Tag: autoimmune disease

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Gene Mutation in Young Girl May Finally Yield Lupus Treatment

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Facial rash characteristic of lupus. Credit: Statpearls

A study published in Nature has identified mutations in an X chromosome gene that senses viral RNA, as a cause of the autoimmune disease lupus, a finding which may explain why the disease is far more common in females, and which might lead to new treatments.

In the study, whole genome sequencing was performed on the DNA of a Spanish child named Gabriela, who was diagnosed with severe lupus at age 7. Such a severe case with early onset of symptoms is rare and suggests a single genetic cause.

In their genetic analysis, the researchers discovered a single point mutation in the TLR7 gene. Referrals from other institutions, they were able to identify other cases of severe lupus where this gene was also mutated.

To confirm that the mutation causes lupus, the team inserted the gene into mice, which went on to develop the disease and showed similar symptoms. 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 said: “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 identified by the researchers makes TLR7 protein bind more readily guanosine and become more active. This in turn increases the sensitivity of the immune cell, making it more likely to incorrectly target healthy tissue.

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

The findings could also explain why lupus is 10 times more common in females than in males. Because TLR7 is located 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.

Study co-author Dr Carmen de Lucas Collantes, said: “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, now a teenager, remains in touch with the research team. She said, “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 investigating the repurposing of existing treatments which target the TLR7 gene. By targeting this gene, they hope to be able to also help patients with related conditions.

Carola added: “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.”

Source: Francis Crick Institute

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Vitamin D Supplements Reduce Autoimmune Disease Risk

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A five year-long randomised, placebo-controlled study found that in older adults taking vitamin D supplements, alone or with omega-3 fatty acids, the risk of developing autoimmune disease was reduced.

Autoimmune diseases (AD) such as rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease and psoriasis, are a leading cause of morbidity and mortality as people age. Few effective treatments are available for AD, but some research has hinted that supplements, including vitamin D and omega-3 fatty acids, could have beneficial effects.

In a new study published in the BMJ, investigators from Brigham and Women’s Hospital evaluated whether taking vitamin D and/or omega fatty acid supplements could affect rates of AD. The large-scale vitamin D and Omega-3 Trial (VITAL), a randomised study which followed participants for approximately five years. Taking vitamin D, or vitamin D and omega-3 fatty acids had a significantly lower rate of AD than placebo.

“It is exciting to have these new and positive results for non-toxic vitamins and supplements preventing potentially highly morbid diseases,” said senior author Karen Costenbader, MD, MPH. “This is the first direct evidence we have that daily supplementation may reduce AD incidence, and what looks like a more pronounced effect after two years of supplementation for vitamin D.”

“Now, when my patients, colleagues, or friends ask me which vitamins or supplements I’d recommend they take to reduce risk of autoimmune disease, I have new evidence-based recommendations for women aged 55 years and older and men 50 years and older,” said Dr Costenbader. “I suggest vitamin D 2000 IU a day and marine omega-3 fatty acids (fish oil), 1000 mg a day – the doses used in VITAL.”

VITAL included 25 871 participants, with men aged 50 and older and women aged 55 and older, conducted to investigate whether taking vitamin D3 and/or omega-3 supplements could reduce the risk for developing cancer, heart disease and stroke in people who do not have a prior history of these illnesses. Prior to the launch of VITAL, investigators determined that they would also look at rates of AD among participants, as part of an ancillary study.

Participants answered questionnaires about new diagnoses of diseases, including rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis and inflammatory bowel disease, with space to write in all other new onset ADs. Medical records were reviewed to confirm reported diagnoses.

“Autoimmune diseases are common in older adults and negatively affect health and life expectancy. Until now, we have had no proven way of preventing them, and now, for the first time, we do,” said first author Jill Hahn, ScD, post-doctoral fellow at the Brigham.

Among patients randomised to vitamin D, 123 participants in the treatment group and 155 in the placebo group were diagnosed with confirmed AD (22 percent reduction). Among those in the fatty acid arm, confirmed AD occurred in 130 participants in the treatment group and 148 in the placebo group. Omega-3 fatty acids alone did not significantly lower incidence of AD, but there was some evidence of a decrease over long periods.

Source: EurekAlert!

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New AIRD Therapies Could Cut Side-effects

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Source: Pixabay

New therapies for autoimmune rheumatic diseases (AIRDs) that are designed to better regulate lipid metabolism could significantly reduce the harmful side-effects caused by conventional treatments, researchers found in a new large-scale review.

AIRDs include rheumatoid arthritis, lupus and Sjögren’s syndrome – conditions which affect millions and all with high rates of morbidity. The pathogenesis of autoimmune conditions is still ill-defined and delivering targeted therapeutic strategies is challenging.

As a result, current treatments for AIRDs are primarily designed to suppress the symptoms (inflammation), but are ‘low target’, ie may also have unintended side-effects. In this regard, AIRDs drugs often cause changes to cell metabolism (such as lipid metabolism) and function, putting patients at greater risk of co-morbidities such as cardiovascular disease (CVD).

Lead author Dr George Robinson (Centre for Rheumatology Research, UCL Division of Medicine) said: “While the mechanisms that cause rheumatic diseases are ill-defined, some recent research indicates cell metabolism may play an important role in triggering or worsening their onset or affect.

“In this review we therefore sought to understand the effect of both conventional and emerging therapies on lipid metabolism in patients with AIRDs.”

For the study, published in the Journal of Clinical Investigation, researchers reviewed more than 200 studies to assess and interpret what is known regarding the on-target/off-target adverse effects and mechanisms of action of current AIRD therapies on lipid metabolism, immune cell function and CVD risk.

Explaining the findings, Dr Robinson said: “Our review found that current AIRD therapies can both improve or worsen lipid metabolism, and either of these changes could cause inflammation and increased CVD risk.

“Many conventional drugs also require cell metabolism for their conversion into therapeutically beneficial products; however drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be different between patients.”

The review noted that optimal combinations of immunosuppressive treatments to better control inflammation could lead to an improved metabolic/lipid profile in AIRDs.

However, many studies also showed that lipid lowering drugs such as statins do not sufficiently lower CVD risk in some AIRDs, possibly because they cannot completely restore the anti-inflammatory properties

Dr Robinson added: “The unfavourable off-target adverse effects of current therapies used to treat AIRDs provides an opportunity for optimal combination co-therapies targeting lipid metabolism that could reduce immune complications and potential increased CVD risk in patients.

“New therapeutic technologies and research have also highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional anti-inflammatory therapies.”

Source: University College London

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New Type of Skin Cell Reveals Secrets of Inflammation

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The surprise discovery of a new type of cell explains how distress to the skin early in life may prime a person for inflammatory skin disease later, according to a new study in Nature. This finding will likely lead to treatments for autoimmune disorders like scleroderma, and inform understanding of inflammatory disease.

“The results reinforce the idea that what you’re exposed to initially may have lasting ramifications,” said lead researcher Michael Rosenblum, MD, PhD. “It appears that early exposure to inflammation can, through these cells we discovered, imprint an ability for tissues to develop inflammatory disease later in life.”

The team came across this new type of cell while investigating the effects of certain actions known to evoke immune response in mice. One of these actions involved knocking out a group of skin cells that suppress the immune system. Without that regulation, said Dr Rosenblum, a unique cell was observed that seemed to act as a shelter for pathogenic immune cells not typically seen in skin tissues.

“We had to knock out one cell population to see that they were controlling the growth and capacity of these other, unknown cells,” he said, noting that the new cells only became apparent in the tissue exposed to inflammatory triggers. “What normally would be a deserted island on the skin was now inhabited by all these strangers,” he said.

The team dubbed these strangers ‘TIFFs’ (Th2-interacting fascial fibroblasts) after the Th2 immune cells that they help to house. The location of TIFFs in the skin suggests that they belong to a group of cells that make up the fibrous connective tissue that is fascia, said lead author Ian Boothby, a graduate student in Dr Rosenblum’s lab.

“Because most organs have fascia of some sort, what we’re learning about TIFFs in skin may well be widely applicable to the rest of the body, meaning that these cells may play a role in a huge number of inflammatory diseases,” he said.

Boothby and Dr Rosenblum when skin without regulatory cells receives inflammatory triggers, the TIFFs spread like wildfire and become a sort of holding pen for the Th2 immune cells. Later in life, when there is even a small insult to the skin, Dr Rosenblum said, the TIFFs open their floodgates, unleashing the Th2 cells.

It seems that, through these cells, early exposure to inflammalation can leave a life-long imprint.

“All you need to do is push the immune system just a little bit, with a wound or with stress, to unleash all the pathogenic cells living in these TIFFs and create an exaggerated inflammatory response,” he said.

The researchers hypothesise that the exaggerated response may manifest as the creation of fibroses in the fascia, the driving force behind inflammatory skin diseases such as scleroderma.

To confirm the presence of TIFFs in human skin, the team obtained samples from volunteers with eosinophilic fasciitis (EF), a rare inflammatory disorder in which eosinophils build up in the skin fascia, the fibrous tissue between the skin and the muscles below it.

Comparing the EF samples to those of healthy skin, the researchers found TIFFs in both, but looked completely different. In healthy skin, the fascia forms a thin, spidery network between fat cells, while in the EF skin sample, the cells had expanded to form thick bands of fibrous tissue.

Revealing the mysteries of inflammation
TIFFs appear to be present in every organ, said Dr Rosenblum, usually found in the fascia surrounding major organs and serve a role in maintaining structure. They’re also prone to interacting with immune cells. He postulates that TIFFs might have evolved as a sort of emergency brigade in case of injury, able to jump-start repair in the case of internal injury.

“In patients with scleroderma or other fibrosing diseases like EF, that repair program may be kind of co-opted, resulting in this chronic wound-healing response,” said Dr Rosenblum. “If we can understand the biology of these cells, we can come in with drugs that revert them back to what they’re supposed to be doing.”

Source: University of California San Francisco

Categories : Immune SystemTags :

Autoimmune Problems May Cause Fibromyalgia

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Photo by Sasun Bughdaryan on Unsplash

New research has shown that many fibromyalgia syndrome (FMS) symptoms are caused by antibodies that increase the activity of pain-sensing nerves throughout the body.

The results show that fibromyalgia is a disease of the immune system, rather than the currently held view that it originates in the brain.

Characterised by widespread muskoleskeletal pain, as well as fatigue and emotional distress, fibromyalgia is estimated to affect1 in 40 people (80% of which are women). It most commonly develops between the ages of 25 and 55, although children can also get it.  

The study by Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, in collaboration with the University of Liverpool and the Karolinska Institute,, demonstrates that the increased pain sensitivity, muscle weakness, reduced movement, and reduced number of small nerve-fibres in the skin that are typical of FMS are all a consequence of patient antibodies.

The researchers injected mice with antibodies from people living with FMS and saw that the mice became more sensitive to pressure and cold, as well as displaying reduced movement grip strength. In contrast, those injected with antibodies from healthy people were unaffected, showing that patient antibodies cause at least part of the disease.

Furthermore, the mice injected with fibromyalgia antibodies recovered after a few weeks, when antibodies had been cleared from their system. This finding strongly suggests that therapies which reduce antibody levels in patients are likely to be effective treatments. Such therapies are already available and are used to treat other disorders that are caused by autoantibodies.

Primary investigator Dr David Andersson, from King’s IoPPN said: “The implications of this study are profound. Establishing that fibromyalgia is an autoimmune disorder will transform how we view the condition and should pave the way for more effective treatments for the millions of people affected. Our work has uncovered a whole new area of therapeutic options and should give real hope to fibromyalgia patients.

“Previous exploration of therapies has been hampered by our limited understanding of the illness. This should now change. Treatment for FMS is focussed on gentle aerobic exercises, as well as drug and psychological therapies designed to manage pain, although these have proven ineffective in most patients and have left behind an enormous unmet clinical need.”

Dr. Andreas Goebel, the study’s principle clinical investigator from the University of Liverpool said, “When I initiated this study in the UK, I expected that some fibromyalgia cases may be autoimmune. But David’s team have discovered pain-causing antibodies in each recruited patient. The results offer amazing hope that the invisible, devastating symptoms of fibromyalgia will become treatable.”

Professor Camilla Svensson, the study’s primary investigator from Karolinska Institute said, “Antibodies from people with FMS living in two different countries, the UK and Sweden, gave similar results, which adds enormous strength to our findings. The next step will be to identify what factors the symptom-inducing antibodies bind to. This will help us not only in terms of developing novel treatment strategies for FMS, but also of blood-based tests for diagnosis, which are missing today.

Dr Craig Bullock, Research Discovery and Innovations Lead at Versus Arthritis said: “This research shows that antibodies found in human blood can cause fibromyalgia-like symptoms in mice, suggesting that these antibodies play a crucial role in the condition. Further research is needed but this offers hope to the millions of people with fibromyalgia that an effective treatment could be found in the relatively near future.”  

Source: Medical Xpress

Journal information: More information: Andreas Goebel et al, Passive transfer of fibromyalgia symptoms from patients to mice, Journal of Clinical Investigation (2021). DOI: 10.1172/JCI144201

Categories : Immune SystemTags :

Newly Discovered ‘Goldilocks’ Protein Keeps the Immune System in Check

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A newly discovered ‘Goldilocks’ protein may be responsible for helping keep the immune system from running amok, according to researchers at the Lunenfeld-Tanenbaum Research Institute (LTRI).

This protein, known as WAVE2, is expressed in all immune cells and plays a critical role in keeping the immune system in balance. To test its role, researchers knocked out the WAVE2 protein in a subset of immune cells in mice, leading to severe autoimmunity and inflammation, as well as an inability to mount an immune response to a viral infection.

Senior author Dr Kathy Siminovitch, said the team also found that in the absence of WAVE2, another protein, known as mTOR, became overly active, sending the immune system into overdrive and leading to immune cell exhaustion.

“Much like Goldilocks, a proper immune response requires such a delicate balance,” said Dr  Siminovitch. “You have to get it just right. By developing a mouse strain in which T cells, key players in immunity, lack WAVE2, we have shown that this protein is absolutely required for balanced immune responses.”

The question of how to keep the immune system in balance is of key importance in the pandemic, where many deaths occur due to cytokine storms as the immune system overreacts, especially in the elderly. 
As part of her work exploring the mechanisms balancing the immune system, Dr Siminovitch helped trace the complex molecular steps that turn a rare gene mutation into Wiskott-Aldrich syndrome, a potentially lethal disease which impairs the immune system of boys.

Future research would look at how the contribution of the WAVE2-mTOR pathway to specific autoimmune, inflammatory and other conditions, such as Alzheimer’s disease.

Source: News-Medical.Net

Journal information: Liu, M., et al. (2021) WAVE2 suppresses mTOR activation to maintain T cell homeostasis and prevent autoimmunity. Science. doi.org10.1126/science.aaz4544.

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Ginger Promising in Countering Autoimmune Diseases

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A pre-clinical study has shown that the common herbal remedy and condiment, ginger, may be effective in countering some autoimmune disease mechanisms.

It is already known that ginger has some anti-inflammatory and anti-oxidative properties, making it a popular herbal remedy for inflammatory conditions.Out of at least 14 bioactive compounds, 6-gingerol, which also gives it its distinctive aroma and taste, is reported by a news study to be therapeutic in countering certain autoimmune disease mechanisms in mice.
In mice with antiphospholipid syndrome or lupus, 6-gingerol inhibited the release of neutrophil extracellular traps, which is triggered in response to the autoantibodies produced by these diseases. 

“Neutrophil extracellular traps, or NETs, come from white blood cells called neutrophils,” said lead author Ramadan Ali, PhD. “These sticky spider-web like structures are formed when autoantibodies interact with receptors on the neutrophil’s surface.”

According to Ali, these webs play an important role in the pathogenesis of lupus and antiphospholipid syndrome where they trigger autoantibody formation and contribute to blood vessel clotting and damage.

The premise of the study was: “Will the anti-inflammatory properties of ginger extend to neutrophils, and specifically, can this natural medicine stop neutrophils from making NETs that contribute to disease progression?”
“This pre-clinical study in mice offers a surprising and exciting, ‘yes’,” Ali said.

The researchers discovered that after giving 6-gingerol, the mice had lower levels of NETs. Clot formation tendency was drastically reduced and 6-gingerol seemed to inhibit neutrophil enzymes called phosphodiesterases, in turn lowering neutrophil activation.

All of the mice had reduced autoantibodies, suggesting a disruption of the inflammatory cycle of autoantibodies stimulating NETs which stimulate more autoantibodies.

Study author and rheumatologist Jason Knight, MD, noted that patients often asked about herbal supplements, about which he had not been taught much. However, the pre-clinical trial results show that 6-gingerol has anti-neutrophil properties that may be protective against autoimmune disease progression.

“As for basically all treatments in our field, one size does not fit all. But, I wonder if there is a subgroup of autoimmune patients with hyperactive neutrophils who might benefit from increased intake of 6-gingerol,” said Knight. “It will be important to study neutrophils before and after treatment so we can determine the subgroup most likely to see benefit.”
For a patient with active antiphospholipid syndrome or lupus, the bioactive compound cannot be the primary therapy, but the natural supplement may help those at high risk for disease development.

“Those that have autoantibodies, but don’t have activated disease, may benefit from this treatment if 6-gingerol proves to be a protective agent in humans as it does in mice,” Ali said.

“Patients with active disease take blood thinners, but what if there was also a natural supplement that helped reduce the amount of clots they produce? And what if we could decrease their autoantibodies?”

Source: Medical Xpress

Journal Information: Ramadan A. Ali et al, Anti-neutrophil properties of natural gingerols in models of lupus, JCI Insight (2020). DOI: 10.1172/jci.insight.138385

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Promising Drug May Worsen Instead of Treat Multiple Sclerosis

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A drug, TEPP-46,  that is being assessed to treat multiple sclerosis (MS) may in fact be worsening the progression of the disease, wrote University of Virginia on the Medical Xpress website.

MS is a debilitating disease which affects over one million people in America, in which the immune system attacks the myelin sheath, creating a range of effects in sufferers, from muscle spasms to numbness.

Presently available drugs to treat MS often have unwanted side effects, such as weakening the immune system. Originally developed to fight cancer, TEPP-46 is small-molecule drug that targets the changes in cellular metabolism that occur in both cancer and MS. However, the drug has been shown to produce off-target effects. In the mouse model used by the researchers, the inflammation was directed away from the spinal cord and into the brain. The researchers believed that this was the result of the drug harmfully changing T cells, but could not explain why. 

“It was not at all what we expected,” said MS researcher Alban Gaultier, PhD, of University of Virginia. “The take-home message is that we should be very careful and do more fundamental research before we propose to take this to clinical trials.”