Author: patienttalk

Posted on Lupus

New and tailored lupus treatments are within reach after scientists discover the cause of the disease

Lupus research


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. 

Posted on Lupus

Scientists find a genetic cause of lupus

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.

Posted on Pain Management

Neuronal plasticity in chronic pain-induced anxiety revealed

Neuronal circuit involved in chronic pain-induced maladaptive anxiet


Neuronal circuit involved in chronic pain-induced maladaptive anxiety. Increased excitability (white arrow) of BNSTCART neurons causes a sustained suppression (black arrow) of LH-projecting BNST neurons during chronic pain, thereby enhancing anxiety-like behavior (Naoki Yamauchi, et al. Science Advances. April 27, 2022). CREDIT Naoki Yamauchi, et al. Science Advances. April 27, 2022

Hokkaido University researchers have shown how chronic pain leads to maladaptive anxiety in mice, with implications for treatment of chronic pain-related psychiatric disorders in humans.

Chronic pain is persistent and inescapable, and can lead to maladaptive emotional states. It is often comorbid with psychiatric disorders, such as depression and anxiety disorders. It is thought that chronic pain causes changes in neural circuits, and gives rise to depression and anxiety.

Researchers at Hokkaido University have identified the neuronal circuit involved in chronic pain-induced anxiety in mice. Their research, which was recently published in Science Advances, could lead to the development of new treatments for chronic pain and psychiatric disorders such as anxiety disorders and major depressive disorder. 

“Clinicians have known for a long time that chronic pain often leads to anxiety and depression, however the brain mechanism for this was unclear,” said Professor Masabumi Minami of the Faculty of Pharmaceutical Sciences at Hokkaido University, the corresponding author of the paper.

The researchers looked at how neuronal circuits were affected by chronic pain in mice. They used an electrophysiological technique to measure the activities of neurons after four weeks of chronic pain. They found that chronic pain caused the neuroplastic change which suppressed the neuronal pathway projecting from the brain region called bed nucleus of the stria terminalis (BNST) to the region called lateral hypothalamus (LH).

Using chemogenetics, an advanced technique to manipulate neuronal activity, they showed that restoration of the suppressed activity of this neuronal pathway attenuated the chronic pain-induced anxiety. These findings indicate that chronic pain-induced functional changes in the neuronal circuits within the BNST leads to maladaptive anxiety.

“These findings could not only lead to improved treatment of chronic pain, but also to new therapeutics for anxiety disorders,” says Minami.

Posted on Arthritis

How one inflammatory disorder exacerbates another

With interactions in the bone marrow, inflammatory disorders exacerbate one another


Inflammation in the gums can increase susceptibility to other forms of inflammation, such as arthritis, through changes to immune cell precursors in the bone marrow, according to new research led by Penn scientists and collaborators. CREDIT Katie Vicari

The immune system remembers. Often this memory, primed by past encounters with threats like bacteria or viruses, is an asset. But when that memory is sparked by internal drivers, like chronic inflammation, it can prove detrimental, perpetuating a misguided immune response.

In a new paper in Cell, researchers from the School of Dental Medicine, together with an international team including colleagues at the Technical University of Dresden, lay out the mechanism by which innate immune memory can cause one type of inflammatory condition—in this example, gum disease—to increase susceptibility to another—here, arthritis—through alterations to immune cell precursors in the bone marrow. In a mouse model, the team demonstrated that recipients of a bone marrow transplant were predisposed to more severe arthritis if their donor had inflammatory gum disease.

“Although we use periodontitis and arthritis as our model, our findings go above and beyond these examples,” says George Hajishengallis, a professor in Penn Dental Medicine and a corresponding author on the work. “This is in fact a central mechanism, a unifying principle underlying the association between a variety of comorbidities.”

The researchers note that this mechanism may also prompt a reconsideration of how bone marrow donors are selected, as donors with certain types of immune memory caused by underlying inflammatory conditions might put bone marrow transplant recipients at a higher risk of inflammatory disorders.

Basis in the bone marrow

In previous work, Hajishengallis had partnered with co-corresponding author Triantafyllos Chavakis of Technical University of Dresden and collaborators to explore the role of innate immune memory. Their findings showed that, just like the adaptive immune system’s T cells and B cells, the innate immune system’s myeloid cells, such as neutrophils and macrophages, could “remember” past encounters, becoming more responsive when exposed to a new threat. The work also pinpointed how this memory was encoded, tracing it to the bone marrow, and showed that this “trained immunity” could be transferred from one organism to another through a bone marrow transplant, protecting recipients from cancer through an innate immune response. 

While that is good news, Hajishengallis and Chavakis also believed that trained immunity could be detrimental in the right contexts. While attending a meeting on innate immunity in Greece in 2019, the two scientists brainstormed over dinner at an outdoor tavern, jotting down their thoughts on a napkin. They later formalized some of their hypotheses about this potential “dark side” of trained immune in a publication in Nature Reviews Immunology in 2021.

“The thoughts went like this: We knew the gum disease periodontitis increased the risk of comorbidities like cardiovascular disease,” says Hajishengallis. “And the reverse is also true: People with the inflammatory disease colitis, for example, have an increased prevalence of periodontal disease. Different mechanisms have been proposed, but no one unifying mechanism could explain this bidirectionality.” 

“We started thinking about a possible unifying mechanism that could underlie the association between several distinct comorbidities,” says Chavakis. 

Building on their earlier discovery related to “trained” precursors in the bone marrow, the scientists set out to see whether they could trace the source of the association between comorbidities to the innate immune training they already knew was happening in the bone marrow.

Setting out to test this hypothesis, the team first showed that, within a week of inducing a mouse to have periodontal disease, the animal’s myeloid cells and their progenitor cells expanded in the bone marrow. Examining these cells weeks later, after periodontitis was intentionally resolved, the researchers did not notice significant changes in how the cells looked or behaved. 

However, these progenitor cells appeared to have memorized the inflammation they were exposed to, as they harbored important epigenetic changes: alterations in molecular markers that affect the ways genes are turned on and off but do not alter the actual DNA sequence. The researchers found that these alterations, triggered by inflammation, could alter the manner in which the genes would be expressed after a future challenge. The overall pattern of epigenetic changes, the researchers noted, was associated with known signatures of the inflammatory response.

Mice with induced periodontal disease also had more severe responses to a later immune system challenge, evidence of trained immunity.

To put the whole picture together regarding the link between inflammatory conditions, the “critical experiment,” as Hajishengallis explains, was a bone marrow transplant. Mice that had periodontitis, a severe form of gum disease, served as donors, as did a group of healthy mice serving as controls. Two hundred stem cells from their bone marrow were transplanted into mice that had never had gum disease and which had had their own bone marrow irradiated. A few months later, these mice were exposed to collagen antibodies, which trigger arthritis. 

“Mice that received the transplant from mice with periodontitis developed more severe arthritis than mice that received a donation of stem cells from periodontally healthy mice,” says Hajishengallis. 

“And higher joint inflammation in recipient mice was due to inflammatory cells deriving from the periodontitis-trained stem cells,” says Chavakis. 

Further experiments suggested that the signaling pathway governed by a receptor for the molecule IL-1 played a vital role in contributing to this inflammatory memory. Mice that lacked IL-1 receptor signaling could not generate the immune memory that made the recipient mice more susceptible to comorbidities, the researchers found. 

The work has implications for bone marrow transplants in humans, a common course of therapy in addressing blood cancers. 

“Of course, it’s a great thing if you find a matching donor for bone marrow transplantation,” says Hajishengallis. “But our findings suggest that it’s important for clinicians to keep in mind how the medical history of the donor is going to affect the health of the recipient.” 

The work also underscores that blocking IL-1 receptor signaling could be an effective approach to mitigate against these knock-on effects of trained immunity.

“We’ve seen anti-IL-1 antibodies used in clinical trials for atherosclerosis with excellent results,” Hajishengallis says. “It could be that it was in part because it was blocking this maladaptive trained immunity.”

Follow-up projects are examining how other inflammatory conditions, may be linked with periodontal disease, a sign, the researchers say, of how crucial oral health is to overall health.

“I’m proud for the field of dentistry that this work, with significance to a wide range of medical conditions, began by investigating oral health,” Hajishengallis says.

Posted on Multiple Sclerosis

Findings open the way for personalised MS treatment

Researchers aim to improve diabetes management in rural and urban communities with low-cost intervention


Currently available therapies to treat multiple sclerosis (MS) lack precision and can lead to serious side effects. Researchers at Karolinska Institutet in Sweden have now developed a method for identifying the immune cells involved in autoimmune diseases, and have identified four new target molecules of potential significance for future personalised treatment of MS. The results, which are published in Science Advances, have been obtained in collaboration with KTH Royal Institute of Technology and Region Stockholm.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that usually develops between the ages of 20 and 40. The disease is driven by immune cells that mistakenly attack the tissue surrounding neurons in the brain and spinal cord. MS causes neurological symptoms such as sensory disorders, difficulties with walking and balance and impaired vision. There is currently no cure, only treatments that reduce relapse rates and alleviate symptoms.

“Existing MS treatments are quite indiscriminate in their effect on the immune system, which risks eventually causing complications, such as infections,” says Mattias Bronge, PhD student in Hans Grönlund’s research group at the Department of Clinical Neuroscience, Karolinska Institutet. “Guiding future treatments more accurately towards the immune cells driving the disease can therefore lead to greater efficacy and fewer side effects.”

Working alongside Professor Tomas Olsson’s research group at Karolinska Institutet, Grönlund and his team have developed a method that makes it possible to identify the T cells that react to certain target molecules – so called autoantigens. The present study describes four new autoantigens that can be added to the handful of ones previously identified in MS and will make a significant contribution to future developments in diagnosis and treatment.

“Our method makes it possible to present these autoantigens in a way that enables us to identify and subsequently disable the T cells that react to them,” says Hans Grönlund, Docent of immunology.

Given that people with MS can react to different autoantigens, it is important to identify each patient’s disease-driving immune cells. This way of creating personalised treatment is called precision medicine.

“Once a patient’s individual autoantigen profile is identified, a treatment can be adapted accordingly,” explains Dr Grönlund. “Most autoimmune diseases are driven by T cells and, if we can find a way to target them in diseases like MS, we can pave the way for more precise treatments with fewer side effects for other autoimmune diseases. Thanks to our long-standing collaboration with Professor Roland Martin at the University of Zürich, our method will be included in a phase 2 clinical study that aims to ‘switch off’ the aggressive T cells which drive MS development and progression.”