Summary of A New Potential Approach to Treating Lupus:
Researchers from Vanderbilt University Medical Center have identified iron metabolism in immune system cells as a potential new approach for treating systemic lupus erythematosus (SLE), the most prevalent form of the chronic autoimmune disease lupus. By blocking an iron uptake receptor, disease pathology was reduced and the activity of anti-inflammatory regulatory T cells was increased in a mouse model of SLE. The study, published in the journal Science Immunology, suggests that targeting iron metabolism in T cells could be a promising new treatment option for lupus, which affects 1.5 million Americans and 5 million people worldwide.
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Lupus: Exploring Iron Metabolism in Immune System Cells as a Potential New Treatment
Introduction
Lupus is a chronic autoimmune disease in which the body’s immune system attacks its own healthy tissues and organs. This results in inflammation and damage to various parts of the body, including the skin, joints, kidneys, heart, lungs, brain, and blood cells. 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. Currently, only one targeted biologic agent has been approved for treating SLE, belimumab in 2011.
Targeting Iron Metabolism in Immune System Cells
Researchers from Vanderbilt University Medical Center recently published their findings in the journal Science Immunology, revealing that by blocking an iron uptake receptor, disease pathology is reduced and the activity of anti-inflammatory regulatory T cells is increased in a mouse model of systemic lupus erythematosus (SLE).
Jeffrey Rathmell, Ph.D., (left), and Kelsey Voss, Ph.D., led a multidisciplinary team that identified iron metabolism in T cells as a potential target for treating lupus. Credit: Vanderbilt University Medical Center
When postdoctoral fellow Kelsey Voss, Ph.D., 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.
Voss and Rathmell drew on the expertise of other investigators at VUMC: Eric Skaar, Ph.D., and his team are experienced in the study of iron and other metals; Amy Major, Ph.D., and her group provided a mouse model of SLE; and Michelle Ormseth, MD, MSCI, and her team recruited patients with SLE to provide blood samples.
Results
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. 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.
Conclusion
Targeting iron metabolism in immune system cells could be a potential new approach for treating systemic lupus erythematosus (SLE), the most prevalent form of the chronic autoimmune disease lupus. The researchers are interested in developing transferrin receptor antibodies that bind specifically to T cells, to avoid any potential off-target effects. They are also interested in studying the details of their unexpected discovery that blocking the transferrin receptor enhances regulatory T-cell activity.
