Lupus, including SLE, occurs when the immune system attacks a person’s own healthy tissues, causing pain, inflammation and tissue damage. Lupus most commonly affects skin, joints, brain, lungs, kidneys and blood vessels. About 1.5 million Americans and 5 million people worldwide have a form of lupus, according to the Lupus Foundation of America.
Treatments for lupus aim to control symptoms, reduce immune system attack of tissues, and protect organs from damage. Only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.
Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE)
Jeffrey Rathmell, PhD, professor of Pathology, Microbiology and Immunology and Cornelius Vanderbilt Chair in Immunobiology and his group have had a long-standing interest in lupus as part of a broader effort to understand mechanisms of autoimmunity.
When postdoctoral fellow Kelsey Voss, PhD, began studying T cell metabolism in lupus, she noticed that iron appeared to be a “common denominator in many of the problems in T cells,” she said. She was also intrigued by the finding that T cells from patients with lupus have high iron levels, even though patients are often anemic.
First, Voss used a CRISPR genome editing screen to evaluate iron-handling genes in T cells. She identified the transferrin receptor, which imports iron into cells, as critical for inflammatory T cells and inhibitory for anti-inflammatory regulatory T cells.
The researchers found that the transferrin receptor was more highly expressed on T cells from SLE-prone mice and T cells from patients with SLE, which caused the cells to accumulate too much iron.
How can we interfere with this mechanism ?
An antibody that blocks the transferrin receptor reduced intracellular iron levels, inhibited inflammatory T cell activity, and enhanced regulatory T cell activity. Treatment of SLE-prone mice with the antibody reduced kidney and liver pathology and increased production of the anti-inflammatory factor, IL-10.
In T cells from patients with lupus, expression of the transferrin receptor correlated with disease severity, and blocking the receptor in vitro enhanced production of IL-10.
The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects (the transferrin receptor mediates iron uptake in many cell types). They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T cell activity.
Kelsey Voss, Allison E. Sewell, Evan S. Krystofiak, Katherine N. Gibson-Corley, Arissa C. Young, Jacob H. Basham, Ayaka Sugiura, Emily N. Arner, William N. Beavers, Dillon E. Kunkle, Megan E. Dickson, Gabriel A. Needle, Eric P. Skaar, W. Kimryn Rathmell, Michelle J. Ormseth, Amy S. Major, Jeffrey C. Rathmell. Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus. Science Immunology, January 30, 2023; 8 (79) DOI: 10.1126/sciimmunol.abq0178