Lupus is an autoimmune disease that can impact anyone, but tends to affects women between the ages of 15 and 45. The disorder has to be managed for a lifetime. The causes have been unclear, and the symptoms affect many organ systems including skin, kidneys, brain, heart, and lungs. There are some treatments, but they tend to be immunosuppressive, which can carry other risks. Lupus can also be fatal.
Scientists have now made a major discovery that will help scientists understand the causes of lupus, and how to treat them more effectively. Reporting in Nature, researchers have described the case of a lupus patient who was diagnosed at age 7, which is unusually young. Whole-genome sequencing revealed that this patient carried a mutation in a gene called TLR7 (Toll-like receptor 7). The mutation is 'gain-of-function' so it doesn't take out the immune protein encoded by this gene, it ramps up its activity. Previous studies have suggested that abnormal increases in TLR7 signaling are related to lupus.
When the researchers studied genetic data from other lupus patients with severe cases, they found other TLR7 mutations. While there may be other causes of lupus, this gene is clearly involved in at least some cases. .
The TLR7 gene is found on the X chromosome, so women carry two copies. But X-chromosome inactivation, which is meant to silence the second copy of X chromosome genes, is often incomplete in this portion of the genome. This may help explain why the disorder is more common in women.
When the mutation was modeled in mice using CRISPR gene editing, the mice showed symptoms of lupus, suggesting that dysfunction in TLR7 can indeed cause the disease.
Although every lupus patient may not have mutations in their TLR7 genes, there are signs in many patients that the TLR7 pathway is overactive, said study co-author Professor Nan Shen, a co-director of the China Australia Centre of Personalized Immunology (CACPI). “By confirming a causal link between the gene mutation and the disease, we can start to search for more effective treatments.”
Normally, TLR7 encodes for a protein that senses viruses, and can bind to guanosine. In the young patient, the genetic mutation seems enhance binding between the TLR7 protein and guanosine, increasing its activity. Immune cells expressing aberrant TLR7 would then become overly sensitive, and might become more likely to launch an autoimmune attack.
The researchers are now looking for compounds that can target TLR7. New therapeutics targeting this protein might help patients with lupus and other autoimmune disorders.
“There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus. TLR7 may also play a role in these conditions,” said corresponding study author Carola Vinuesa, a principal investigator at the Centre for Personalized Immunology in Australia, among other appointments.