A newly published study in the scientific journal Science Immunology has investigating how MAIT cells (mucosa-associated invariant T cells) behave in different tissues. The Karolinska Institutet study shows that these immune cells, which play an important role in the body’s defence against microbes, exhibit different properties depending on the tissue they are in.
MAIT cells are a type of T cell that recognise by-products formed when microbes synthesise riboflavin. This makes them unique in the way they detect and fight infections. The researchers examined MAIT cells from blood, barrier tissues and lymphoid tissue samples from organ donors to understand how these cells function in different tissues.
Different MAIT cells in intestines and liver
“We found that MAIT cells in the intestines have a specialised immunoregulatory profile with high expression of the regulatory enzyme CD39, suggesting that they play a role in protecting the intestinal barrier,” says Johan Sandberg, Professor at the Center for Infectious Medicine (CIM), at the Department of Medicine, Huddinge, Karolinska Institutet.
“In the liver, on the other hand, MAIT cells predominantly exhibit high expression of the marker CD56 and an increased ability to fight microbes.”
The study also shows that the number of MAIT cells in the blood decreases with age but is preserved in the tissues. At the same time, tissue-adapted functions in the intestines and liver become increasingly evident with age.
“Our results highlight the functional heterogeneity of MAIT cells and their adaptation to different tissues.”
The results of the study add a new dimension to the understanding of the immune system and how different types of immune cells specialise to protect different tissues against infections.
“This gives us a better understanding of how this arm of the immune system works and can help us develop new treatments for infectious diseases,” says Johan Sandberg.
Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash
Cancer has been described as “a wound that does not heal,” implying that the immune system is unable to wipe out invading tumour cells. A new discovery reported in PNAS confirms that a key molecule can reprogram immune cells into turncoats that promote cancer growth.
Studying the behaviour of these “pro-tumour” immune cells is important because they could be targets for therapies that block their harmful activity, said Minsoo Kim, PhD, corresponding author of the study and a research leader at the Wilmot Cancer Institute.
Kim led a team of scientists investigating the dynamic interactions that occur between cells in the tumor environment, and the underlying factors that cause the harmful transformation of immune cells from good to bad.
They found that PAF (platelet-activating factor) is the key molecule that controls the destiny of the immune cells. PAF not only recruits cancer-promoting cells, but it also suppresses the immune system’s ability to fight back. In addition, they found that multiple cancers rely on the same PAF signals.
“This is what could be most significant,” said Kim. “Because if we find a treatment that could interfere with PAF, it could potentially apply to many types of cancer.”
Much of the team’s work focused on pancreatic cancer cells. It is one of the most deadly cancers, with a five-year survival rate of about 12%, and is notoriously hard to treat because pancreatic tumours are surrounded by a toxic stew of proteins and other tissues that protect the cancer from the immune system’s natural role to attack invaders. They also studied breast, ovarian, colorectal, and lung cancer cells, using advanced 3D imaging technology to watch the behaviour of immune cells as they swarmed to the cancerous region.
By analysing the immune system of female-to-male transgender individuals, Swedish researchers demonstrate the role of sex hormones in regulating the immune system. This newfound knowledge, published in Nature, explains differences between men and women, particularly in terms of immune signalling, and can be used to develop new immunological medications according to researchers.
Sex differences in the immune system are regulated both by genetics and by sex hormones. However, immunological comparisons between men and women can never fully distinguish the significance of genetic versus hormonal variations.
Now, three Swedish research groups led by Karolinska Institutet and Uppsala University has conducted a unique study analysing the regulation and adaptation of the immune system over time in 23 trans men who have undergone gender-affirming testosterone treatment, starting at the age of 18–37 years.
“We have followed individuals who were assigned female sex at birth and later received testosterone treatment in adulthood. Their genetic profile remains unchanged, while their hormone profile shifts entirely from typically female to male hormone levels,” says Petter Brodin, paediatrician and professor of paediatric immunology at the Department of Women’s and Children’s Health, Karolinska Institutet, who led the study together with Nils Landegren, assistant professor at Uppsala University, and Olle Kämpe, Professor at the Department of Medicine, Solna, Karolinska Institutet. “This unique change allows us, for the first time, to identify which parts of a person’s immune system are directly regulated by sex hormones rather than genetic sex differences.”
The researchers can now demonstrate that increased testosterone levels and the accompanying reduction in oestrogen particularly affect the balance between two crucial immune signalling systems: antiviral interferon type 1 (IFN-1) and proinflammatory signals such as tumour necrosis factor alpha (TNFα).
Specifically, they found that testosterone modulates a cross-regulated axis between type-I interferon and tumour necrosis factor. This is mediated by functional attenuation of type-I interferon responses in both plasmacytoid dendritic cells and monocytes. Conversely, testosterone potentiates monocyte responses leading to increased tumour necrosis factor, interleukin-6 and interleukin-15 production and downstream activation of nuclear factor kappa B-regulated genes and potentiation of interferon-γ responses, primarily in natural killer cells.
The immune system changes throughout life
They also have a hypothesis about why the immune system needs to be dynamically regulated by hormones throughout life.
“All individuals must be able to adjust their immune systems over the course of their lives to be optimally regulated for the conditions and challenges we face. During puberty and sexual maturation, new demands arise, and the immune system must be regulated differently to enable pregnancy in women and muscle growth in men,” says Petter Brodin.
By regulating these key functions via sex hormones, this can be achieved, and in women, it is dynamically controlled even during a menstrual cycle,” he adds.
The results of the study open an entirely new field of research, according to Nils Landegren.
“The newfound knowledge will help us better influence people’s immune systems even without using sex hormones. For example, new drugs can be developed to impact these regulatory mechanisms and thus rebalance the immune response, especially for women with the autoimmune rheumatic disease SLE,” he explains.
However, the results also have a more direct implications for transgender individuals.
“This research is also of crucial for transgender individuals undergoing gender-affirming hormone therapy, and I believe that this group deserves significantly more scientific attention and follow-up to ensure their long-term health,” says Petter Brodin.
More than half of us are carriers of chronic herpesvirus infections. But even though the herpes simplex virus can infect nerve cells, it rarely causes serious infection of the brain. Researchers from Aarhus University have now discovered a key element of the explanation.
The researchers have discovered a previously unknown defence mechanism in the body that is the reason why herpes infection causes a serious and potentially fatal brain inflammation in only one out of 250 000 cases. The study has recently been published in the scientific journal Nature.
“The study has exciting perspectives because it gives us a better understanding of how the brain defends itself against viral infections,” says Professor Søren Riis Paludan from the Department of Biomedicine at Aarhus University. He is the article’s last author, a Lundbeck Foundation Professor and centre director of the Excellence Centre CiViA.
“We’ve discovered how our body prevents herpesvirus from entering into the brain, even though 50–80% of us are chronically infected with this particular virus. The idea behind CiViA is that we want to understand how the body fights infections without harming itself at the same time. The mechanism we’ve found doesn’t cause inflammatory reactions,” he says.
The answer lies in the protective TMEFF1 gene.
The brain uses a novel mechanism to keep the virus out
Many years of experimenting with the genome-wide CRISPR screening technology and development of mice that lacked the critical gene have finally convinced the researchers that TMEFF1 produces a protein that prevents herpesvirus from entering into nerve cells.
The study in Nature is accompanied by another article describing two patients with brain inflammation caused by herpesvirus infection, called herpes encephalitic. In a collaborative study led by researchers in New York, the research group in Aarhus discovered that two children who developed herpes encephalitis were carrying a genetic defect that disabled the protective TMEFF1 gene.
“The new study is groundbreaking because it updates the basic understanding of immunity against viral infections,” explains Søren Riis Paludan.
“This is interesting for immunologists because it illustrates that there are still many immunological mechanisms in the brain that we don’t know about. “The study is also relevant for neuroscience because it sheds light on how the brain, so to say, prevents unwanted visitors from intruding without causing harm to the brain itself, i.e. the neuronal cells,” he says.
May provide a better understanding of Alzheimer’s
Søren Riis Paludan hopes that the study is the first step towards revealing a completely new range of brain defence mechanisms. One of the tracks that the researchers will now investigate is what the discovery may mean for the development of dementia.
Research has already demonstrated a correlation between infection with herpesviruses and later development of Alzheimer’s disease.
“Perhaps our discovery of a new antiviral mechanism in the brain can help to clarify whether individual differences in this particular mechanism or similar mechanisms can give the virus access to the brain and accelerate neurodegenerative processes,” says Søren Riis Paludan.
When it comes to allergies, mast cells are key immune system players, releasing pro-inflammatory substances in response to allergens. Now, scientists in Germany have discovered something weird: other immune cells nested inside them like Russian dolls. But how exactly did these cells wind up there?
As reported in the journal Cell, the researchers observed mast cells observed capturing and making use of neutrophils. This surprising discovery sheds new light on how our immune system works, particularly during allergic reactions.
Mast cells, residing in tissues and critical for initiating inflammation, are filled with granules containing pro-inflammatory substances. These granules are released upon encountering potential dangers, including allergens, causing allergic reactions – which for some includes innocuous materials like pollens. But despite how common allergies are, the interaction between mast cells and other immune cells at sites of allergic responses has been largely unexplored.
The research group at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the University of Münster used specialised microscopy to visualise the real-time dynamics of activated mast cells and other cell types during allergic reactions in living mouse tissues. The team discovered a surprising interaction: neutrophils were found inside mast cells.
“We could hardly believe our eyes: living neutrophils were sitting inside living mast cells. This phenomenon was completely unexpected and probably would not have been discovered in experiments outside a living organism and highlights the power of intravital microscopy,” says Tim Lämmermann, research leader and Director at the Institute of Medical Biochemistry at the University of Münster.
Pulling a neutrophil trick to trap neutrophils
Neutrophils are frontline immune system defenders, responding quickly and broadly to potential threats. They circulate in the blood and quickly exit blood vessels at sites of inflammation. They are well-equipped to combat pathogens by engulfing the invaders, releasing antimicrobial substances, or forming web-like traps known as ‘neutrophil extracellular traps’. Additionally, neutrophils can communicate with each other and form cell swarms to combine their individual functions for the protection of healthy tissue. While much is known about neutrophils’ role in infections and sterile injuries, their role in inflammation caused by allergic reactions is less understood.
“It quickly became clear that the double-pack immune cells were no mere coincidence. We wanted to understand how mast cells trap their colleagues and why they do it,” explains Michael Mihlan, first and co-corresponding author of the study. Once the team was able to mimic the neutrophil trapping observed in living tissue in cell culture, they we were able to identify the molecular pathways involved in this process. The researchers found that mast cells release leukotriene B4, a substance commonly used by neutrophils to initiate their own swarming behaviour.
By secreting this substance, mast cells attract neutrophils. Once the neutrophils are close enough, mast cells engulf them into a vacuole, forming a cell-in-cell structure that the researchers refer to as ‘mast cell intracellular trap’ (MIT). “It is ironic that neutrophils, which create web-like traps made of DNA and histones to capture microbes during infections, are now trapped themselves by mast cells under allergic conditions,” says Tim Lämmermann.
Recycled neutrophils to boost mast cell function
With the help of an international team, the researchers confirmed the formation of MITs in human samples and investigated the fate of the two cell types involved after trapping. They found that trapped neutrophils eventually die, and their remains get stored inside mast cells. “This is where the story takes an unexpected turn. Mast cells can recycle the material from the neutrophils to boost their own function and metabolism. In addition, mast cells can release the newly acquired neutrophil components in a delayed manner, triggering additional immune responses and helping to sustain inflammation and immune defense”, says Michael Mihlan.
“This new understanding of how mast cells and neutrophils work together adds a whole new layer to our knowledge of allergic reactions and inflammation. It shows that mast cells can use neutrophils to boost their own capabilities – an aspect that could have implications for chronic allergic conditions where inflammation occurs repeatedly,” says Tim Lämmermann. The researchers have already begun investigating this interaction in mast cell-mediated inflammatory diseases in humans, exploring whether this discovery could lead to new approaches to treating allergies and inflammatory diseases.
Researchers in Belgium have discovered a new population of macrophages, important innate immune cells that populate the lungs after injury caused by respiratory viruses. These macrophages are instrumental in repairing the pulmonary alveoli. This groundbreaking discovery promises to revolutionise our understanding of the post-infectious immune response and opens the door to new regenerative therapies.
Respiratory viruses, typically causing mild illness, can have more serious consequences, as shown during the COVID pandemic, including severe cases requiring hospitalisation and the chronic sequelae of “long Covid.” These conditions often result in the destruction of large areas of the lungs, particularly the alveoli responsible for gas exchanges. Ineffective repair of these structures can lead to ARDS or a permanent reduction in the lungs’ ability to oxygenate blood, causing chronic fatigue and exercise intolerance.
While the role of macrophages during the acute phase of respiratory viral infections is well known, their function in the post-inflammatory period has been largely unexplored. This study by the GIGA Institute at the University of Liège reveals that atypical macrophages, characterised by specific markers and transiently recruited during the early recovery phase, play a beneficial role in regenerating pulmonary alveoli.
Led by Dr Coraline Radermecker and Prof. Thomas Marichal from the Immunophysiology Laboratory, the study was conducted by Dr Cecilia Ruscitti and benefited from the ULiège’s advanced technological platforms, including flow cytometry, fluorescence microscopy, and single-cell RNA sequencing. “Our findings provide a novel and crucial mechanism for alveolar repair by these atypical macrophages,” explains Coraline Radermecker. “We have detailed their characteristics, origin, location in the damaged lung, the signals they require to function, and their role in tissue regeneration, specifically acting on type 2 alveolar epithelial cells, the progenitors of alveolar cells.” The scientific community had overlooked these macrophages because they express a marker previously thought to be specific for another immune cell population, the neutrophils, and because they appear only briefly during the repair phase before disappearing.
“Our study highlights the reparative role of these macrophages, countering the prevailing idea that macrophages following respiratory viral infections are pathogenic,” adds Thomas Marichal. “By targeting the amplification of these macrophages or stimulating their repair functions, we could develop therapies to improve alveolar regeneration and reduce complications from serious respiratory infections and ARDS.”
To illustrate, consider the lungs as a garden damaged by a storm (viral infection). These newly discovered macrophages act like specialised gardeners who clear debris and plant new seeds, enabling the garden to regrow and regain its vitality.
Creative artwork featuring colourised 3D prints of influenza virus (surface glycoprotein hemagglutinin is blue and neuraminidase is orange; the viral membrane is a darker orange). Note: Not to scale. Credit: NIAID
A new study shows that about one in 50 people develop autoantibodies against type 1 interferons, mostly later in life, rendering them more susceptible to viral diseases like COVID-19. The study, published in the Journal of Experimental Medicine, is based on an analysis of a large collection of historical blood samples.
Virus infections trigger the cells of the immune system to release type 1 interferons. These proteins act as early messengers that warn uninfected cells and tissues that a virus is spreading. This allows cells to prepare themselves so that they are ready to fight the virus when it reaches them.
In individuals with a compromised type 1 interferon system, severe viral infections can occur because the body cannot mount a full defense. Recent research has shown that about 5 to 15% of people who are in hospital with severe COVID or influenza have a deficiency in their type 1 interferon response. This is because their blood contains autoantibodies – antibodies that target a person’s own structures – that bind type 1 interferons and stop the messenger from functioning.
Unique samples for blood analysis
“With our study, we wanted to find out what causes the immune systems of some people to turn against themselves and to also understand the consequences of having autoantibodies against type 1 interferons,” says study head Benjamin Hale, professor at the Institute of Medical Virology of the University of Zurich (UZH).
His research team utilized a very large collection of frozen blood samples from the Swiss HIV Cohort Study, originally donated for research on HIV infection. They analysed the samples of around 2000 adults who had donated blood samples twice a year for several decades. “This study was only possible because of this unique biobank of stored longitudinal blood samples and well-curated clinical data,” says Hale. The fact that the donors were people living with HIV had no relevance for the results, because in this cohort the virus was suppressed by treatment.
Ageing population is vulnerable
First, the UZH team analysed the blood samples for the presence of autoantibodies against type 1 interferons to find out who had developed the autoantibodies, when this occurred, and how long these autoantibodies lasted in the blood.
The analysis revealed that around 2% of individuals produced autoantibodies against type 1 interferons in their lifetime and that this typically occurred between the ages of 60 to 65. This confirms prior studies that reported that the prevalence of autoantibodies against type 1 interferons might increase with age.
Next, by studying clinical data, researchers at the Department of Infectious Diseases and Hospital Epidemiology of the University Hospital Zurich (USZ) were also able to understand which factors contributed to the development of autoantibodies against type 1 interferons. The individuals who developed them appeared to be prone to also producing antibodies against other proteins formed by their own bodies. This so-called loss of self-tolerance can occur in some people as they age. “These individuals may produce antibodies against their own type 1 interferons because they are both prone to making autoantibodies and are exposed to high levels of type 1 interferons, for example because their immune system produces interferons against other infections at the time,” supposes Hale.
Lifelong consequences of autoantibodies
Importantly, the study found that once developed, these autoantibodies remained detectable in the blood of individuals for the rest of their lives. People with autoantibodies against type 1 interferons, even when they had developed them as far back as in 2008, were more likely to suffer from severe COVID in 2020. “These autoantibodies have consequences for individuals decades later, leading to a compromised type 1 interferon system and reduced immunity against viruses,” says Hale.
Understanding these risk factors might lead to future diagnostic tests that can identify older individuals who are more prone to developing this deficiency, and therefore help with measures to prevent autoantibodies ever developing. Identifying individuals with autoantibodies against type 1 interferons could also help to prioritize these people for vaccines or antivirals to prevent severe viral infections.
Study reveals epigenetic changes in regulatory T cells of hepatitis C patients post-treatment
A new study published in the Journal of Hepatology has revealed the lasting effects of chronic Hepatitis C virus (HCV) infection on the immune system, even after the disease has been successfully treated. The researchers discovered that traces of “epigenetic scars” remain in regulatory T cells and exhibit sustained inflammatory properties long after the virus is cleared from the body.
Chronic hepatitis C, can lead to severe complications such as liver cirrhosis and liver cancer. The advent of highly effective direct-acting antivirals (DAAs) has resulted in high cure rates for this chronic viral infection. However, it has been reported that the immune system of patients does not fully recover even after being cured.
The study examined patients with chronic HCV infection who achieved sustained virologic response (SVR) after DAA treatment. SVR means that the HCV virus is not detected in blood for 12 weeks after treatment, which is a strong indicator that the virus has been eradicated from the body. The researchers found that the frequency of activated TREG cells remained elevated during treatment and continued to be high even after the virus was eliminated.
The researchers then performed comprehensive analyses, including RNA sequencing and ATAC-seq, which revealed that the transcriptomic and epigenetic landscapes of TREG cells from HCV patients remained altered even after eradication of the virus. Inflammatory features, such as increased TNF signaling, were sustained in TREG cells, indicating long-term immune system changes induced by the chronic infection. These activated TREG cells from HCV patients continued to produce inflammatory cytokines like TNF, IFN-γ, and IL-17A even after clearance of the virus. The researchers followed the patients for up to six years after achieving SVR and found that inflammatory features still persisted.
The study’s results have significant implications for the long-term management of patients who have been treated for chronic HCV infection. Despite successful viral clearance, the persistence of inflammatory features in TREG cells suggests that these patients may be at risk for ongoing immune system dysregulation. This could potentially lead to chronic inflammation and related health issues.
Director Shin Eui Cheol, leader of the study, explained: “Our findings highlight the need for ongoing monitoring even after HCV has been cleared. By understanding the underlying mechanisms of these persistent immune changes, we can develop more effective strategies to ensure complete recovery and improve the quality of life for HCV patients.”
The research team is now focusing on further investigating the mechanisms behind the sustained inflammatory state of TREG cells. They aim to explore potential therapeutic interventions that could reverse these epigenetic and transcriptomic changes.
“We are now interested in seeing whether other chronic viral infections also cause long-lasting epigenetic changes in our immune systems,” said Director Shin. “One of our goals is to identify clinical implications of these persistent immune alterations.”
A rare autoimmune disease has been newly described as a COVID-related syndrome, following an investigation by the University of California San Diego School of Medicine and Leeds University.
It started when Pradipta Ghosh, MD, a professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, received an email from Dennis McGonagle, PhD, professor of investigative rheumatology at the University of Leeds in the UK. This was the beginning of an international collaboration, one that uncovered a previously overlooked COVID-related syndrome and resulted in a paper in eBioMedicine, a journal published by The Lancet.
McGonagle asked if she was interested in collaborating on a COVID-related mystery. “He told me they were seeing mild COVID cases,” Ghosh said. “They had vaccinated around 90 percent of the Yorkshire population, but now they were seeing this very rare autoimmune disease called MDA5 – autoantibody associated dermatomyositis (DM) in patients who may or may not have contracted COVID, or even remember if they were exposed to it.”
McGonagle told of patients with severe lung scarring, some of whom presented rheumatologic symptoms – rashes, arthritis, muscle pain – that often accompany interstitial lung disease. He was curious to know if there was a connection between MDA5-positive dermatomyositis and COVID.
“DM is more common in individuals of Asian descent, particularly Japanese and Chinese,” Ghosh said. “However, Dr McGonagle was noting this explosive trend of cases in Caucasians.”
“But that’s the least of the problem,” Ghosh said. “Because he said, ‘Oh, and by the way, some of these patients are progressing rapidly to death.'”
Ghosh is the founding director of the Institute for Network Medicine at UC San Diego School of Medicine, home to the Center for Precision Computational Systems Network (PreCSN – the computational pillar within the Institute for Network Medicine). PreCSN’s signature asset is BoNE – the Boolean Network Explorer, a powerful computational framework for extracting actionable insights from any form of big-data.
“BoNE is designed to ignore factors that differentiate patients in a group while selectively identifying what is common (shared) across everybody in the group,” Ghosh explained. Previous applications of BoNE allowed Ghosh and her team to identify other COVID-related lung and heart-afflicting syndromes in adults and children, respectively.
As a rheumatologist, McGonagle specialises in inflammatory and autoimmune conditions. Ghosh said that McGonagle’s roster of patients, all within the UK’s National Health System (NHS), helped to facilitate the investigation.
“The NHS has a centralised health care database with comprehensive medical records for a large population, making it easier to access and analyse health data for research purposes,” Ghosh explained.
Ghosh and McGonagle put together a team to probe what they found was indeed an entirely new syndrome.
The study began with McGonagle lab’s detection of autoantibodies to MDA5 – an RNA-sensing enzyme whose functions include detecting COVID and other RNA viruses. A total of 25 patients from the group of 60 developed lung scarring, also known as interstitial lung disease. Ghosh noted that the lung scarring was bad enough to cause eight people in the group to die due to progressive fibrosis. She said that there are established clinical profiles of MDA5 autoimmune diseases.
“But this was different,” Ghosh said. “It was different in behaviour and rate of progression – and in the number of deaths.”
Ghosh and the UC San Diego team explored McGonagle’s data with BoNE. They found that the patients who showed the highest level of MDA5 response also showed high levels of interleukin-15.
“Interleukin-15 is a cytokine that can cause two major immune cell types,” she explained. “These can push cells to the brink of exhaustion and create an immunologic phenotype that is very, very often seen as a hallmark of progressive interstitial lung disease, or fibrosis of the lung.”
BoNE allowed the team to establish the cause of the Yorkshire syndrome – and pinpoint a specific single nucleotide polymorphism that is protective. By right of discovery, the group was able to give the condition a name: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID. It’s MIP-C for short, “Pronounced ‘mipsy,'” Ghosh said, adding that the name was coined to make a connection with MIS-C, a separate COVID-related condition of children.
Ghosh said that it’s extremely unlikely that MIP-C is confined to the United Kingdom. Reports of MIP-C symptoms are coming from all over the world. She said she hopes the team’s identification of interleukin-15 as a causative link will jump start research into treatment.
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.
