Tianfu Wu, University of Houston associate professor of biomedical engineering, reports potential lupus nephritis biomarkers which may be useful for developing more accurate clinical blood tests for the disease, replacing the existing invasive test, the painful renal biopsy. CREDIT University of Houston

The nature of a typical clinical test for lupus nephritis (LN), an inflammation of the kidneys and a leading cause of mortality in lupus patients, is fraught with difficulty. The invasive renal biopsy can be painful and may cause kidney damage. Unfortunately, 60% of patients with the often-disabling autoimmune disorder systemic lupus erythematosus (SLE) will face this burden as they advance into potentially fatal lupus nephritis.    

“Given the heterogenetic nature and unmet needs in precision diagnosis and classification of SLE/LN patients for personalized medication, identification of novel biomarkers, particularly in the form of a biomarker panel, is of paramount importance,” reports Tianfu Wu, University of Houston associate professor of biomedical engineering, in the journal Frontiers in Immunology.  

So, Wu and his team met that need using the large-scale study of proteins involved in the immune system, known as immunoproteomics, combined with bioinformatics, which combines gene expression data with computer storage and analysis.  

A total of 300 immunoglobulin-binding proteins were discovered in the screening, among which 77 proteins were detectable only in LN samples. Bioinformatics-assisted selection allowed the team to further identify ten potential immunoglobulin-binding proteins, which form circulating immune complexes (ICx) as potential biomarkers in LN. 

“Immunoproteomics-based discovery studies have enabled us to identify promising immune complexes in LN, which are associated with clinical parameters including renal pathology indices,” said Wu. “These ICx may be useful for the development of more accurate and clinical blood tests for this disease and if validated, this test may be able to replace the existing invasive tests at some point.” 

The first author of the article is Chenling Tang, a doctoral student in Wu’s lab. Other collaborators include Min Fang, Gongjun Tan, Shu Zhang, Bowen Yang, Yaxi Li1, Ting Zhang and Chandra Mohan from the University of Houston and Ramesh Saxena, University of Texas Southwestern Medical Center in Dallas. 

Lupus research being conducted at The John Curtin School of Medical Research (JCSMR) at ANU CREDIT Tracey Nearmy/The Australian National University

Researchers from The Australian National University (ANU) have identified a gene called TLR7 that, when over-activated, is responsible for causing lupus, an autoimmune disease that can be life-threatening in severe cases.  

TLR7 is programmed to help the immune system guard against viral infections, but in its mutated form, it can become aggressive and cause the immune system to attack healthy cells.

The discovery, made by an international team of scientists, could pave the way for new and more effective treatments for lupus, but without the side-effects associated with current therapies.

Current treatments often leave patients more susceptible to infection and can also lower the patient’s quality of life. The research is published in Nature.

“This is the first time scientists have shown a genetic variation of the TLR7 gene to be a driver of autoimmune disease,” senior author Dr Vicki Athanasopoulos, from the ANU John Curtin School of Medical Research (JCSMR), said.

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

There is currently no cure for lupus, a disease that is estimated to affect nine times more women than men. Symptoms can vary from mild to severe and can include inflammation in organs and joints, impacted movement, skin rashes and fatigue. In extreme cases, complications can be fatal.  

Senior author Professor Carola Vinuesa, from the ANU Centre for Personalised Immunology and the Francis Crick Institute in the United Kingdom, said: “It has been a huge challenge to find effective treatments for lupus; current treatments are predominantly immune-suppressors, which work by dialling down the immune system to alleviate symptoms. 

“Although there may only be a small number of people with lupus who have mutant variants of TLR7, the fact that we have confirmed gain-of-TLR7 function to be a cause of lupus means we can now start to search for new treatments.” 

The TLR7 mutation was discovered in a young Spanish girl called Gabriela, who was diagnosed with lupus when she was seven years old.  

Using a gene-editing tool, the researchers introduced the human-derived mutation into mice to study whether the disease developed in the rodents.   

“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,” PhD scholar Grant Brown, also 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.” 

Dr Athanasopoulos said: “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.” 

The researchers say the mouse model can be used to test new and existing drug therapies that inhibit the TLR7 gene, in a bid to provide some reprieve to patients suffering from lupus.  

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

The researchers are now working with pharmaceutical companies to develop new drugs or tweak existing ones to explicitly target the TLR7 gene and other proteins acting in the same biochemical pathway to the TLR7 protein.  

“There are other systemic autoimmune diseases, like rheumatoid arthritis and dermatomyositis, which fit within the same broad family as lupus,” Professor Vinuesa said.  

“TLR7 may also play a role in these conditions.” 

The research findings may also help explain why women are about nine times more likely to develop lupus compared to men. TLR7 is present in the X chromosome, and women have two X chromosomes and two copies of the TLR7 gene. Men only have one X chromosome.  

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

An international team of researchers has identified DNA mutations in a gene that senses viral RNA, as a cause of the autoimmune disease lupus, with the finding paving the way for the development of new treatments. 

Lupus is a chronic autoimmune disease which causes inflammation in organs and joints, affects movement and the skin, and causes fatigue. In severe cases, symptoms can be debilitating and complications can be fatal. 

There is no cure for the disease, which affects around 50,000 people in the UK, and current treatments are predominantly immune-suppressors which work by dialling down the immune system to alleviate symptoms.

In their study, published in Nature today (27 April), the scientists carried out whole genome sequencing on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus when she was 7 years old. Such a severe case with early onset of symptoms is rare and indicates a single genetic cause.

In their genetic analysis, carried out at the Centre for Personalised Immunology at the Australian National University, the researchers found a single point mutation in the TLR7 gene. Via referrals from the US and the China Australia Centre of Personalised Immunology (CACPI) at Shanghai Renji Hospital, they identified other cases of severe lupus where this gene was also mutated. 

To confirm that the mutation causes lupus, the team used CRISPR gene-editing to introduce it into mice. These mice went on to develop the disease and showed similar symptoms, providing evidence that the TLR7 mutation was the cause. The mouse model and the mutation were both named ‘kika’ by Gabriela, the young girl central to this discovery. 

Carola Vinuesa, senior author and principal investigator at the Centre for Personalised Immunology in Australia, co-director of CACPI, and now group leader at the Crick says: “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. 

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

Professor Nan Shen, co-director of CACPI adds: “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 mutation the researchers identified causes the TLR7 protein to bind more easily to a nucleic acid component called guanosine and become more active. This increases the sensitivity of the immune cell, making it more likely to incorrectly identify healthy tissue as foreign or damaged and mount an attack against it.

Interestingly, other studies have shown mutations that cause TLR7 to become less active are associated with some cases of severe COVID-19 infection, highlighting the delicate balance of a healthy immune system.*

The work may also help explain why lupus is about 10 times more frequent in females than in males. As TLR7 sits on the X chromosome, females have two copies of the gene while males have one. Usually, in females one of the X chromosomes is inactive, but in this section of the chromosome, silencing of the second copy is often incomplete. This means females with a mutation in this gene can have two functioning copies.

Dr Carmen de Lucas Collantes, a co-author of this study says: “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”.

Gabriela, who remains in touch with the research team and 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.”

The researchers are now working with pharmaceutical companies to explore the development of, or the repurposing of existing treatments, which target the TLR7 gene. And they hope that targeting this gene could also help patients with related conditions.

Carola adds: “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 has started a new laboratory at the Francis Crick Institute to further understand the disease-causing mechanisms that occur downstream of key mutations like the one found on the TLR7 gene.

In the brain, a synapse (orange) is seen being wrapped around and attacked by immune cells called microglia (green), leading to synapse loss. CREDIT Boston Children’s Hospital

Up to 75 percent of patients with systemic lupus erythematosus — an incurable autoimmune disease commonly known as lupus — experience neuropsychiatric symptoms. But so far, our understanding of the mechanisms underlying lupus’ effects on the brain has remained murky. Now, new research from Boston Children’s Hospital has shed light on the mystery and points to a potential new drug for protecting the brain from the neuropsychiatric effects of lupus and other central nervous system (CNS) diseases. The team has published its surprising findings in Nature.

“In general, lupus patients commonly have a broad range of neuropsychiatric symptoms, including anxiety, depression, headaches, seizures, even psychosis,” says Allison Bialas, PhD, first author on the study and a research fellow working in the lab of Michael Carroll, PhD, senior author on the study, who are part of the Boston Children’s Program in Cellular and Molecular Medicine. “But their cause has not been clear — for a long time it wasn’t even appreciated that these were symptoms of the disease.

Collectively, lupus’ neuropsychiatric symptoms are known as central nervous system (CNS) lupus. Carroll’s team wondered if changes in the immune system in lupus patients were directly causing these symptoms from a pathological standpoint.

“How does chronic inflammation affect the brain?”

Lupus, which affects at least 1.5 million Americans, causes the immune systems to attack the body’s tissues and organs. This causes the body’s white blood cells to release type 1 interferon-alpha, a small cytokine protein that acts as a systemic alarm, triggering a cascade of additional immune activity as it binds with receptors in different tissues.

Until now, however, these circulating cytokines were not thought to be able to cross the blood brain barrier, the highly-selective membrane that controls the transfer of materials between circulating blood and the central nervous system (CNS) fluids.

“There had not been any indication that type 1 interferon could get into the brain and set off immune responses there,” says Carroll, who is also professor of pediatrics at Harvard Medical School.

So, working with a mouse model of lupus, it was quite unexpected when Carroll’s team discovered that enough interferon-alpha did indeed appear to permeate the blood brain barrier to cause changes in the brain. Once across the barrier, it launched microglia — the immune defense cells of the CNS — into attack mode on the brain’s neuronal synapses. This caused synapses to be lost in the frontal cortex.

“We’ve found a mechanism that directly links inflammation to mental illness,” says Carroll. “This discovery has huge implications for a range of central nervous system diseases.”

Blocking inflammation’s effects on the brain

The team decided to see if they could reduce synapse loss by administering a drug that blocks interferon-alpha’s receptor, called an anti-IFNAR.

Remarkably, they found that anti-IFNAR did seem to have neuro-protective effects in mice with lupus, preventing synapse loss when compared with mice who were not given the drug. What’s more, they noticed that mice treated with anti-IFNAR had a reduction in behavioral signs associated with mental illnesses such as anxiety and cognitive defects.

Although further study is needed to determine exactly how interferon-alpha is crossing the blood brain barrier, the team’s findings establish a basis for future clinical trials to investigate the effects of anti-IFNAR drugs on CNS lupus and other CNS diseases. One such anti-IFNAR, anifrolumab, is currently being evaluated in a phase 3 human clinical trial for treating other aspects of lupus.

“We’ve seen microglia dysfunction in other diseases like schizophrenia, and so now this allows us to connect lupus to other CNS diseases,” says Bialas. “CNS lupus is not just an undefined cluster of neuropsychiatric symptoms, it’s a real disease of the brain — and it’s something that we can potentially treat.”

The implications go beyond lupus because inflammation underpins so many diseases and conditions, ranging from Alzheimer’s to viral infection to chronic stress.

“Are we all losing synapses, to some varying degree?” Carroll suggests. His team plans to find out.