Researchers Uncover Key Missing Link in Understanding Autoimmune Disorders
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.
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. The team of researchers 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.
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.
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.
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. 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.
It is a promising target for other conditions that similarly lead to excess immune proteins of the same type.
Ref: Poddar S, Chauvin SD et al. ArfGAP2 promotes STING proton channel activity, cytokine transit, and autoinflammation. Cell, February 12, 2025. DOI: 10.1016/j.cell.2025.01.027
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