Groundbreaking study discovers the cause of lupus

Lupus is a chronic autoimmune disorder that triggers inflammation in organs and joints, affects mobility, impacts skin health, and causes fatigue. At its worst, the condition can be debilitating, and some complications can even be life-threatening.

Despite affecting around 50,000 individuals in the UK alone, there is still no cure for lupus. Current treatments primarily focus on immune suppressors, which work by tempering the immune response to alleviate symptoms.

A breakthrough, however, might be on the horizon. Recently, an article in Nature highlighted the discovery of DNA mutations in a gene that detects viral RNA, identifying this as a root cause of lupus. This represents the first time a mutation in the TLR7 gene has been directly linked to the onset of lupus, offering new insight into the origins of the disease.

The discovery emerged from a global research effort involving whole-genome sequencing on the DNA of a young Spanish girl named Gabriela, who was diagnosed with severe lupus at just seven years old. Her early and severe symptoms suggested a single genetic cause, making her case particularly significant.

Researchers pinpointed a specific mutation in the TLR7 gene, which causes the TLR7 protein to bind more easily to a nucleic acid called guanosine, leading to increased protein activity. This heightened sensitivity of immune cells causes them to mistake healthy tissue for foreign or damaged tissue, prompting an attack.

Further studies, including those at the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, identified additional severe lupus cases with mutations in the same gene. To verify that this mutation causes lupus, the team used CRISPR gene-editing technology to introduce the mutation into mice.

These mice developed lupus-like symptoms, providing strong evidence that the TLR7 mutation was indeed the cause. Gabriela, the girl central to this discovery, named both the mouse model and the mutation ‘kika.’

Dr. Carola Vinuesa, the senior author and principal investigator at the Centre for Personalised Immunology in Australia and now group leader at the Crick Institute, reflected on the challenges faced in treating lupus. “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,” she explained. Notably, only one new treatment for lupus has been approved by the FDA in the last 60 years.

Professor Nan Shen, co-director of CACPI, emphasized the importance of this discovery, stating, “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.”

This discovery also sheds light on why lupus is about 10 times more common in females than in males. TLR7 is located on the X chromosome, and females have two copies of this gene, while males have only one. Typically, one X chromosome in females is inactive, but in this region, the silencing is often incomplete. As a result, females with a mutation in the TLR7 gene can have two functioning copies, increasing their susceptibility to lupus.

Dr. Carmen de Lucas Collantes, a co-author of the study, shared that identifying TLR7 as the cause of lupus in Gabriela’s severe case ended what she described as a "diagnostic odyssey." This finding brings hope for more targeted therapies, not only for Gabriela but also for other lupus patients who may benefit from this discovery.

Gabriela's case has unlocked a crucial piece in the puzzle of lupus, a disease that has long confounded researchers. Although past studies had suggested a link between the TLR7 gene and lupus, this research provides the first definitive proof of a causal relationship.

The discovery is a significant step toward developing more effective treatments for lupus. Current therapies mainly involve immune-suppressing drugs, which can cause serious side effects and increase the risk of infections. The research team hopes their findings will lead to therapies that specifically target the TLR7 gene, offering a more focused and effective treatment approach.

Beyond lupus, this study could have broader implications for other autoimmune diseases, such as rheumatoid arthritis and dermatomyositis, which share similar characteristics. Dr. Vinuesa, who is now leading new research at the Francis Crick Institute, believes this study has opened up a new avenue for exploring the role of the TLR7 gene in autoimmune diseases. She hopes these findings will pave the way for treatments that target this gene and potentially benefit patients with lupus and other related conditions.

Gabriela, who is now a teenager and still in contact with the research team, takes pride in her role in advancing our understanding of lupus. She hopes her story will inspire others with the condition to remain hopeful and continue their fight for a cure. “I hope that my experience will give hope to other people with lupus and make them feel that they are not alone in this fight,” she said. “I am so grateful to the researchers who worked on this study, and I hope their findings will lead to new treatments that can help so many people who suffer from this disease.”

This research was supported by the National Health and Medical Research Council of Australia, the Australian Research Council, and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. Researchers from institutions in Australia, China, the United States, and Spain contributed to this groundbreaking study.

Lupus symptoms tend to vary from person to person, and can include pain and swelling in one or more joints, red spots on the skin, excessive fatigue, skin lesions after sun exposure, hair loss, increased light sensitivity, mouth ulcers and nose ulcers.

Lupus symptoms can affect any organs or parts of the body, and can vary from person to person depending on the phase of the disease. They can come and go, and present with alternating periods of flare-ups and remission.

The main signs and symptoms of lupus are:

If any of these symptoms emerge, you should consult a family doctor or rheumatologist for testing to confirm or rule out lupus.

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