The study showed that introducing the TLR7 variant in an animal model led to the development of autoimmune symptoms and potential development of systemic lupus erythematosus (SLE).
A new report appears to confirm for the first time that a particular genetic variant plays a causal role in the development of systemic lupus erythematosus (SLE) in certain patients.
The authors say the new information could be critical in developing new therapies to treat lupus.
Writing in Nature, the authors explained that emerging evidence has suggested that increased signaling of toll-like receptor 7 (TLR7) can play a key role in the development of lupus. However, despite evidence of TLR7 causing lupus in animal models, a human case caused by TLR7 variants had not yet been reported, and the investigators said it is not yet clear how TLR7 signaling might cause autoimmune diseases like lupus.
The new study began with a 7-year-old girl from Spain in whom SLE was diagnosed after she presented with refractory autoimmune thrombocytopenia and with elevated antinuclear antibodies and hypocomplementemia. Her symptoms later worsened, including inflammatory arthralgia and renal involvement.
Bioinformatics analysis of the patient showed she had a TLR7 variant (missense TLR7Y264H). The investigators decided to use gene editing to introduce that variant in a mouse model in order to determine whether it led to SLE-like autoimmune disease—and it did.
“This newly generated mouse model provides us with a framework to continue to understand the immune system and how autoimmune diseases develop in humans,” said study co-author Grant Brown, a PhD student at Australian National University, in a statement about these findings.
The authors added that it is unclear how many patients with SLE have the disease because of TLR7, noting that the number could be small. However, “the fact that we have confirmed gain-of-TLR7 function to be a cause of lupus means we can now start to search for new treatments.”
Most current therapies are immune suppressors, but the new research creates the possibility for therapeutic approaches that are more targeted toward the cause of the disease, they emphasized.The animal model developed here could be used to test potential therapies targeting TLR7, they posited.
“Autoimmune diseases such as lupus have many causative factors, from our genetics to environmental influences, making them difficult to study,” Brown said in the statement. “Therefore, if we can better understand how these diseases develop, we have a greater chance of developing more tailored therapeutics with fewer side effects for patients.”
In some cases, existing therapies could be altered to target TLR7 or other proteins on the same biochemical pathway, the authors noted.
Finally, the investigators said their research might also help solve one other lingering question about SLE: Why are women more likely than men to receive an SLE diagnosis? The investigators noted that TLR7 is present on the X chromosome. Therefore, it could be that women are more likely to have SLE because they have 2 X chromosomes and men have just 1.
“This means females with an overactive TLR7 gene can have 2 functioning copies, potentially doubling the harm,” the authors concluded.
Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. Published online April 27, 2022. doi:10.1038/s41586-022-04642-z