Natural method for clearing cellular debris provides new targets for lupus treatment
Cells that die naturally generate a lot of internal debris that can trigger the immune system to attack the body, leading to diseases such as lupus.
Now Georgia Health Sciences University researchers report that an enzyme known to help keep a woman's immune system from attacking a fetus also helps block development of these autoimmune diseases that target healthy tissues, such as DNA or joints.
The findings point toward new treatment strategies for autoimmune diseases, which are on the rise in light of a germ-conscious society that regularly destroys many of the previously pervasive microbes that made the immune system more tolerant.
"The basic premise of lupus is you have lost normal tolerance to yourself, your own proteins and DNA," said Dr. Tracy L. McGaha, GHSU immunologist and corresponding author of the study published in Proceedings of the National Academy of Sciences.
They found that IDO, or indoleomine 2,3-dioxegenase, helps promote tolerance to debris generated by natural cell death and that when IDO is removed from the mix, the debris spurs an immune response that can trigger autoimmune disease. In mice genetically programmed to develop lupus, blocking IDO resulted in earlier, more aggressive disease.
"This connects IDO and macrophages. It's a newly described role for IDO in regulation of tolerance toward self," McGaha said. Consequently, increasing IDO production or its downstream effects might be a way to regain lost tolerance, he said.
They studied activity in the spleen, a hard-working immune organ, that constantly filters blood. In a perfectly orchestrated defense, the entrance to the spleen is surrounded by immune cells that scour blood for viruses, bacteria, even fat and cholesterol floating by.
A nearby subset of macrophages, which are essentially scavengers, then capture and consume the undesirables, McGaha said. Interestingly, a lot of what macrophages consume is dead immune cells.
Macrophages also appear to help keep the peace by preventing the immune system from joining the fray. McGaha earlier found that if he destroyed macrophages, then fed the spleen dead cells, there was inflammation instead of calm. "That tells us there is something inherent in this subset of macrophages that is important for the suppressive process," McGaha said referencing the paper published in 2011 in the journal Blood.
The new paper shows IDO is part of that "something." Efficient elimination of cell debris while keeping nearby immune cells quiet is important because some debris is known to grab the attention of the immune system, McGaha said. He noted that it's normal and healthy for damaged cells to become targets.
"We are really interested in this process of normal cell debris removal because in lupus, it's thought to be one of the main drivers of inflammation," he said.
The immune system has points of expansion and regulation where it decides whether or not to act. Knowing key points, such as IDO's regulatory role, provides treatment targets that can interrupt a destructive cascade of immune activity, McGaha said. Previous studies have shown evidence of self-attack is present many years before disease symptoms appear, he said.
Environmental assaults, such as a bad sunburn, can be the initial trigger of the abnormal immune response in diseases like lupus. In healthy individuals, the immune system rises to the occasion of an infection then goes back to baseline. In autoimmune disease, patients tend not to return to normal levels.
GHSU's Drs. Andrew Mellor and David Munn reported in 1998 in the journal Science that the fetus expresses IDO to help avoid rejection by the mother's immune system. Subsequent studies have shown tumors also use it and that it could help transplanted organs escape rejection. They suggested that McGaha look at IDO as a regulatory mechanism used by macrophages.