Understanding Lupus: Gene Responsible For Autoimmune Disease Discovered

Lupus is a challenge to diagnose, but once you know you have it there are ways to manage it.

Australian National University (ANU) researchers believe they have discovered the potential cause of the autoimmune disease lupus.

Senior researcher Vicki Athanasopoulos from the ANU John Curtin School of Medical Research (JCSMR) said in an ANU news release that the discovery of a gene called Toll-like receptor seven or TLR7 that, when over-activated, causes the autoimmune disease said the discovery could revolutionise lupus treatments.

“This is the first time scientists have shown a genetic variation of the TLR7 gene to be a driver of autoimmune disease,” Athanasopoulos said.

“This raises the exciting possibility of developing new drugs targeting TLR7, potentially revolutionising treatments for lupus.”

The TLR7 gene is normally programmed to assist the immune system in guarding against viral infections. However, when mutated, the gene becomes aggressive and causes the condition lupus, where the immune system attacks the body’s healthy cells.

The current treatments for lupus often result in the patient being more susceptible to infection and can lower their quality of life. This discovery could lead to the development of more effective drugs that do not have the side effects of those currently available.

The researchers attempted to determine whether introducing the human-derived TLR7 mutation into mice using a gene-editing tool would cause the rodents to develop lupus. (Natali_ Mis/Shutterstock)

The Discovery

The TLR7 mutation was discovered in a young girl from Spain named Gabriela, who was diagnosed with lupus at the age of seven. Following the discovery, the researchers attempted to determine whether introducing the human-derived mutation into mice using a gene-editing tool would cause the rodents to develop lupus.

“Mice carrying the mutant TLR7 protein developed a condition that mimicked severe autoimmune disease in human patients, providing evidence that the TLR7 mutation causes lupus,” researcher Grant Brown from JCSMR said.

“This newly generated mouse model provides us with a framework to continue to understand the immune system and how autoimmune diseases develop in humans.”

Athanasopoulos said in an email to The Epoch Times that the TLR7 gene normally binds to short RNA sequences from things such as infectious viruses.

“Our work found that one of the mutations in the TLR7 gene found in a young patient resulted in the TLR7 protein having enhanced binding to RNA and thereby resulting in increased activation of the TLR7 biochemical pathway,” he said.

“We also used modelling of the structure of the TLR7 protein and found that the mutation alters the region within the TLR7 protein that binds to RNA molecules.”

Problems With Current Lupus Treatments

The senior author of the study Prof. Carola Vinuesa from the ANU Centre for Personalised Immunology and the Francis Crick Institute in the United Kingdom, said that finding effective treatments for lupus has been very challenging. Vinuesa said that the current treatments for lupus are mostly immune suppressors, which alleviate symptoms by dialling down the immune system.

“Some of the current therapies used to treat lupus can either be quite toxic or have adverse side effects or simply be ineffective in some patients with more complex disease,” Athanasopoulos said.

“Virtually all therapies can impact quality of life, and it depends significantly on the intensity of treatment.

“Less intense, first-line treatments such as hydroxychloroquine can improve QOL by reducing the frequency and intensity of lupus flares.”

However, she said that more severe flare-ups of the condition require “intensive immunosuppression,” which often majorly affects the patient’s quality of life. For example, corticosteroids are used to suppress the immune system and have multiple side effects, including but not limited to weight gain, mood disturbance, decreased resistance to infection, and osteoporosis.

“At the most intensive levels of therapy, agents such as cyclophosphamide have risks of bone marrow failure and infertility which can have enormous impacts on an individual’s life.”

She said that even though there may only be a few people with lupus who have mutant TLR7 variants, by confirming gain-of-function TLR7 variants to be a cause of lupus, the search for new treatments can begin.

Autoimmune conditions can range from rashes to debilitating illnesses (Ternavskaia Olga Alibec/Shutterstock)

Developing New Treatments With the TLR7 Variant

Lupus is estimated to affect nine times more women than men. The condition has no cure, and its symptoms can include inflammation in the organs and joints, impacted movement, skin rashes and fatigue. The symptoms can vary from mild to severe, but in extreme cases, the condition can be fatal.

The researchers said that the mouse model could be used to test new and existing drugs on their ability to inhibit the TLR7 gene.

“We hope that our work can help in the development of new drugs to help treat or prevent disease flares,” said Athanasopoulos.

She said that the team’s work established an animal model with the same TLR7 mutation, which causes “lupus-like disease”, as was found in Gabriela.

“We will trial new inhibitors of the TLR7 protein and of other proteins that work in the same biochemical pathway as TLR7 and determine if this can prevent or ameliorate disease in our animal model.”

“This can form the basis for further human clinical trials.”

“Our animal model, along with the human TLR7 variant, paves the way for designing and trialling targeted therapeutics to help patients with a similar type of TLR7-mediated lupus,” she said in the release.

How The Discovery Helps In Understanding Lupus

“Our research aims to elicit a further understanding of these complex diseases, which we know little about,” Brown said.

“Autoimmune diseases such as lupus have many causative factors from our genetics to environmental influences, making them difficult to study.

“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.”

At the moment, the researchers are working alongside pharmaceutical companies to develop drugs that specifically target the TLR7 gene and other proteins acting in the TLR7 proteins biochemical pathway. To accomplish this, they are both creating new medicines and tweaking existing ones.

“There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus,” Vinuesa said. “TLR7 may also play a role in these conditions.”

The findings of this study may also explain why lupus is more common in women than men because the TLR7 gene is present in the X chromosome. Females have two X chromosomes and, therefore, two copies of the TLR7 gene, while men only have one.

“This means females with an overactive TLR7 gene can have two functioning copies, potentially doubling the harm,” Vinuesa said.