may be possible to treat SAVI and other disorders by stopping the release of these molecules.
After screening a variety of proteins, the investigators found one called ArfGAP2 that seems to be critical to the release of cytokines. Additional work showed that when SAVI cells do not generate ArfGAP2, cytokines are not released when STING is active.
“It’s like a train station and ArfGAP2 is acting as the conductor, directing which molecules are to be shipped out,” explained co-corresponding study author David Kast, PhD, an assistant professor at Washington University School of Medicine in St. Louis. “If STING and ArfGAP2 are not working together, the trains are stopped.”
In a mouse model of SAVI, that was also engineered to lack the ArfGAP2 protein, the destructive immune reaction did not happen. This seems to confirm that if ArfGAP2 is deactivated, the autoimmune response will stop in SAVI.
Since other disorders relate to immune overactivity, such as the cytokine storms that can arise during serious infections, these findings may aid other conditions.
“Diseases like SAVI that are super rare can provide valuable insights, because if you can figure out how a rare disease mutation is working, you learn something about the normal proteins that all of us have," noted co-corresponding study author Jonathan Miner, MD, PhD, an associate professor at University of Pennsylvania Perelman School of Medicine, among other appointments. "Then suddenly you’ve opened the doors to all these new avenues of potential therapies for many, many different classes of diseases.”
Sources: Washington University School of Medicine, Cell
