East Montgomery Times

In recent research conducted by the Perelman School of Medicine at the University of Pennsylvania, a potential pathway for treating autoimmune diseases has been identified. The study, published in Cell, suggests that regulating cell acidity may be key to addressing severe inflammation associated with many immune disorders.

The protein STING is known to trigger inflammation within the body. When malfunctioning due to genetic mutations, it can lead to conditions characterized by severe inflammation. One such condition is STING-associated vasculopathy with onset in infancy (SAVI), which affects more than 50 individuals diagnosed since 1980 and offers limited treatment options. This condition causes significant inflammation in vital organs and often results in patients not surviving beyond their first two decades.

STING plays a crucial role in regulating acidity within the Golgi apparatus—a cellular structure responsible for processing proteins and lipids. The acidity levels in this organelle can impact cytokine transportation, which is essential for immune system function.

Dr. Jonathan Miner, an associate professor at Penn's Colton Center for Autoimmunity, stated: “We already knew STING regulated Golgi apparatus acidity... But the exact way STING controlled acidity wasn’t totally clear.” Through genetic screening of a SAVI patient, researchers identified ArfGAP2 as a protein affecting STING's ability to regulate cell acidity.

Alongside co-senior author Dr. David Kast from Washington University in St. Louis, Miner’s team found that ArfGAP2 significantly influences STING's proton channel activity related to Golgi apparatus acidity regulation. Experiments on small animal models showed that deleting ArfGAP2 led to decreased STING activity and reduced inflammation.

Miner remarked on these findings: “It is remarkable that something as small as the acidity of a tiny organelle within a cell could make such a big difference.”

Beyond SAVI, STING's involvement extends to numerous diseases including some lupus forms and retinal vasculopathy with cerebral leukoencephalopathy (RVCL). Miner noted: “Our exploration not only illuminates the genetic foundations of autoimmunity but also opens up new avenues for transformative treatments aimed at improving the lives of millions.”

The researchers aim to develop clinical therapies targeting ArfGAP2 disruption potentially through oral medications. This research received funding from two National Institutes of Health grants and support from the Clayco Foundation.