Lupus is an autoimmune disease that causes pain, inflammation, and tissue damage. It can affect the brain, skin, joints, kidneys, lungs, and blood vessels. Five million people around the world are thought to have some form of lupus, including systemic lupus erythematosus (SLE). The only treatments for the disease aim to reduce autoimmune attacks and protect organs. But researchers may have now opened up a new treatment avenue for SLE. New work has shown that when iron uptake is blocked in T cells, anti-inflammatory activity is boosted, inflammation is reduced, and disease pathology is reduced. The findings have been reported in Science Immunology.
First study author and postdoctoral fellow Kelsey Voss, Ph.D., was investigating how T cell metabolism relates to lupus, and found that iron seemed to be relevant to many of the problems in T cells in lupus patients. The T cells of lupus patients often carry high levels of iron, though iron deficiency is often a problem for those patients.
With the CRISPR gene editor, Voss screened genes involved in iron metabolism in T cells. The transferrin receptor imports iron to T cells, and was found to be crucial to inflammatory T cells, and also inhibits regulatory T cells that tamp down inflammation.
T cells from patients with SLE or an SLE mouse model were found to express abnormally high levels of the transferrin receptor, which causes the high iron levels in those T cells. As a result, mitochondria function is disrupted and signaling is altered, noted Voss.
An antibody can block the activity of the transferrin receptor, reducing iron levels in the T cells, which inhibits inflammatory activity and enhances anti-inflammatory activity. When the SLE mouse model was treated with this antibody, kidney and liver function was restored and levels of an anti-inflammatory molecule, IL-10, increased in those mice.
"It was really surprising and exciting to find different effects of the transferrin receptor in different types of T cells," Voss said. "If you're trying to target an autoimmune disease by affecting T cell function, you want to inhibit inflammatory T cells but not harm regulatory T cells. That's exactly what targeting the transferrin receptor did."
These findings were confirmed in cells from lupus patients. Now, the scientists want to create antibodies that bind specifically to transferrin receptors on T cells, to avoid unwanted effects on other cell types.
"It has been a real challenge to come up with new therapies for lupus," said Jeffrey Rathmell, Ph.D., a professor and chair at Vanderbilt University Medical Center. "The patient population and the disease are heterogeneous, which makes it difficult to design and conduct clinical trials." This research may change that.
Sources: Vanderbilt University Medical Center, Science Immunology
