Newly Discovered Lupus Trigger Traced Back To Single Mutation

The speed and voracity with which our innate immune system responds to invaders is great – until it turns against us. That happens in autoimmune conditions like lupus, and researchers have been trying to better understand how the system gets so out of control. In a new study, not only have scientists identified a new control mechanism that can trigger lupus, but also traced it back to a single genetic mutation.

The team, based at the Max Planck Institute for Infection Biology, focused on Toll-like receptor-7 (TLR7); this is a protein found in immune cells that acts as a sensor for the genetic material of viruses and bacteria. When detected, the receptor triggers an immune response.

However, for this response to happen quickly and with appropriate strength, immune cells are constantly producing and degrading receptors to maintain a balanced number of them. Too many, and things can go wrong, increasing the chance of the immune cells reacting against the body’s own cells and leading to lupus.

“From earlier experiments in mice carried out a few years ago at the University of Berkeley in California, we already knew that too many of these receptors are a problem,” explained group leader Olivia Majer in a statement.

To figure out how a cell could end up with too many receptors, Majer and the team looked toward the molecules that help to break them down. In doing so, they identified a protein complex called BORC and demonstrated that this requires another protein, UNC93B1, in order to degrade TLR7.

Neither BORC nor UNC93B1 had previously been associated with lupus, but thanks to lupus specialist Fabian Hauck and a patient at the Ludwig Maximilian University Hospital in Munich, the team’s findings were confirmed; the patient had a single mutation in the gene encoding UNC93B1.

“When I got the first call from Fabian Hauck, I thought it was too good to be true,” says Majer, “but within eight busy weeks of joined effort, we were able to confirm that the mutation in UNC93B1 was the cause of this patient’s lupus.”

Lupus is estimated to affect at least 5 million people worldwide. Due to the immune system attacking the body’s own tissue, it can result in symptoms ranging from fatigue and skin rashes to severe damage to the lungs and kidneys. Actress and singer Selena Gomez was diagnosed with lupus in her early 20s, and received a kidney transplant back in 2017 due to the effects of the disease.

It’s hoped that by identifying this new mechanism and the role of UNC93B1, testing for mutations in the protein could become a new part of lupus treatment. With further research, it may even represent a new therapeutic target for minimizing or stopping the damage caused by the disease in the first place.

The study is published in the journal Science Immunology.

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