The immune response is a complex system of proteins, cells, and signals that respond to foreign invaders. A recent study published in Nature Immunology found two proteins, PLD3 and PLD4, that play an essential role in how the immune system detects and responds to infection. "In particular, they play a role in how the immune system responds when foreign DNA, such as that from viruses or bacteria, is present. That was unexpected and completely unknown," says Amanda Gavin, Ph.D., assistant professor at Scripps Research and one of the study's first authors.
PLD3 and PLD4 were named due to their role as phospholipases or proteins that degrade lipids. Previous studies suggested that PLD3 and PLD4 play a role in disease, but exactly what role they played was previously unknown. Mutations in the genes encoding PLD3 have been linked to Alzheimer’s disease while mutations in genes encoding PLD4 have been associated with autoimmune disorders such as rheumatoid arthritis and system sclerosis. These proteins share a similar molecular structure to proteins PLD1 and PLD2 which degrade lipids, but it appears that this structural similarity did not dictate functional similarity. "It took us a long time to work out the enzymatic activity of these proteins because we were looking in the wrong place," Gavin explains. "We were very surprised to learn that these proteins are actually enzymes that degrade DNA."
The study, conducted at Scripps Research Institute, utilized knockouts of the PLD3 and PLD4 protein genes to investigate their role in disease. Mice were created with nonfunctioning versions of the PLD3 and PLD4 proteins. Without PLD3 and PLD4 functioning, the mice had defective livers, high levels of inflammation, and bodies similar to children diagnosed with hemophagocytic lymphohistiocytosis while also dying at a younger age. However, the researchers did not see any signs or manifestation of Alzheimer’s, rheumatoid arthritis, or system sclerosis in the mice. The results showed that dendritic cells, a type of immune cell, were detecting the mice’s DNA as foreign causing it to be attacked by the immune response. The role of PLD3 and PLD4 was shown to prevent this by degrading DNA to stop the autoimmune reaction from happening.
Hemophagocytic lymphohistiocytosis is a condition in which the body makes too many activated immune cells. While the disease in mice was similar to that of hemophagocytic lymphohistiocytosis in children, further studies will need to be done to know if PLD3 and PLD4 are involved in the disease in people. If these proteins do play a role in human disease further mouse studies could be used to screen for potentially effective drugs. Further studies on PLD3 and PLD4 and how they help the immune system detect DNA, and what happens when this process goes wrong, could contribute to new approaches in cancer immunotherapy and treatment of a range of autoimmune disorders.
To learn more about hemophagocytic lymphohistiocytosis watch the video below!