29 April 2022

Lupus on the X chromosome

Scientists have made a breakthrough in understanding the genetic nature of lupus

Svetlana Maslova, Hi-tech+

Researchers have discovered a gene whose mutations lead to an abnormal immune response against healthy tissues. Their discovery explains why women are 10 times more likely to develop systemic lupus erythematosus and points to targeted strategies for the treatment of autoimmune disease.


Over the past 60 years, only one drug has been approved for the treatment of systemic lupus erythematosus, an incurable autoimmune disease that affects internal organs and joints, provoking debilitating symptoms as the disease progresses. Today, patients are forced to take immunosuppressants in order to pacify the immune system and somehow alleviate the symptoms. Until now, the lack of understanding of the causes of lupus development made the development of targeted treatment options impossible, but thanks to the discovery of an international group of researchers, the situation has finally changed.

Thanks to a small patient named Gabriella, scientists were able to prove that lupus is caused by a mutation in the TLR7 gene.

At the age of seven, the girl was diagnosed with lupus. Extremely rare cases of lupus in children of this age indicate the genetic nature of the disease, so scientists sequenced Gabriella's genome and compared the data with other severe cases of lupus in patients from different countries. In all of them, the TLR7 mutation was detected, according to the website of the Francis Crick Institute.

Mouse models helped confirm the results. With the help of CRISPR gene editing, they were injected with a damaged gene and soon the rodents showed symptoms of lupus.

"The identification of TLR7 as the cause of lupus has put the horses on a diagnostic odyssey and gives hope for the emergence of targeted treatment methods," commented co—author Carmen de Lucas Collantes.

The mechanism of lupus development

Scientists have found that the mutation causes the TLR7 protein to bind more easily to the nucleic acid component guanosine and become more active. As a result, this increases the sensitivity of immune cells, increasing the likelihood of identifying healthy tissue as foreign and, as a result, attacking it.

The TLR7 mutation also explains why women are ten times more likely to have lupus. The fact is that TLR7 is located on the X chromosome, so a woman has two copies of the gene, and men have one. Thus, when mutated, women have two functional copies of the gene, which increases the risk of developing the disease.


Scientists are already working with pharmaceutical companies to explore the possibility of repurposing existing drugs to target TLR7. In parallel, a search is underway for new compounds that can target the TLR7 pathway, which, as clinical observations have shown, shows signs of hyperactivity in many patients with lupus.

It is noteworthy that the discovery of the TLR7 mutation may benefit in the treatment of other systemic autoimmune diseases, such as rheumatoid arthritis and dermatomyositis. They all belong to the same large family as lupus, so new treatment strategies may work for them as well.

The article by Brown et al. TLR7 gain-of-function genetic variation causes human lupus is published in the journal Nature – VM.

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