A study published in Nature on April 27, 2022, provides evidence indicating that the currently incurable chronic autoimmune disease, systemic lupus erythematosus (SLE), is caused by gain-of-function mutations in a gene called TLR7 that increases its affinity for the nucleoside guanosine and the cyclic nucleotide cGMP, resulting in abnormal TLR7 activation and childhood-onset SLE.

“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,” said Carola Vinuesa, PhD, senior author of the study and principal investigator at the Centre for Personalized Immunology in Australia, co-director of CACPI (China Australia Centre of Personalised Immunology), and group leader at the Francis Crick Institute. “This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise”.

The study was published in an article titled ‘TLR7 gain-of-function genetic variation causes human lupus.’ The findings pave the way for the development of new treatments for SLE, which causes inflammation in organs and joints, affects movement and skin health, and causes chronic fatigue. In severe cases, symptoms can be debilitating with fatal complications.

Lupus affects 1.5 million Americans, and at least five million people worldwide. Current treatment options are primarily drugs that dial down the immune system to alleviate symptoms, resulting in additional complications.

Co-author, Nan Shen, PhD, a professor and co-director at CACPI said, “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.”

The international team of scientists that conducted the study carried out whole genome sequencing on the DNA of a Spanish child, who was diagnosed with severe lupus at age seven. Genetic analysis carried out at the Australian National University uncovered a single point mutation (Y264H) in the TLR7 gene.

Carmen de Lucas Collantes, PhD, a co-author of this study said, “Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies.” Subsequently the team identified other SLE cases with the same mutation.

To confirm that the mutation causes lupus, the team introduced the mutation in mice using CRISPR gene-editing. The mutant mice showed symptoms like SLE, confirming that the TLR7 point mutation was a genetic cause of SLE.

Crossing TLR7 mutant mice with mice deficient for MyD88, an adaptor protein downstream of TLR7, the researchers rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes, further confirming the causative role of the TLR7 mutation in the development of SLE.

Through cellular studies, the team showed that the mutant TLR7 protein increases the sensitivity of immune cells, making it more likely to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it. The authors show increased TLR7 signaling abnormally increases the survival of B lymphocytes that express the B cell receptor, in addition to CD11c-expressing B cells in the germinal center of lymphoid organs.

SLE is about ten times more frequent in females. Since the TLR7 gene is an X-chromosome gene, the current study may explain why gain-of-function mutations in the gene are more deleterious in females who may have two copies of the abnormal gene.

The team is currently collaborating with pharmaceutical companies to repurpose drugs that target TLR7 for the treatment of SLE. Collantes, who is starting a new laboratory at the Crick Institute, intends to investigate the disease-causing mechanisms that occur downstream of the TLR7 mutation. Collantes believes TLR7 may also play a role in other autoimmune diseases such as rheumatoid arthritis and dermatomyositis.

The seven-year-old patient, Gabriella, who is now a teenager, says, “I hope this finding will give hope to people with lupus and make them feel they are not alone in fighting this battle. Hopefully the research can continue and end up in a specific treatment that can benefit so many lupus warriors who suffer from this disease.”