Researchers have identified a mechanism that requires just a single genetic mutation to trigger a form of the autoimmune disease lupus in children.

Testing for mutations in the UNC93B1 gene could enable early diagnosis and a new treatment target for this lifelong condition where the immune system attacks healthy tissue, causing chronic inflammation that potentially damages almost any of the body's organs.

If that inflammation can be prevented by targeting this newly discovered mechanism, it could substantially lessen the impact of the disease, which affects around 5 million people, primarily women of childbearing age.

Led by the Max Planck Institute for Infection Biology in Germany, the team discovered that a group of proteins called the BORC complex is needed to properly break down a protein called toll-like receptor 7 (TLR7).

TLR7 identifies nonspecific genetic material belonging to viruses and bacteria, serving as part an innate defense system that holds the front line until our adaptive immune system takes over. A balance of these receptors is important for a quick immune response.

"We wanted to understand what happens when this balance is disturbed," explains infection biologist Olivia Majer from the Max Planck Institute.

"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."

Majer and colleagues found that when the BORC complex isn't working properly, TLR7 can accumulate in immune cells, making them less sensitive to activation by intruder genetic material and more likely to attack our body's tissues.

"A greater amount of receptor biases towards recognizing the body's own genetic material," says Majer. "This leads to an immune response against self, a trigger for the autoimmune disease lupus."

They also found that the protein Unc93B1, encoded by the UNC93B1 gene, is needed for BORC to properly break down TLR7.

A mutation in the gene that makes TLR7 protein has recently been identified as a cause of lupus. However, neither BORC nor Unc93B1 have been linked to lupus in humans.

This changed when the study team was contacted by a researcher in Munich who found exactly what Majer and team suspected; a UNC93B1 gene mutation in a young lupus patient.

"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," Majer says.

A mutation in one copy of the UNC93B1 gene is all that's needed to affect TLR7, though the authors mention that at first this didn't seem to apply to the patient's father, who also carried the mutation. But despite lacking obvious symptoms, on further testing, the father showed signs of mild inflammation.

What's more, a concurrent study found two other families with a different UNC93B1 gene mutation also have lupus, further cementing Unc93B1's role in preventing excessive TLR7 signaling and autoimmune issues in humans.

The BORC complex maintains the health of nerve cells, and it seems to also play a role in the immune system, a connection that hasn't been confirmed before.

One specific part of the complex is especially important for transporting vesicles over long distances within nerve cells. When BORC function was weakened in mice, it led to damaged nerve cells and difficulty with movement.

This suggests that if BORC doesn't work properly in humans, it might first show up in neurodegenerative disorders, which, the researchers write, "notably, frequently cooccur with autoinflammatory or autoimmune disease and often share genetic variants and pathways."

Majer and team think this might be why there haven't been any findings of BORC mutations related to autoimmune diseases in genetic studies so far, and say more research is needed to fully understand these processes.

Their work "may pave the way for improved treatment through TLR7-targeted precision medicine," the authors conclude.

The research has been published in Science Immunology.