An international team of researchers looked into lupus and has finally identified a cause of this autoimmune disease. They examined the DNA mutations of a gene that senses viral RNA, and the findings they have may bring about further development of new treatments.
Right now, the cure for the chronic autoimmune disease hasn’t been found yet. Lupus causes inflammation in organs and joints as well as have impact on movement and the skin. These can oftentimes can be controlled, but at times, debilitating symptoms and complications happen, and these are extremely fatal.
Lupus impacts roughly a quarter-million people in both the US and UK. As a form of treatment, the patients are prescribed mostly immune-suppressors that help dial down the immune system to assuage symptoms.
However, scientists believe that more can be done. So, they carried out whole genome sequencing on the DNA of a Spanish child named Gabriela. She had been diagnosed with severe lupus when she was just 7 years old. This type of severe case with early onset of symptoms is considered rare. It also points toward a single genetic cause.
The analysis was published April 27 in Nature. In it, they talked about finding a single point mutation in the TLR7 gene. Via referrals they made from the US and the Shanghai Renji Hospital in China, they were able to identify other cases of severe lupus and saw how there was mutation in the same gene.
They needed to confirm that the mutation happening is the cause behind lupus. In order to do this, the team used CRISPR gene-editing to introduce it into mice. True enough, the rodents eventually developed the disease and showed similar symptoms. This was proof that the TLR7 mutation was the culprit. The mouse model and the mutation were both named ‘kika’ by Gabriela, the patient who was being treated at the Centre for Personalized Immunology at the Australian National University.
“It has been a huge challenge to find effective treatments for lupus, and the immune-suppressors currently being used can have serious side effects and leave patients more susceptible to infection,” said Carola Vinuesa, senior author, principal investigator, and leader of the new Autoimmunity Laboratory at the Francis Crick Institute. This was where she will go on with the research as well. She added, “There has only been a single new treatment approved by the FDA in about the last 60 years.”
“This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise,” Vinuesa explained.
There may not be too many patients with lupus who have variants in TLR7 itself. Still, many of them will have signs of overactivity in the TLR7 pathway. The researchers’ goal is to confirm a causal link between the gene mutation and the disease itself because they want to develop more effective treatments in the future.
The mutation that was discovered by the team identified what causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. Because of what’s taking place, there is more sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged before the body begins to attack it.
Ironically, there are other studies that have shown how mutations that cause TLR7 to become less active are linked with some cases of severe COVID-19 infection, highlighting “the delicate balance of a healthy immune system.”
More Likely to Happen with Females
The research outcome may also help shine some light on why lupus is about 10 times more likely to happen in females than in males. It may be because TLR7 is found on the X chromosome. This is where women have two copies of it. The men, on the other hand, only have one of that gene. In many cases, one of the X chromosomes remains inactive in females. For the ones with lupus, in this section of the chromosome, the silencing of the second copy remains unfinished. Simply put, those with a mutation in this gene may have two functioning copies.
“Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery,” explained Dr. Carmen de Lucas Collantes, a co-author of the study.
The researchers of the study are collaborating with pharmaceutical companies to look into the development of, or the repurposing of existing treatments. They aim to target the TLR7 gene in order to help those who suffer from related conditions such as rheumatoid arthritis and dermatomyositis. These diseases actually belong to the same broad family as lupus and are somewhat connected to the other in one form or another.
Gabriela has now grown to become a teenager. In the years that have passed, she stays in contact with the research team. She has expressed hope that what the found will help people with lupus feel like they have an ally with them in the battle. She shared, “Hopefully the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”
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