A new study partly funded by the Lupus Research Alliance (LRA) may help explain how the immune system attacks patients’ DNA in lupus. Together with the laboratory of Dr. David Raulet at the University of California, Berkeley, Dr. Joshua Woodward of the University of Washington in Seattle and his colleagues discovered a protein door in cells that allows messenger molecules that may promote these attacks to spread.
When cells in the body detect DNA from bacteria or viruses, they alert the immune system to fight back. But in lupus, patients’ DNA stimulates the immune system, leading to inflammation and damaged tissue.
To send out an alert, cells that have detected DNA require messenger molecules called cyclic dinucleotides, or CDNs. Two years ago, a team that included Dr. Woodward and his University of Washington colleague Dr. Keith Elkon, recipient of a Target Identification in Lupus grant from the LRA, discovered that blood cells from some patients with lupus produced one type of CDN, but they didn’t find the molecule in blood cells from patients who didn’t have the disease. The researchers suspect that in patients with lupus the blood cells may be releasing CDNs, which could then enter other cells throughout the body, resulting in inflammation and other symptoms.
But they still needed to figure out how these CDNs could get inside other cells whose outer layer is supposed to keep the molecules out. Dr. Woodward and his colleagues identified a protein that serves as an open door for CDNs, allowing them to move into cells. The scientists also found that they could close this door with methotrexate, an existing treatment for lupus and rheumatoid arthritis, and sulfasalazine, a therapy approved for rheumatoid arthritis and ulcerative colitis. Both drugs reduced the amount of CDNs that cells take in, the researchers reported in Nature.
“Our prior studies suggest that CDNs may be key mediators of autoimmune diseases like lupus. With the support of the LRA we have been exploring new ways to inhibit their production and the inflammation they cause with the hope of developing new therapies,” said Dr. Woodward. “The discovery of the door through which CDNs can gain entry into cells may pave the way for new therapeutic development. If we can find new inhibitors that can lock the door, we may dampen inflammation and alleviate disease severity.”
“CDN entry into cells is a new therapeutic avenue to explore for lupus,” said Dr. Teodora Staeva, Chief Scientific Officer of the LRA.