Genetic Cause of Lupus Discovered

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According to an international team of researchers, a genetic mutation is the likely cause of the autoimmune disease, lupus.

In a study, published in the journal Nature, a team of scientists identified a mutation in the TLR7 gene as the cause of Lupus. This is the first time that researchers have found a genetic mutation for an autoimmune disease. Furthermore, the discovery opens doors for new drugs that can target the specific gene and ultimately treat Lupus.

This is the first time a TLR7 mutation has been shown to cause lupus, providing clear evidence of one way this disease can arise.

Carola Vinuesa, senior author and principal investigator

The team first discovered the mutation in 12-year-old Gabriela. The Spanish child received a severe lupus diagnosis at the age of 7. Since such a severe case with early onset of symptoms is rare, scientists suspected a genetic cause. Hence, they conducted whole-genome sequencing on her DNA. This led to the discovery of a single point mutation in the TLR7 gene. Furthermore, researchers conducted genetic analyses on several other severe lupus cases. The cases were collected via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital and revealed the same genetic mutation.

According to the study authors, the mutation causes the TLR7 protein to bind more easily to guanosine and activates it. Guanosine is a nucleic acid component, and its activation causes immune cells to become more sensitive. The cells then identify healthy body tissue as foreign and attack it. Thus, bringing about the autoimmune condition.

Identification of TLR7 as the cause of lupus in this unusually severe case ended a diagnostic odyssey and brings hope for more targeted therapies for Gabriela and other lupus patients likely to benefit from this discovery.

Dr Carmen de Lucas Collantes, study author

10 Times More Common in Females

Lupus is a chronic autoimmune condition that affects approximately 5 million people worldwide. 90% of cases occur in women and most people develop symptoms between the ages of 15-44. There are different types of lupus: neonatal lupus, drug-induced lupus, cutaneous lupus, and systemic lupus erythematosus (SLE). Approximately 70% of all lupus cases are SLE. This particular form of lupus is more severe and affects multiple organs including the lungs, kidneys, heart, and blood.

Signs and symptoms of lupus can vary from person to person. A person typically goes through multiple cycles of flare-ups and remissions. Since the symptoms often vary and resemble other diseases, diagnosis is often difficult. Doctors generally diagnose the disease based on levels of certain biomarkers in the patient’s blood.

The most common signs and symptoms include:

  • fever
  • fatigue
  • joint and muscle pain with swelling
  • characteristic butterfly rash covering the cheeks and nose
  • sensitivity to light
  • headaches
  • chest pain, shortness of breath
  • memory problems
  • unusual hair loss
  • fingers and toes turn pale or blue on exposure to cold or stress

In severe cases, complications such as kidney failure, seizures, anemia, inflammation of the blood vessels, myocarditis, and pneumonia. Pregnant women with lupus have a higher risk of preeclampsia, preterm birth, and loss of pregnancy.

There is currently no cure for lupus. Treatments are limited and mostly involve the use of immune suppressors. These further increase the chances of infections and cause several other adverse effects. According to study author Carola Vinuesa, in the last 60 years, the FDA has only approved a single new treatment for lupus. Therefore, there is a need for more safe and effective treatment options for lupus.

Lupus Gene Introduced in ‘Kika’

To further confirm that the mutation causes lupus, the team used gene-editing to introduce the mutation into a mouse model named ‘kika’. As predicted, the mice developed lupus and demonstrated similar symptoms. Thus, proving that TLR7 gene mutation is a cause of lupus.

Although the study found the mutation in only a small number of cases, the TLR7 pathway is overactive in people with lupus. Therefore, Vinuesa believes that targeting TLR7 even in patients without the rare mutations will likely benefit them. Moreover, since the gene is situated on the X-chromosome, it also gives an insight into why lupus is more common in females.

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.

Carola Vinuesa, senior author and principal investigator

The team is currently working on developing treatments that target the TLR7 gene; not only does the gene play a role in lupus but also in other autoimmune diseases. Vinuesa has also set up a new laboratory at the Francis Crick Institute to further investigate key mutations that are involved in various disease mechanisms.

CAR-T Therapy Shows Promise

In a previous study, researchers at Universitätsklinikum Erlangen used CAR-T therapy to treat a 16-year-old with severe SLE. CAR-T cell therapy involves modification of patients’ own immune cells to help them develop chimeric antigen receptors (CAR) on their surface. These modified T cells can then recognize and attack autoreactive cells in the body.

According to the study published in the New England Journal of Medicine, within 6 months of infusion, the 16-year-old had a significant reduction in her disease severity. The treatment effectively destroyed her autoreactive B cells causing remission of her symptoms. Not only did CAR-T cell therapy help treat her joint pain but also her breathing.

The researchers are currently looking to conduct clinical trials for the treatment.


Brown, G.J., Cañete, P.F., Wang, H. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349–356 (2022).


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