An abnormal retention of mitochondria can trigger the cascade of inappropriate and harmful immune activity that is characteristic of lupus, the report said.
Lupus may be triggered by a defective process in the development of red blood cells (RBCs), according to a study that said the finding could lead to new methods for classifying and treating patients with this disease.
Led by researchers at Weill Cornell Medicine, the report found that in a number of lupus patients, maturing red blood cells fail to get rid of their mitochondria. This abnormal retention of mitochondria can trigger the cascade of inappropriate and harmful immune activity that is characteristic of the disease.
Previous studies have shown defective mitochondria within immune cells of lupus patients. In the current study, the researchers examined red blood cells, which are supposed to have no mitochondria at all. They found that a large number of patients with lupus had red blood cells with detectable levels of mitochondria—and these cells were especially frequent in patients with the most severe lupus symptoms. By contrast, healthy controls had no mitochondria-containing red blood cells.
“Our findings support that red blood cells can play a really important role in driving inflammation in a subgroup of lupus patients,” senior author Virginia Pascual, MD, the Drukier Director of the Gale and Ira Drukier Institute for Children’s Health and the Ronay Menschel Professor of Pediatrics at Weill Cornell Medicine, said in a statement.
Another scientist then studied how human red blood cells normally rid themselves of mitochondria as they mature, as prior studies had mainly examined this in mice, and why this process could be defective in lupus patients.
Further experiments revealed how these abnormal red blood cells cause inflammation. In general, as red blood cells age or display signs of damage they are removed by scavenger immune cells called macrophages.
Antibodies that bind red blood cells also facilitate their removal. Once ingested by macrophages, the red blood cells’ mitochondrial DNA stimulates a powerful inflammatory pathway called the cGAS/STING pathway, which in turn drives type I interferon production.
Underlining the relevance of these findings, “those lupus patients with mitochondria-containing red blood cells and evidence of circulating anti-RBC antibodies had higher interferon signatures compared to those who didn’t,” said the researcher, Simone Caielli, PhD, assistant professor of immunology research at the Drukier Institute and the Department of Pediatrics at Weill Cornell Medicine.
The team now continuing to study the complex process by which mitochondria are retained in red blood cells and end up driving abnormal immune activation. Identifying patients whose lupus symptoms are driven this way might pave the way for a warning system to future lupus flares and to identify specific therapies for them.
The researchers published their findings in Cell.