Tag: lupus

Categories : Immune SystemTags : Leave a comment

T Cells, not B Cells, Are the Culprit of Kidney Damage in Lupus

On By ModernMedia
Chronic kidney disease (CKD). Credit: Scientific Animations CC4.0

Kidney damage is a serious complication affecting individuals with lupus, an autoimmune disease where immune B cells malfunction and produce antibodies that attack the body’s own cells, tissues, and organs.

B cells, when they make autoantibodies, have been blamed for the illness, prompting the development of several FDA-approved medications that target them. However, lupus nephritis is inevitable in more than half of patients with lupus and B cell depletion is often ineffective therapeutically.

Now, in a study published April 20 in Immunity, Yale scientists have found that the kidney damage culprit is actually a specific T cell – the CD8 T cell.

“People have been, to some extent, ignoring CD8 T cells because of their focus on B cells and the production of autoantibodies,” says lead author Jafar Al Souz, an MD-PhD student in the lab of Joseph Craft, MD, Paul B. Beeson Professor of Medicine (Rheumatology) and professor of immunobiology at Yale School of Medicine. “But we need to think more deeply about why current therapies fail in some patients.”

T cells drive kidney damage in lupus

Previous work in the Craft Lab has shown that blocking T cells’ activity in mouse models of lupus could spare the animals from kidney injuries. That result prompted Al Souz to look closer at this subset of the immune cells.

“What I saw was that these T cells in the sick kidney had a killer phenotype; they were very activated with the potential to cause kidney damage,” he says. Nearly all of these cells were CD8 T cells – also known as cytotoxic T lymphocytes – which are generally tasked with identifying and killing pathogens. That they are aggravated in the kidneys of mouse models of lupus shows that the cells see the kidney as a foreign invader that needs to be destroyed, Al Souz says.

He also found that when the CD8 T cells were depleted, the kidney function was maintained.

Using single-cell multiomics, a high-resolution technique to simultaneously measure the various molecular characteristics of a cell, analysing simultaneous RNA production, gene regulation, and T cell identity, the researchers pinned down the origin of the CD8 T cells to the renal lymph nodes.

“What gave us the biggest clue was that the CD8 T cells in the kidney had very strong overlap with the cells in renal lymph nodes,” Al Souz says. T cells normally undergo rapid proliferation, where one T cell multiplies and generates identical offspring that target the same antigen proteins. “We know that once a T cell is activated in renal lymph nodes, it will leave, go to the circulation and then enter kidneys. So, the fact that we saw identical T cells in renal lymph nodes, circulation, kidneys tells us that the lymph nodes were actually the site of origin.”

What is unique about these CD8 T cells is their capacity to self-renew like stem cells, a discovery that sheds light on a long-held mystery of why it’s hard to stop treatment in patients with lupus. “Constant therapy is needed because these CD8 T cells in the lymph nodes continually supply the kidney with T cells that can damage the organ,” says Craft, who is also the director of the Colton Center for Autoimmunity at Yale.

Targeting T cells for treatment

To draw parallels in humans, the researchers used single-cell RNA sequencing to analyse biopsies from 156 patients with lupus nephritis and 30 healthy individuals. Just as they found in mice, the researchers identified kidney-infiltrating CD8 T cells with the stem-like property in the patients. Unlike in healthy individuals, there was a significantly higher proportion of CD8 T cells that were always active and ready to cause damage in the patients’ kidneys.

“Generally, CD8 T cells are good at pumping the brakes and limiting damage potential upon chronic activation. But we found that in lupus, even when molecules that should stop these T cells from damaging healthy cells are present, it didn’t make the T cells lose function and the capacity for kidney injury,” Al Souz says.

The tendency for T cells to attack a person’s own cells is a typical autoimmune response. For example, in type 1 diabetes – an organ-specific autoimmune disease – T cells mistakenly recognise pancreatic beta cells as foreign and destroy them, thereby stopping insulin production. In cancer and chronic diseases, the ability for T cells to replenish could be beneficial, leading to the elimination of pathogens and tumours. However, the role of T cells in systemic autoimmune diseases like lupus has not been fully described.

“Our results show that there’s more to it than what we understand,” Al Souz says.

By identifying the real culprit, the researchers hope that future treatment of lupus nephritis will be more targeted. “The first step is knowing that it’s abnormal in the first place,” Craft says. “Now, we can think about strategies to lower the number of active CD8 T cells back to the normal range.”

By Kristel Tjandra

Source: Yale School of Medicine

Categories : Immune SystemTags :

Researchers Discover that Lupus is Triggered by Epstein-Barr Virus

On By ModernMedia
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

Epstein-Barr virus (EBV) one, of humanity’s most ubiquitous infectious pathogens, is to blame for systemic lupus erythematosus Stanford Medicine investigators and their colleagues have found.

The Epstein-Barr virus (EBV), which resides silently inside 95% of the world’s population, is directly responsible for making a minuscule number of immune cells go rogue and persuade far more of their fellow immune cells to launch a widespread assault on the body’s tissues, the scientists have shown.

The findings were published in Science Translational Medicine.

“This is the single most impactful finding to emerge from my lab in my entire career,” said William Robinson, MD, PhD, a professor of immunology and rheumatology and the study’s senior author. “We think it applies to 100% of lupus cases.”

The study’s lead author is Shady Younis, PhD, professor and instructor in immunology and rheumatology.

About five million worldwide – 90% of them women – have lupus in which the immune system attacks the contents of cell nuclei. This results in damage to organs and tissues throughout the body, with symptoms varying widely among individuals.

Practically the only way to not get EBV is to live in a bubble.”

With appropriate diagnosis and medication, most lupus patients can live reasonably normal lives, but for about 5% of them the disorder can be life-threatening, said Robinson,. Existing treatments slow down disease progression but don’t cure it, he said.

The virus meets the B cell

By the time we’ve reached adulthood, the vast majority of us have been infected by EBV. Transmitted in saliva, EBV infection typically occurs in childhood, from sharing a spoon with or drinking from the same glass as a sibling or a friend, or maybe during our teen years, from exchanging a kiss. EBV can cause mononucleosis, “the kissing disease,” which begins with a fever that subsides but lapses into a profound fatigue that can persist for months.

“Practically the only way to not get EBV is to live in a bubble,” Robinson said. “If you’ve lived a normal life,” the odds are nearly 20 to 1 you’ve got it.

Once you’ve been infected by EBV you can’t get rid of it, Robinson said, even if you remain or become symptom-free. EBV belongs to a large family of viruses, including those responsible for chickenpox and herpes, that can deposit their genetic material into the nuclei of infected cells. There the virus slumbers in a latent form, hiding from the immune system’s surveillance agents. This may last as long as the cell it’s hiding in stays alive. Or, under certain conditions, the virus may reactivate and force the infected cell’s replicative machinery to produce myriad copies of themselves that break out to infect other cells and other people.

Among the cell types in which EBV takes up permanent residence are B cells, immune cells that do a couple of important things after they ingest bits of microbial pathogens. For one, they can produce antibodies: customised proteins that find and bind immune-system-arousing proteins or other molecules (immunologists call them “antigens”) on microbial pathogens that have infected an individual, or are trying to. For another, B cells are “professional antigen-presenting cells”: They can process antigens and display them on their surfaces to encourage other immune cells to raise the intensity of their hunt for the pathogen in question. That’s a substantial force multiplier for kick-starting an immune response.

Our bodies harbour hundreds of billions of B cells, which, through many cell divisions, develop an enormous diversity of antibodies. In the aggregate, these antibodies can bind an estimated 10 billion to 100 billion different antigenic shapes. This is why we’re able to mount a successful immune response to so many different pathogens.

Oddly, about 20% of the B cells in our bodies are autoreactive. They target antigens belonging to our own tissues – not by design, but due to the random way B-cell diversity comes about: through sloppy replication, apparently engineered by evolution to ensure diversification. Fortunately, these B cells are typically in a dopey state of inertia, and they pretty much leave our tissues alone.

But at times, somnolent autoreactive B cells become activated, take aim at our own tissues and instigate one of the disorders collectively called autoimmunity. Some awakened autoreactive B cells crank out antibodies that bind to proteins and DNA inside the nuclei of our cells. Such activated “antinuclear antibodies” — the hallmark of lupus — trigger damage to tissues randomly distributed throughout the body, because virtually all our body’s cells have nuclei.

The vast majority of EBV-infected people (most of us, that is) have no idea they’re still sheltering a virus and never get lupus. But essentially everyone with lupus is EBV-infected, studies have shown. An EBV-lupus connection has been long suspected but never nailed down until now.

The antinuclear B cell gets ornery

Although latent EBV is ubiquitous in the sense that almost everybody carries it, it resides in only a tiny fraction of any given person’s B cells. As a result, until the new study, it was virtually impossible for existing methods to identify infected B cells and distinguish them from uninfected ones. But Robinson and his colleagues developed an extremely high-precision sequencing system that enabled them to do this. They found that fewer than 1 in 10,000 of a typical EBV-infected but otherwise healthy individual’s B cells are hosting a dormant EBV viral genome.

Employing their new EBV-infected-B-cell-identifying technology along with bioinformatics and cell-culture experimentation, the researchers found out how such small numbers of infected cells can cause a powerful immune attack on one’s own tissues. In lupus patients, the fraction of EBV-infected B cells rises to about 1 in 400 — a 25-fold difference.

It’s known that the latent EBV, despite its near-total inactivity, nonetheless occasionally nudges the B cell it’s been snoozing in to produce a single viral protein, EBNA2. The researchers showed that this protein acts as a molecular switch – a “transcription factor” – activating a battery of genes in the B cell’s genome that had previously been at rest. At least two of the human genes switched on by EBNA2 are recipes for proteins that are, themselves, transcription factors that turn on a variety of other pro-inflammatory human genes.

The net effect of all these genetic fireworks is that the B cell becomes highly inflammatory: It dons its “professional antigen-presenting cell” uniform and starts stimulating other immune cells (called helper T cells) that happen to share a predilection for targeting cell-nuclear components. These helper T cells enlist multitudes of other antinuclear B cells as well as antinuclear killer T cells, vicious attack dogs of the immune system.

When that militia bulks up, it doesn’t matter whether any of the newly recruited antinuclear B cells are EBV-infected or not. (The vast majority of them aren’t.) If there are enough of them, the result is a bout of lupus.

What comes next?

Robinson said he suspects that this cascade of EBV-generated self-targeting B-cell activation might extend beyond lupus to other autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and Crohn’s disease, where hints of EBV-initiated EBNA2 activity have been observed.

The million-dollar question: If about 95% of us are walking around with latent EBV in our B cells, why do some of us, but not all of us, get autoimmunity? Robinson speculates that perhaps only certain EBV strains spur the transformation of infected B cells into antigen-presenting “driver” cells that broadly activate huge numbers of antinuclear B cells.

Many companies are working on an EBV vaccine, and clinical trials of such a vaccine are underway. But that vaccine would have to be given soon after birth, Robinson noted, as such vaccines are unable to rid an already-infected person of the virus.

Stanford University’s Office of Technology Licensing has filed a provisional patent application on intellectual property associated with the study’s findings and technologies used to obtain them. Robinson, Younis and a third study co-author, Mahesh Pandit, PhD, a postdoctoral scholar in immunology and rheumatology, are named inventors on the application. They are co-founders and stockholders of a company, EBVio Inc., a company exploring an experimental lupus treatment, ultradeep B-cell depletion. This procedure involves total annihilation of all circulating B cells, which are replaced over the following few months by new, EBV-free B cells born continually in the bone marrow. Robinson is also a director of EBVio Inc. and a co-founder and shareholder of Flatiron Bio, LLC.

Source: Stanford Medicine

Categories : AgeingTags :

How Aging Quiets Lupus and Brings Relief to Some Older Patients

On By ModernMedia
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

Researchers have found that certain antiviral genes become less active over time in lupus, revealing why some patients see their symptoms fade as they age.

It causes the immune system’s first-line viral defences, known as interferons, to attack the body. Nearly every organ is at risk, leading to conditions like kidney and heart disease.

But unlike many other autoimmune or chronic illnesses, lupus can improve as patients reach their 60s and 70s. University of California San Francisco researchers have now found a potential explanation.

“I see my younger lupus patients in their 20s, 30s, and 40s every few months, monitoring them closely for signs of severe disease, but many of my older patients just once a year to touch base,” said Sarah Patterson, MD, assistant professor of medicine in the division of rheumatology at UCSF. “If patients make it through those risky decades, they sometimes see a dramatic improvement.”

Now, Patterson and colleagues have published a study in Science Translational Medicine that reveals how this works.

By analysing blood samples from patients across the age spectrum, the team discovered that aging turns down the activity of certain immune genes in people with lupus, leading to fewer interferons and other inflammatory proteins in the body.

The study found that in healthy adults, inflammation-related genes and proteins rose slowly over the years, a process that has been dubbed “inflammaging.” In patients with lupus, however, the expression of these genes and proteins were abnormally high in mid-life but decreased as the decades went by.

“Inflammaging seemed to be reversed in the lupus patients,” said Chaz Langelier, MD, PhD, associate professor of medicine at UCSF and senior author of the paper. “But it wasn’t fully reversed. The lupus patients still had a greater level of inflammatory signaling compared to healthy adults in older age.”

That reversal reflected what Patterson has seen in her patients — a return to something approaching healthy older age.

Next, the team intends to test whether drugs that block interferons are more or less effective in lupus patients at different ages. They also hope to extend the approach to understand other inflammation-related conditions, such as rheumatoid arthritis, COPD, and atherosclerosis.

Source: University of California San Francisco

Categories : Cardiovascular DiseaseTags :

New Study Supports Caution on Corticosteroids Use in Lupus Heart Condition

On By ModernMedia
Human heart. Credit: Scientific Animations CC4.0

A new study of more than 2900 patients provides evidence that it’s likely best to use as little corticosteroid medicine as possible when treating people who have lupus pericarditis, a common heart complication of the autoimmune disease Systemic Lupus Erythematosus (SLE).

This study, funded by the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI) and led by Johns Hopkins Medicine cardiologists and rheumatologists who led the study say their analysis of data affirms that using steroids to curb heart inflammation and other painful symptoms for lupus patients is also a risk factor for recurring pericarditis,.  

Results of this study were published in JAMA Network Open.

The American Heart Association defines pericarditis as inflammation of the pericardium, the twin-layered sac-like structure surrounds the heart to hold it in place and help protect it. Pericarditis typically presents as chest pain that can be exacerbated by lying flat and improved by leaning forward. This pain can last anywhere from a few days to several months. Treatment options for pericarditis include use of colchicine, an anti-inflammatory medication that prevents the recurrence of pericarditis, and corticosteroids.

Pericarditis occurs in 15% to 30% of patients with SLE, a chronic autoimmune disease that causes the body’s immune system to attack its own tissues. “It is well known that, in the general population, one fifth of patients who experience pericarditis end up experiencing one or more recurrences. Surprisingly, even though pericarditis is the most common cardiac complication of Lupus, we could not find any information on recurrent of pericarditis in this patient population,” says Dr Luigi Adamo, MD, PhD, director of Cardiac Immunology at Johns Hopkins University and co-senior author of this study.

Researchers set out to address this gap in knowledge and examine the risk factors contributing to the recurrence.

For the new analysis, researchers used data gathered among the Hopkins Lupus Cohort, a large ongoing study group that includes information on 2,931 patients diagnosed with SLE between 1988 to 2023 and the investigators focused on data from 590 patients also diagnosed with pericarditis. Pericarditis in the data set was identified using the Safety of Estrogens in Lupus Erythematosus National Assessment – SLE Disease Activity Index (SELENA-SLEDAI), a standard tool in the assessment of SLE clinical activity.   

Study results showed that 20% of patients with Lupus who experienced pericarditis had a recurrence. Recurrent pericarditis was most prevalent among patients within the first year of pericarditis onset, with recurrence decreasing in the following years. Younger patients and those with uncontrolled disease were at greater risk of recurrence. It was noted that oral prednisone therapy, a tool frequently used to treat pericarditis in patients with autoimmune diseases, was associated with a higher chance of pericarditis recurrence in patients with SLE.

“The cardiology literature has shown that use of corticosteroids increases the risk of recurrent pericarditis in the general population. Nevertheless, steroids are very frequently used by rheumatologists to treat lupus pericarditis. Therefore, the findings from this study underscore the importance of minimising oral corticosteroid use in patients with lupus and indicate the need for alternative strategies.” said Andrea Fava, MD, a rheumatologist who specialises in care of patients with lupus and co-senior author of the study.

Source: Johns Hopkins Medicine

Categories : Dermatology Immune SystemTags :

Topical Mupirocin Reduces Cutaneous Lupus Inflammation

On By ModernMedia
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

Researchers have found that topical mupirocin is effective in reducing rashes caused by systemic lupus erythematosus. Instead of directly lowering inflammation, the treatment kills bacteria that promote it. The findings are published in Arthritis & Rheumatology.

Cutaneous lupus erythematosus is a common manifestation of systemic lupus erythematosus, caused by the autoimmune conditions. The condition is characterised by rashes on various parts of the body including the face and scalp, hair loss and scarring of the skin.

The standard treatment for cutaneous lupus erythematosus is using immunosuppressants and biologic drugs to reduce inflammation. While the medications can be helpful, many patients with systemic lupus erythematosus already take several drugs and are looking for alternatives to pills.

J. Michelle Kahlenberg, MD, PhD, a professor of internal medicine in the Division of Rheumatology at University of Michigan Health led a team of researchers investigating topical mupirocin which is one such alternatives.

This trial was based on Kahlenberg’s previous discovery that cutaneous lupus rashes are often colonised with a common skin bacteria, Staphyloccous areus, also known as staph, and contributes to inflammation in the rashes. Mupirocin kills this type of bacteria.

The study randomly selected systemic lupus erythematosus patients currently experiencing cutaneous lupus erythematosus flares to treat their skin lesions with mupirocin or with an inactive control, petrolatum jelly.

Samples from the nose and lesional skin were used to determine baseline and post treatment Staphylococcus abundance and microbial community profiles. Paired samples collected prior to treatment with the topical solution and seven days after treatment showed decreases in lesional staphylococcus aureus in the mupirocin treated samples.

Importantly, the reduction in staph also was accompanied by a reduction in inflammatory signals, including interferon-driven gene expression, in the lesions.

“In addition to decreasing the inflammation by decreasing lesional staphylococcus aureus, the mupirocin treatment also lowered skin monocyte levels, which are important in driving cutaneous lupus,” said Kahlenberg.

Mupirocin is a prescription treatment, and while this early study showed signs of decreasing inflammation, the study wasn’t designed to see if it can decrease the rash of cutaneous lupus erythematosus.

“Additional larger studies are needed to determine whether topical antibiotics will be helpful to make rashes go away,” Kahlenberg said.

“However, this is an exciting first step to show that there may be additional treatments that can improve inflammation beyond our usual immunosuppressant and biologic drugs.”

Source: Michigan Medicine – University of Michigan

Categories : Diseases, Syndromes and ConditionsTags :

Kidney Damage in Lupus Comes from an Unexpected Source

On By ModernMedia
When the NKp46 receptor of the ILCs is blocked (right), the lupus nephritis recedes. Blue: cell nuclei.
Credit: Charité | Frauke Schreiber

A Berlin-led research team has uncovered critical regulators of severe kidney damage in patients with the autoimmune disorder lupus. A small, specialised population of immune cells – called innate lymphoid cells (ILCs) – trigger an avalanche of effects that cause harmful kidney inflammation, also known as lupus nephritis.

The research, published this week in Nature, upends conventional wisdom that autoantibodies are primarily responsible for lupus nephritis.

“While autoantibodies are required for tissue damage, they are by themselves not sufficient. Our work reveals that ILCs are required to amplify the organ damage,” says Dr Masatoshi Kanda, a senior paper author who was a Humboldt Fellow at Max Delbrück Center and is now at the Department of Rheumatology and Clinical Immunology, Sapporo Medical University in Japan.

Lupus, or systemic lupus erythematosus, is most often diagnosed between the ages of 15 and 45. Symptoms can range from mild to severe. But what causes kidney damage in some patients – some to the point of requiring dialysis – has been unclear.

“The role of ILCs in lupus or lupus nephritis was entirely unknown,” says Professor Antigoni Triantafyllopoulou, a senior paper author at the German Rheumatology Research Center (DRFZ), an institute of the Leibniz Association, and at the Department of Rheumatology and Clinical Immunology at Charité – Universitätsmedizin Berlin. “We have now identified most of the circuit controlled by ILCs by looking at the whole kidney at single-cell resolution.”

Unusual immune cells

ILCs are a small group of immune cells that – unlike most other immune cells that circulate throughout the body – live in a specific tissue or organ.

“They are in the tissue all the time, from the time of embryonic development, which makes them very different from other immune cells,” says Professor Andreas Diefenbach, a senior paper author and director of the Institute of Microbiology, Infectious Diseases and Immunology at Charité – Universitätsmedizin Berlin.

Diefenbach’s lab was among those that discovered ILCs in the mid-2000s. Most of his research is focused on ILCs in the gut and how they modify tissue function. In this study, Triantafyllopoulou and Kanda teamed up with his group and Dr Mir-Farzin Mashreghi at the DRFZ to find out whether ILCs were present in the kidney and what role they might play in lupus nephritis.

The whole single-cell picture

To unravel this mystery, the team turned to single-cell RNA sequencing, which identifies genes that are active, or “switched on,” in individual cells and helps researchers understand the cell’s identity and function.

Kanda, a rheumatologist who was studying bioinformatics in Professor Norbert Hübner’s lab at the Max Delbrück Center at the time, developed a specialized protocol for single-cell RNA sequencing of mouse and human kidneys. “Masatoshi’s protocol was very good at pulling out and preserving multiple types of kidney cells, which gave us a much more complete overview of how lupus affects the whole kidney,” explains Triantafyllopoulou. The team sequenced nearly 100 000 individual kidney and immune cells of various types and functions.

The key receptor

Through experiments in mice, the team learned that a subgroup of ILCs with a receptor called NKp46 must be present and activated to cause lupus nephritis. When NKp46 is activated, this subgroup of cells ramped up production of a protein called GM-CSF, which stimulates invading macrophages to multiply. In the kidney, a flood of incoming macrophages caused severe tissue damage and fibrosis.

“These ILCs are really amplifiers in this system,” Diefenbach says. “They are small in population, but they seem to fertilise the whole process.”

When the team blocked NKp46 with antibodies or the receptor was genetically removed, kidney tissue damage was minimal. They also blocked GM-CSF with similar anti-inflammatory effects.

“Critically, autoantibody levels did not change when NKp46 was inhibited, but kidney tissue damage was reduced, which shows autoantibodies are not directly responsible for kidney inflammation,” Triantafyllopoulou explains.

The team also compared the results to sequencing data from tissue taken from human patients with lupus and found ILCs present, though more work is required to fully understand how to target ILCs in human kidneys. Nevertheless, the insights gained through these detailed studies point to new antibody therapies for patients with severe forms of lupus. The hope is to prevent the need for kidney dialysis in these patients.

Source: Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Categories : Diseases, Syndromes and Conditions Environmental EffectsTags :

Does Air Pollution Affect Lupus Risk?

On By ModernMedia
Photo by Kouji Tsuru on Pexels

New research published in Arthritis & Rheumatology indicates that chronic exposure to air pollutants may increase the risk of developing lupus, an autoimmune disease that affects multiple organs.

For the study, investigators analysed data on 459 815 participants from the UK Biobank. A total of 399 lupus cases were identified during a median follow-up of 11.77 years. Air pollutant exposure was linked with a greater likelihood of developing lupus. Individuals with a high genetic risk and high air pollution exposure had the highest risk of developing lupus compared with those with low genetic risk and low air pollution exposure.

“Our study provides crucial insights into the air pollution contributing to autoimmune diseases. The findings can inform the development of stricter air quality regulations to mitigate exposure to harmful pollutants, thereby reducing the risk of lupus,” said co–corresponding author Yaohua Tian, PhD, of the Huazhong University of Science and Technology, in China.

Source: Wiley

Categories : Immune SystemTags :

Interferons Drive Lupus Symptoms and Affect Treatment

On By ModernMedia
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0

In a new study, researchers from Johns Hopkins Medicine say they have uncovered insights as to why lupus symptoms and severity present differently in individuals with the autoimmune condition. The team says this is a crucial step forward in understanding biological mechanisms behind lupus, and may also lead to shifts in how clinicians treat patients with the condition.

The full report, published in Cell Reports Medicine, concludes that specific combinations and elevated levels of immune system proteins, known as interferons, are associated with certain lupus symptoms such as skin rashes, kidney inflammation and joint pain. Interferons normally help to fight infection or disease, but are overactive in lupus, causing widespread inflammation and damage. The study also shows that other common lupus-related symptoms cannot be explained by increased interferon levels.

“For years, we have accumulated knowledge that interferons play a role in lupus,” says corresponding author and rheumatologist Felipe Andrade, MD, PhD, associate professor of medicine at the Johns Hopkins University School of Medicine. He says this research began with questions about why certain lupus treatments were ineffective for some patients. “We have seen instances where the patient surprisingly didn’t improve – we wondered if certain interferon groups were involved.”

Some lupus treatments are designed to suppress a specific group of interferons, known as interferon I. In clinical trials for these treatments, the team observed some patients failing to improve, despite genetic tests showing high interferon I levels before treatment, or what experts call a high interferon signature. The team believed that two other interferon groups, interferon II and interferon III, may be to blame for these poor treatment responses.

To investigate, the team looked at how different combinations of interferon I, II or III, and their overactivity, may present in people with lupus. Researchers took 341 samples from 191 participants to determine the activity of the three interferon groups, and used human cell lines engineered to react to the presence of each specific interferon group to analyse the samples. Through this process, researchers determined that the majority of participants fell into four categories: those only with increased interferon I; those with a combination of increased interferons I, II and III; those with a combination of increased interferons II and III; or those with normal interferon levels.

Researchers were able to use these findings to also make several associations between these interferon combinations and lupus symptoms. In those with elevated interferon I, lupus was mainly associated with symptoms affecting the skin, such as rashes or sores. Participants with elevated levels of interferon I, II and III exhibited the most severe presentations of lupus, often with significant damage to organ systems, such as the kidneys.

Not every symptom found in lupus was associated with elevated interferons, though. The formation of blood clots and low platelet counts, which also affect clotting, did not have an association with increased levels of interferon groups I, II or III. Researchers say this indicates that both interferon-dependent and other biological mechanisms are involved in this complex disease. The study also found that genetic testing of genes associated with these interferon groups, or the interferon signature, did not always indicate elevated interferon levels. They plan to investigate this in future studies.

“What we’ve seen in our study is that these interferon groups are not isolated; they work as a team in lupus and can give patients different presentations of the disease,” says rheumatologist Eduardo Gómez-Bañuelos, MD, PhD, assistant professor of medicine at Johns Hopkins and the study’s first and additional corresponding author. Evaluating a patient’s elevated interferon combinations allows for a better understanding of how they may react to treatments, and would allow clinicians to group them into clinical subtypes of lupus, Gómez-Bañuelos explains.

Source: Johns Hopkins Medicine

Categories : Cardiovascular Disease Obstetrics & GynaecologyTags :

Monitoring for Foetal Heart Condition in Pregnant Women with Autoimmune Antibodies

On By ModernMedia
Photo by Mart Production on Pexels

Some individuals with anti-Ro/SSA antibodies (anti–Sjögren’s-syndrome–related antigen A autoantibodies, also called anti-Ro antibodies) have autoimmune diseases such as lupus or Sjögren’s syndrome, but many have no symptoms. A clinical trial published in Arthritis & Rheumatology found that high levels of these antibodies in pregnant women are associated with foetal atrioventricular block (AVB), which occurs when inflammation and subsequent scarring prevent electric signals from the heart’s atria from reaching the ventricles. The disease is associated with life-long pacing and can be fatal.

In the trial, called Surveillance To Prevent AV Block Likely to Occur Quickly (STOP BLOQ), the incidence of AVB increased with higher levels of anti-Ro/SSA antibodies, reaching 7.7% for those in the top quartile, which increased to 27.3% in those with a previous child who had AVB, although participant numbers in that category were small.  Antibody titres did not change over time. The trial also revealed that home-based foetal heart rate monitoring reliably detected conduction abnormalities, which may reduce the need for serial echocardiograms.

“Examining the levels of anti-Ro/SSA antibodies is an important advance since for women with low titres, monitoring is probably not necessary and for those with high titres the increased risk supports surveillance,” said corresponding author Jill Buyon, MD, of NYU Langone Health. She added that this study also indicated that titres of antibodies do not change and that additional factors besides antibodies contribute to risk.

“That home monitoring can rapidly and accurately identify early foetal conduction disease is a major step forward that may significantly decrease the need for echocardiograms and hopefully facilitate reversibility,” added senior author and research professor Bettina Cuneo MD, of the University of Arizona-Tucson College of Medicine.

Source: Wiley

Categories : Diseases, Syndromes and ConditionsTags :

Obinutuzumab Reduces Lupus Kidney Flareups and Preserves Function

On By ModernMedia
Photo by Robina Weermeijer on Unsplash

In a post hoc analysis of the phase 2 NOBILITY trial, researchers found that treatment with obinutuzumab was superior to placebo for preserving kidney function and preventing flares in patients with lupus nephritis, a kidney condition associated with the autoimmune disease lupus.

Obinutuzumab is a recombinant, humanised type II anti-CD20 IgG1 monoclonal antibody glycoengineered to enhance antibody-dependent cell-mediated cytotoxicity and phagocytosis.

In the analysis, which is published in Arthritis & Rheumatology, compared with standard-of-care treatment alone, the addition of obinutuzumab to lupus nephritis treatment reduced the risk of developing a composite outcome of death, fall in kidney function, or treatment failure by 60%. Adding obinutuzumab also reduced the risk of lupus nephritis relapses by 57% and significantly decreased the rate of decline in kidney function over the trial’s two years duration.    

Overall, 38% of obinutuzumab-treated patients compared with 16% of placebo-treated patients achieved a complete remission of lupus nephritis by week 76, with the need for fewer glucocorticoids.   

“These data are really important because the ultimate goal of lupus nephritis therapy is to preserve kidney survival so patients never have to face the need for dialysis or transplantation because their kidneys failed,” said corresponding author Brad Rovin, MD, of Ohio State University Wexner Medical Center. “The addition of obinutuzumab to standard lupus nephritis therapy may increase the likelihood of achieving this goal.”

Source: Wiley