A groundbreaking study has shed light on how some people may inherit autoimmune conditions
For the very first time, a single gene variant has been found that causes lupus. The research, published in Nature, suggests one reason why women are disproportionately affected by the condition, and could open a new avenue of investigation for systemic autoimmune conditions more generally.
Lupus, or systemic lupus erythematosus, is a chronic autoimmune disease that can cause fatigue, joint pain and inflammation of organs including the heart, lungs, kidneys and brain. It affects about 28 out of every 100,000 people, and 90% of these are women.
Lupus cannot be cured but can be managed. Current treatments aim to reduce symptoms and prevent organs being damaged by inflammation. In practice, this involves immunosuppressants and steroids, which can make affected people more vulnerable to infections.
As with many autoimmune conditions, the exact way lupus is caused is not understood, although both genetic and environmental factors appear to be involved.
The new study is the first of its kind to make a connection between a single gene variant and lupus.
Finding the gene
The key to the discovery was one patient: a Spanish girl, named Gabriela, who was diagnosed with severe lupus at the atypically early age of seven.
Whole genome sequencing revealed that Gabriela had a single missense variant in the TLR7 gene, which causes a single amino acid substitution in the corresponding protein. This change causes the TLR7 protein to become overactive, known as a gain-of-function variant.
TLR7 is an important protein in the immune system, where it binds to viral RNAs and signals to other immune cells to destroy the invading virus and infected cells. When it becomes overactive, it starts binding mistakenly to healthy tissues and cells, causing the inflammation that characterises lupus.
Furthermore, the TLR7 gene is located on the X-chromosome which may help explain why lupus disproportionally affects women, as they have two copies.
To prove that Gabriela’s variant was able to cause lupus by itself, the researchers created mice with the same genetic change, all of which showed signs of the condition.
“This is the first time a TLR7 variant has been shown to cause lupus, providing clear evidence of one way this disease can arise,” said study leader Professor Carola Vinuesa, from the Francis Crick Institute in London.
The future for patients
The researchers stress that Gabriela’s variant won’t be the cause for all people with lupus but could shed light on the mechanism by which it develops in a wider range of patients.
“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,” said co-author Professor Nan Shen.
“By confirming a causal link between the gene variant and the disease, we can start to search for more effective treatments,” he added.
The researchers now plan to partner with pharmaceutical companies to develop new treatments targeting TLR7, as well as looking for existing drugs that can be modified or repurposed. They also think that TLR7 may play a role in other autoimmune conditions, including rheumatoid arthritis.