New discovery unravels mystery behind overactive immune responses

Autoimmune diseases, which are estimated to affect more than 15 million people in the U.S., occur when the body responds to immune-system false alarms, and infection-fighting first responders are sent out to attack threats that aren't there. Scientists have long understood how the false alarms get triggered, but the second step of dispatching the immune response has been a mystery.

Now, scientists at Washington University School of Medicine in St. Louis and the Perelman School of Medicine at the University of Pennsylvania have identified a key component to launching immune activity – and overactivity. The researchers identified a protein in cells that spurs the release of infection-fighting molecules. The protein, whose role in the immune system had not previously been suspected, provides a potential target for therapies that could prevent overreactive immune responses that are at the root of several debilitating illnesses.

Their paper appeared online in Cell on Feb. 12 and will be published on March 20.

The team of researchers, co-led by Jonathan Miner, MD, PhD, an associate professor of Rheumatology and Microbiology and a member of Penn's Colter Center for Autoimmunity, and David Kast, PhD, an assistant professor in the Department of Cell Biology & Physiology at WashU Medicine, made the discovery by studying a rare autoimmune disease called STING-associated vasculopathy with onset in infancy (SAVI). The condition is extremely rare, occurring in one of every 1 million births. It leads to the immune response attacking tissues in the lungs and limbs of patients, often resulting in death before adulthood.

Studying rare diseases where the root cause of the disease is caused by a single mutation can not only reveal the biological role of the affected gene and the disease-causing disruptions it incites, but also provide insight into more-common conditions.

SAVI is caused by changes to a protein in cells called STING, which ordinarily acts as a molecular watchdog that responds to the presence of viral DNA by activating the component of the cell that generates immune proteins. These immune proteins are then released from the cell to signal to the body's immune system of the need to attack the viral invaders, and where in the body the immune cells need to go. In SAVI, STING is overactive, triggering constant immune activity that ultimately damages healthy tissue.

In addition to signaling the cell to make the immune-response proteins, called cytokines, the researchers discovered that STING also has a novel role in releasing those proteins from where they are made in the cell. How that release process worked was unknown, but finding a way to control it could be a promising avenue for treating SAVI as well as other autoimmune disorders.

Using immune cells that were sensitive to the disease-causing mutations in STING, the team performed a screen to identify proteins that prevented this sensitivity. One protein, ArfGAP2, stood out, as it seemed to be strongly connected to the final step when the immune response proteins get released.

The team further validated this finding in SAVI cells that did not produce ArfGAP2. Without it, STING could not drive the release the immune proteins.

It's like a train station and ArfGAP2 is acting as the conductor, directing which molecules are to be shipped out. If STING and ArfGAP2 are not working together, the trains are stopped."

David Kast, PhD, Assistant Professor, Department of Cell Biology & Physiology at WashU Medicine

The team reasoned that stopping the never-ending "trains" in SAVI's constant immune response could be a means of treating the rare disease.

The team tested that idea in a mouse that was genetically modified to have SAVI, but did not produce the ArfGAP2 protein. They found that the lung- and limb-destroying immune response typical of the disease did not occur, which confirmed that if the protein could be neutralized, the overactive immune response could be turned off.

Miner, who initiated the project when he was at WashU Medicine, said that it is a promising target for other conditions that similarly lead to excess immune proteins of the same type. This could include the "cytokine storms" characteristic of COVID-19 or the brain inflammation linked to immune responses in Alzheimer's disease.

"Diseases like SAVI that are super rare can provide valuable insights," said Miner, "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. Then suddenly you've opened the doors to all these new avenues of potential therapies for many, many different classes of diseases."