Lupus nephritis, which affects about half of lupus patients, causes severe inflammation of the kidneys, potentially requiring dialysis or organ transplant.This may have changed when one of Rathmell’s postdoctoral fellows observed that iron seemed to be a “common denominator in many of the problems in T cells.” She was equally intrigued by the finding that, despite a tendency to be anemic, patients with lupus had T cells with high iron levels.
To explore these peculiar findings, Voss used a CRISPR genome editing tool to evaluate iron-handling genes in T cells. This led to the discovery that the transferrin receptor, a carrier protein that imports iron into cells, was critical to inflammatory T cells and inhibitory to anti-inflammatory regulatory T cells. This receptor, which was more highly expressed in T cells found in SLE-prone mice and human lupus patients, caused cells to accumulate too much iron.
“We see a lot of complications coming from that — the mitochondria don’t function properly, and other signaling pathways are altered,” Voss said. “When the team used an antibody to block the transferrin receptor, they found it reduced the level of iron within T cells, inhibited inflammatory T cell activity and enhanced regulatory T cell activity.
An analysis of T cells from lupus patients revealed that expression of the transferrin receptor correlated with disease severity. Blocking the receptor in vitro was found to promote the production of IL-10. Spurred by these findings, the team hopes to develop transferrin receptor antibodies that are capable of binding directly to T cells to prevent any off-target effects of future therapy.
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