Ученые выявили генетическую мутацию в гене TLR7 как причину тяжелого системной красной волчанки

A genetic analysis found a single point mutation in the TLR7 gene and then identified other cases of severe lupus where this gene was also mutated. Lupus is a chronic autoimmune disease which causes inflammation in organs and joints, affects movement and the skin, and causes fatigue. In severe cases, symptoms can be debilitating and complications can be fatal. The work resulted from whole genome sequencing on the DNA of a Spanish child 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. To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice. These mice went on to develop the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery. The mutation the researchers identified causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it. The work may also help explain why lupus is about 10 times more frequent in females than in males. As TLR7 sits on the X chromosome, females have two copies of the gene while males have one. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies. Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system. Carola Vinuesa, senior author and principal investigator at the Centre for Personalised Immunology in Australia, co-director of CACPI, and now group leader at the Crick says: “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. 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”. Professor Nan Shen, co-director of CACPI adds: “While it may only be a small number of people with lupus who have variants in TLR7 itself, we do know that many patients have signs of overactivity in the TLR7 pathway. By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”