The genetic cause of lupus has been identified

An international team of researchers have identified DNA mutations in genes that sense viral RNA as the cause of lupus in the autoimmune disease, and their discovery paved the way for the development of new therapies.

Lupus is a chronic autoimmune disease that causes inflammation of organs and joints, affects movement and skin, and causes fatigue. In severe cases, the symptoms are debilitating and the complications can be fatal.

There is no cure for this disease, which affects about 50,000 people in the UK, and current treatments are primarily immunosuppressive drugs, which work by dialing down the immune system to relieve symptoms.

In their study, Nature Today (April 27), scientists have made a whole-genome sequence on the DNA of a Spanish child named Gabriella, who was diagnosed with severe lupus at the age of seven. Such severe cases with early onset of symptoms are rare and indicate a single genetic cause.

In their genetic analysis conducted at the Personalized Immunology Center of the Australian National University, researchers said TLR7 gene. Through referrals from the Center for Individual Immunology of China and Australia (CACPI) at the United States and Shanghai Jiao Tong University, they identified other cases of severe lupus erythematosus in which this gene is also mutated.

To confirm that the mutation causes lupus, the team introduced it into mice using CRISPR gene editing. These mice developed the disease, showed similar symptoms, and provided evidence that the TLR7 mutation was the cause. Both the mouse model and the mutation were named “Kika” by Gabriella, the central girl in this discovery.

Carola Vinuesa, Senior Author and Principal Researcher at the Australian Center for Personalized Immunology, Co-Director of CACPI and now Crick’s Group Leader, said: The suppressors currently in use can cause serious side effects and make patients more susceptible to infections. Over the last 60 years, only one new treatment has been approved by the FDA.

“This is the first time that the TLR7 mutation has been shown to cause lupus and provides clear evidence of one possible way for the disease to occur.”

Although only a few people with lupus may have the mutation TLR7 As such, we know that many patients show signs of overactivity in the TLR7 pathway. By ascertaining the causal relationship between genetic mutations and disease, we can begin to seek more effective treatments. “

Professor Nan Shen, Co-Director of CACPI

Researcher-identified mutations make the TLR7 protein easier Nucleic acid It is a component called guanosine, which makes it more active. This increases the sensitivity of immune cells and increases the likelihood of misidentifying healthy tissue as foreign or damaged and launching an attack on it.

Interestingly, other studies have shown that mutations that reduce TLR7 activity are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of the healthy immune system. I am.

This study may also help explain why lupus is about 10 times more frequent in women than in men.As TLR7 Located 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 silencing of the second copy is often incomplete in this section of the chromosome. This means that a woman with a mutation in this gene can have two functional copies.

Dr. Carmen de Lucas Corantes, co-author of this study, said: TLR7 The cause of lupus in this unusually severe case is because it ends the diagnostic odyssey and provides hope for more targeted treatments for Gabriella and other lupus patients who are likely to benefit from this finding. ..

In contact with the research team, Gabriella, now a teenager, said: It ends up in a specific treatment that can benefit so many lupus warriors suffering from this disease. “

Researchers are currently working with pharmaceutical companies to investigate the development or diversion of existing therapies. TLR7 gene. And they hope that targeting this gene will also help patients with related symptoms.

“There are other systemic autoimmune diseases that belong to the same broad family as lupus, such as rheumatoid arthritis and dermatomyositis. TLR7 may also be involved in these conditions,” Carola added.

Carola has opened a new laboratory at the FrancisCrick Institute to further understand the mechanisms responsible for diseases that occur downstream of important mutations such as those found in the TLR7 gene.