Scientists are discovering the genetic cause of lupus, a chronic autoimmune disease

An international team of researchers has identified a cause of lupus autoimmune disease within the DNA mutations of a gene that detects viral RNA, findings that will lead to the development of new treatments.

There is currently no cure for chronic autoimmune disease that causes inflammation in organs and joints and affects movement and skin, sometimes with debilitating symptoms and life-threatening complications.

Lupus affects about a quarter of a million people in the United States and the United Kingdom, and current treatments are predominantly immunosuppressants that work by lowering the immune system to relieve symptoms.

But recently, scientists reported that the entire genome was sequenced in the DNA of a Spanish girl named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.

In his analysis published on April 27 a Nature, researchers report finding a single point mutation in the TLR7 gene. Through references from the US and Shanghai Renji Hospital in China, they identified other cases of severe lupus where this gene was also mutated.

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To confirm that the mutation causes lupus, the team used CRISPR gene editing to introduce it into mice. These mice developed the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and mutation were called “kika” by Gabriela, the young woman who was treated at the Center for Personalized Immunology at the National University of Australia.

“It has been a great challenge to find effective treatments for lupus, and the immunosuppressants currently in use can have serious side effects and leave patients more susceptible to infection,” said Carola Vinuesa, lead author, principal investigator and leader of the study. new Autoimmunity Laboratory at the Francis Crick Institute where research will continue. “There’s only been one new FDA-approved treatment in the last 60 years.”

“This is the first time that a TLR7 mutation has been shown to cause lupus, providing clear evidence of a way in which this disease can arise.”

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There may be a small number of people with lupus who have variants in the same TLR7, but many patients have signs of hyperactivity in the TLR7 pathway. By confirming a causal link between gene mutation and disease, researchers can begin to develop more effective treatments.

The mutation that the researchers identified makes the TLR7 protein more easily bound to a nucleic acid component called guanosine and becomes more active. This increases the sensitivity of the immune cell, making it more likely to misidentify healthy tissue as foreign or damaged and attack it.

Interestingly, other studies have shown that mutations that make TLR7 less active are associated with some cases of severe COVID-19 infection, highlighting “the delicate balance of a healthy immune system.”

10 times more likely in women

The work can also help explain why lupus is about 10 times more common in women than in men.

Because TLR7 is on the X chromosome, women have two copies of the gene while men have one. Normally, one of the X chromosomes is inactive in women, but in this section of the chromosome, the silencing of the second copy is often incomplete. This means that women with a mutation in this gene can have two functional copies.

“The identification of TLR7 as the cause of lupus in this unusually severe case ended in a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients who are likely to benefit from this discovery,” says Dr. Carmen de Lucas Collantes, co-author of the study.

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Researchers are now working with pharmaceutical companies to explore the development or reuse of existing treatments, which target the TLR7 gene. And they hope that targeting this gene can also help patients with related conditions such as rheumatoid arthritis and dermatomyositis, which belong to the same broad family as lupus.

Now a teenager who keeps in touch with the research team, Gabriela expressed hope that the discovery will make people with lupus feel like they are not alone in fighting their battle. “Hopefully the research can continue and end in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”

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