DNA mutations in a gene that considers viral RNA a cause of the autoimmune disease lupus have been identified, thus paving the way for the development of new therapies.
Lupus is a chronic autoimmune illness that causes inflammation in organs and joints, affects movement and the skin, and causes fatigue. In severe cases, symptoms may be debilitating, and complications may ensue.
There is no cure for this disease, which affects around 50,000 people in the United Kingdom, and the current treatment is mostly immune-suppressors that work by dialing down the immune system to relieve symptoms.
The researchers conducted a whole genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was seven years old. This severe case with early onset of symptoms is rare and indicates a single genetic cause.
The researchers obtained a single point mutation in theTLR7gene in their genetic experiments at the Australian National University. Through referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at the Renji Hospital, they identified other instances of severe lupus, including this gene mutation.
To confirm that the mutation causes lupus, a team of scientists used CRISPR gene-editing to introduce it into mice. These mice continued to develop the disease and showed similar symptoms, indicating that the TLR7 mutation was the cause. Gabriela, the young girl responsible for this discovery, named the mouse model and the mutation.
The Crick, a senior author and principal investigator at the Centre for Personalised Immunology in Australia, believes the decision to develop effective therapies for the lupus is huge challenge, and immune-suppressors currently being used can have harmful side effects, leaving patients more susceptible to infection. There has only been a single new treatment developed by the FDA in over the past 60 years.
This is the first time that a TLR7 mutation has been shown to cause lupus, indicating that there is one possibility this disease may arise.
While it may only be a small number of people with lupus who have variants inTLR7self, we do know that many patients have signs of overactivity in the TLR7 pathway. We can begin to identify the causal link between the gene mutation and the disease by establishing a more effective approach.
The TLR7 protein is more easily attached to a nucleic acid component called guanosine and becomes active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and initiate an attack against it.
Other studies have shown that mutations that cause TLR7 to become less active are linked to certain instances of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system.
Females have two copies of the X chromosome, while males have one. Usually, in females, one of the X chromosomes is inactive, but the silencing of the second copy is often incomplete. This means females with a mutation in this gene may have two functioning copies.
The author of this study claims that the identification ofTLR7as the cause of lupus in this unusually severe case had ended a diagnostic odyssey and offers hope for more targeted therapies for Gabriela and other lupus patients.
Gabriela, who is still in touch with the research team and is now a teenager, says: I hope this study will inspire people with lupus and make them feel confident in their quest. Hopefully, the research will continue and end up in a specific approach that will benefit so many lupus warriors who have lupus.
The researchers are working with pharmaceutical companies to discuss the development or repurposing of existing treatments that target theTLR7gene. They hope that targeting this gene may also assist patients with related conditions.
Other systemic autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, may be involved in these situations. TLR7 may also play a role in these situations.
Carola has established a newlaboratoryat the Francis Crick Institute in order to better understand the disease-causing mechanisms that occur downstream of key mutations, like the one found on the TLR7 gene.