An international research group directed by UMC Utrecht have developed and characterised two first-in-class antibodies that specifically block the high-affinity IgG receptor FcγRI. Their findings open new perspectives for therapeutic modulation of FcγRI-driven inflammation in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and immune thrombocytopenia (ITP).
FcγRI, also known as CD64, is a high-affinity receptor on myeloid cells that binds to the Fc region of immunoglobulin G (IgG) antibodies. It plays a key role in immune defence by triggering cellular functions such as phagocytosis and cytokine production. In a normal immune response, FcγRI is activated by immune complexes – clusters of antibodies bound to pathogens, which mark them for clearance. In autoimmune diseases, however, the immune system mistakenly targets the body’s own tissues (such as joint proteins in RA, nuclear antigens in SLE, or platelets in ITP), which results in the production of autoantibodies that form immune complexes. These misdirected complexes activate FcγRI unnecessarily, driving chronic inflammation and subsequent tissue damage.
The study, led by Prof Jeanette Leusen, PhD from the Antibody Therapy research group at the Center for Translational Immunology (UMC Utrecht) and carried out by PhD candidate Tosca Holtrop MSc, was a true team effort, in collaboration with experts from Kiel University (Germany), Leiden University Medical Center, Utrecht University, and Friedrich-Alexander University Erlangen-Nürnberg (Germany).
Discovery of first-in-class antibodies
For over 30 years, scientists have tried to generate antibodies against the IgG-binding domain of CD64, but the receptor’s extremely high affinity for IgG made this impossible with earlier technologies. Combining the UMAB unique immunisation method with novel phage display antibody libraries, the team bypassed this challenge by excluding the Fc region of the antibodies. This allowed them to discover two unique Fc-silent antibodies, C01 and C04, that bind purely via their Fab domains to FcγRI. Crystal structural analysis confirmed that C01 binds precisely within the IgG-binding site on EC2, making binding mutually exclusive.
High affinity for FcγRI
Quantitative binding studies revealed that both antibodies have higher affinity for FcγRI than human IgG, allowing them to efficiently displace IgG or pathogenic immune complexes up to 60 percent and block binding up to 90 percent. Importantly, neither antibody triggered FcγRI activation, a critical distinction from earlier anti-FcγRI antibodies, which could inadvertently trigger receptor clustering and cytokine release.
Subsequently. an in vitro model for immune thrombocytopenia was set-up, where C01 and C04 effectively inhibited opsonized platelets from binding to immune cells from ITP patients. In a preclinical in vivo ITP model, the antibodies significantly reduced IgG-dependent platelet depletion. The antibodies were also tested in an in vitro rheumatoid arthritis models, where they effectively inhibited patient-derived autoantibody–immune complex binding to monocytes, macrophages, and neutrophils from healthy donors.
Promising therapeutic candidate drugs
The study demonstrates that direct Fab-mediated inhibition of FcγRI is feasible and effective, opening a new avenue for treating autoimmune diseases characterised by IgG-autoantibody complexes. By preventing immune complex–driven activation without triggering the receptor, C01 and C04 represent a promising next step toward targeted, inflammation-sparing immunotherapy. “I think we found the needle in the haystack, after searching over a decade and thanks to a true team effort,” says Jeanette Leusen, principal investigator of the study. “Each research partner contributed a critical piece, from antibody discovery and structure determination to patient sample testing and preclinical models. Only together could we bring this to fruition. These antibodies not only provide a unique tool for studying FcγRI biology, but also hold promise as therapeutic candidates in autoimmune and infectious diseases.”
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.
“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.
Sepsis is the No.1 cause of death in the intensive care unit of hospitals worldwide and a major concern for health scientists and medical professionals alike.
Dr Scott Widenmaier (PhD), an associate professor in the Department of Anatomy, Physiology and Pharmacology in USask’s College of Medicine, has zeroed in on a specific protein that might be key to helping the body fight back against the potentially life-threatening condition.
By manipulating this protein, researchers believe there is a new avenue to protect patients against sepsis. Widenmaier and his team have had their research recently published in Cellular and Molecular Gastroenterology and Hepatology.
“Sepsis is the largest cause of death in the intensive care unit globally,” Widenmaier said. “Sepsis can cause damage to organs like the heart, kidney, and lungs. It can also cause liver dysfunction, and when this occurs, the liver is not able to properly perform its functions that are useful in helping the body deal with an infection.”
Sepsis is caused by the body’s immune system response to infection causing damage to the body itself. As Widenmaier puts it, many people believe that bacteria or a virus they acquire are what causes people to get sick. However, it’s the body’s response to the infection that results in severe sickness and can escalate to sepsis – what Widenmaier identified as “a dysregulated immune response that leads to life-threatening complications.”
“The immune system releases cytokines and various factors that are trying to kill the bacteria or the virus, but the process of doing it actually dramatically changes our physiology and leads to us being really sick,” Widenmaier said.
While conventional methods for treating sepsis have been targeted at mitigating the infections that might lead to sepsis, Widenmaier said more recent studies have recognised that the body itself has built-in disease tolerance mechanism that could be harnessed to protect itself from the potential damage. In other words, when disease tolerance is working well, the process of killing the infection won’t cause the person to get nearly as sick and preserve healthy organ function.
Widenmaier and his team identified a “transcription factor” protein in the liver called NRF1, which acts as a “molecular switch” to help control the body’s own disease tolerance response. In experimental models infected with E. coli, over-expressing the NRF1 protein led to better overall responses to infection and protection against sepsis.
When over-expressed, the protein enables the liver to secrete more very low-density lipoprotein (VLDL) particles, which better protects organs against damage caused by sepsis. It’s this connection between the NRF1 “switch” and the liver’s production of VLDL that Widenmaier says may be a promising approach to improve the outcomes of patients with sepsis.
“Our lab is very interested in finding ways to either pharmacologically or genetically manipulate NRF1 to promote health,” he said.
Widenmaier credited his team – including colleagues, students and trainees – for their work in identifying this potential target for sepsis treatments and for the resulting research paper.
The next step for this research would be to see how feasible this pathway might be for treatment and whether it is still active in conditions when sepsis is very common – and while they aren’t at the stage of human trials yet, Widenmaier said he wants to delve deeply into this new area in the search for better sepsis care.
“We want to explore this quite intensively,” he said. “There’s a lot of clinical investigators across the country … I’m interested in continuing those connections and trying to strengthen them, and hopefully we can find a place where clinicians and our lab can benefit from the science.”
Study finds sensory cells that detect tissue damage, irritants also rein in harmful immune responses to protect the lungs
Clusters of mouse vagus nerve sensory cells reveal the presence of TRPV1, a molecular sensor that detects irritants, heat, and inflammation. A new HMS study reveals nerve cells with this sensor play a central role in taming inflammation and tissue damage in the lung during flu infection. Image: Chiu Lab.
A group of nerve cells known for their role in detecting chemical irritation, tissue damage, heat, and pressure now emerge as critical defenders against the worst ravages of the flu caused by an overactive immune response, according to new research by scientists at Harvard Medical School and the Harvard T.H. Chan School of Public Health.
The cells, called TRPV1 vagal nociceptors, live in the vagus nerve, which sends signals from internal organs – including the heart, lungs, and gut – to the brain to help regulate heart rate, breathing, digestion, and other functions. In the lungs, these cells trigger the protective cough reflex that forces the airways to expel foreign particles, mucus, and other irritants.
But the new research, published in Science Immunologyand conducted in mice, shows that in the setting of flu, these cells do much more – they rein in the immune system and avert the smoldering inflammation that often occurs in the aftermath of a viral infection and can injure healthy tissue.
Each year, the flu sickens millions and kills between 290 000 and 650 000 people worldwide, according to the World Health Organization. While the immune system helps fight off the virus, an excessive inflammatory response can inflict tissue damage and worsen illness. The findings are especially relevant in the wake of the COVID-19 pandemic, which revealed how an aberrant immune response following viral infection can sometimes lead to serious organ damage and even organ failure.
“Our research shows that the infected lung is a battleground where nerves and immune cells engage in a delicate dance to safeguard our health,” said co-senior study author Isaac Chiu, professor of immunology in the Blavatnik Institute at HMS. “Understanding this powerful neuro-immune signaling axis will be increasingly important as we design better ways to prevent and treat immune-mediated damage in viral infections, which can sometimes be worse than the direct damage caused by the virus itself.”
The findings, he added, raise the possibility that vagus nerve function may be one variable that explains why some people with the flu go on to develop long-lasting and devastating immune-driven damage in their lungs while others recover once the initial infection is resolved.
“Flu infections are highly variable in severity and there is a need to understand why certain groups of people, such as the elderly, experience worse disease,” said study first author Nicole Almanzar, a doctoral student in the Chiu Lab. “Our study demonstrates that the nervous system is actively involved in regulating the response of the lungs to infection, offering a new perspective on viral infections that could help explain why particular factors increase risk of severe infections.”
The new study illuminates the complex interaction between body and brain and adds to a growing body of research showing that the nervous and immune systems engage in highly orchestrated crosstalk during infection to modulate body defenses.
One of Chiu’s earlier studies found that during bacterial infections of the lung, the same set of vagal nerve neurons suppressed the immune defences. In the new study, however, the immune-taming function of these cells worked to shield the lung from excessive damage during viral infection.
“Context clearly matters,” Chiu said.
Disabling the neurons worsened flu damage in the lungs
In a set of experiments, researchers exposed a group of mice with genetically disabled or chemically silenced TRPV1 neurons to influenza A virus. Mice without these nerve cells fared notably worse than mice with functioning TRPV1 cells. Even though the overall amount of virus in the lungs was the same in both groups, mice lacking TRPV1 neurons suffered more severe lung pathology, higher levels of harmful inflammation, and lower survival rates. Interestingly, Almanzar noted, even though the overall viral load remained the same, the spread of the virus within the lobes of the lungs was more pronounced in mice without these protective neurons.
The researchers also found that the absence of TRPV1 neurons altered the lung’s immune landscape. The lungs of mice lacking these neurons had an overabundance of neutrophils and macrophages – two types of immune cells that, in excess, can worsen tissue damage. At the same time, interferon signalling – one of the body’s most important viral-defence pathways – was seriously impaired in these immune cells.
In another experiment, the researchers used an antibody to deplete inflammation-driving cells in flu-infected mice lacking TRPV1 neurons. These animals had notably better survival than untreated mice lacking these protective neurons. The observation further underscores how nerve cells help prevent harmful immune reactions that can sometimes be more dangerous than the virus itself.
The researchers noted that they do not yet know precisely how TRPV1 neurons restrain the march of inflammatory cells at the molecular level – a question they plan to explore in subsequent work.
“The vagus nerve is powerfully controlling inflammation, but how it does so remains a mystery to be solved,” Chiu said. “But we’re excited that it plays such a strong role in viral infections.”
Harnessing the immune brake for therapy
Moving forward, this insight opens the door to exciting new avenues for therapy. Instead of only targeting the flu virus or dampening immune activity, the research team said, future treatments could mimic the function of nerve cells to ensure the delicate balance between protective and damaging immune responses is not thrown off.
The idea is not that far-fetched, the researchers said, noting that the FDA recently approved a therapy for rheumatoid arthritis by vagus nerve stimulation.
“Imagine if you could harness this brake to control inflammation in the lungs and beyond,” Chiu said. “By stimulating related circuits where the vagus nerve shuts down immune cells, one could envision treating immune-mediated dysfunction of many kinds, including that caused by viral infections.”
Many diseases affect men and women differently. Asthma tends to strike men earlier in life, yet more women develop asthma as they get older. Parkinson’s is more common in men, but Alzheimer’s is more common in women.
The differences are even more stark when it comes to autoimmune disease. Women are around two and a half times more likely than men to develop multiple sclerosis and nine times more likely to develop lupus.
Why would some diseases strike one sex more than another? And why do some tissues, such as the lungs and brain, seem especially vulnerable to these sex-based differences?
To answer these questions, scientists at La Jolla Institute for Immunology (LJI) are leading new research into how our immune cells defend specific parts of the body.
“In just the last two years, LJI scientists have uncovered a whole new body of information about how the immune systems of men and women are very different,” says Saphire. “We’re looking at what is genetically encoded in our XX or XY chromosomes, and how hormones like oestrogen and testosterone affect what is genetically programmed into our immune cells.”
In the paper, the researchers define biological sex (in an immunology context) as the presence of XX chromosomes in females and XY chromosomes in males. “Every cell in your body is either XX or XY,” says Saphire. “That X chromosome has many, many immune-related genes. Women have two copies of each. That gives them, in a sense, twice the palette of colours to paint from in formulating an immune response. It can also give them a stronger immune response for those genes that are doubly active – active in both copies simultaneously.
Sex hormones are important for much more than reproductive function. Immune cells can also sense hormones such as oestrogen and testosterone and use them to determine which genes to turn on or off and which ones to turn on more brightly or dim. This means similar immune cells can do different things, depending on whether that cell is from a male or a female.
Further, female cells vary in which of their two copies of X is “turned on.” As a result, women have organs with a collage, or mosaic, of immune cells that work differently in different tissues. This innate “variety” of immune cells appears to be an effective way to ward off infectious disease (women are better than men at fighting off pathogens such as SARS-CoV-2).
But scientists have also found that having more genes from X chromosomes may predispose women to autoimmune disease. This increased X chromosome “dosage” is closely linked to a higher risk for autoimmune diseases such as Sjögren’s syndrome and scleroderma.
New research into sex-based immune system differences is also critical for developing new cancer immunotherapies, Sharma explains.
“We’re increasingly understanding how sex-based differences affect disease outcomes. When it comes to medicine, one size doesn’t fit everybody,” says Sharma, who directs LJI’s Center for Sex-Based Differences in the Immune System. “This is leading to new research, particularly in the cancer field, toward precision medicine. We’re asking how a person’s individual immune system is contributing to controlling that cancer through immunotherapy.”
Saphire and Sharma also highlight environmental factors, such as nutrition and chemical exposures, that may add to the complex interplay of chromosomes and sex hormones. Men and women also appear to have some signature differences in their skin and gut microbiomes.
The researchers hope these foundational discoveries can lead to medical advances for all, and they’re working with collaborators across the country to move this research forward. “It takes a team to translate these findings,” says Sharma.
Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash
By measuring interactions between cells, the method offers insights into how the human body fights viral infections, how malfunctions can lead to autoimmune diseases and why immunotherapies work for some people but not others.
A healthy immune system is trained to detect and destroy infections and cancer cells. This defence is based on a complex communication system at cellular level, in which different immune cells each perform a specialised task: recognising infectious agents, alerting other immune cells, and eliminating harmful cells or pathogens. Problems arise when communication between different cell types is disrupted, potentially leading to a variety of diseases.
For example, cancer cells often develop strategies to specifically disrupt or circumvent the exchange of information in the immune system – this allows them to evade immune surveillance and grow unhindered. “Modern immunotherapies have fundamentally changed the treatment of certain types of cancer by restoring or specifically strengthening communication between immune cells,” explains Prof Simon Haas, one of the leaders of the study.
Dr Daniel Hübschmann, also head of the study, adds: “However, not all patients respond equally well to these therapies and reliable methods for predicting which patients will benefit most are still lacking.”
Decoding immune cell communication for personalised cancer therapies
Scientists have now developed a technology that overcomes many of these hurdles through a better understanding of immune cell communication. With this method, made possible by interdisciplinary collaboration, millions of cell-cell interactions can be measured quickly and cost-effectively, both in research laboratories and in the clinic.
The scientists are using the newly developed technology to investigate the behaviour and kinetics of immunotherapies and to gain insights into how these therapies work at the level of cell-cell interactions. They were able to show that the approach enables the prediction of individual therapy responses and can thus create a central basis for personalised immunotherapies and targeted therapy decisions.
In addition, the researchers were able to use their new technology to visualise, in high resolution, how cells of the immune system interact with each other during viral infections and autoimmune diseases. The results allow them to develop dynamic maps of immune cell networks, illustrating for the first time how the immune defence is coordinated in different tissues.
Together with clinical partners, the team is now working on translating these findings from research into practice, for example to better predict treatment success and utilise immunotherapies in a more personalised manner.
Trained immunity – a process being explored in vaccine and therapy development to boost immune defences – appears to be counterproductive in certain contexts, researchers at McGill University and the Research Institute of the McGill University Health Centre (The Institute) have found.
Trained immunity is when the body’s first line of defence remembers past threats and becomes more reactive, responding more strongly to future infections even if they are different, by changing immune cells’ behaviour.
In an earlier study, the researchers had determined beta-glucan, a molecule found in the cell walls of fungi like yeast and mushrooms, can reduce lung damage during influenza infection. That study had focused on beta-glucan’s impact on neutrophils.
However, in a new study, published in the journal eLife, the team found exposure to beta-glucan can reprogram alveolar macrophages in a way that worsens lung damage during severe inflammation caused by viral or bacterial products. These cells help keep the lungs clean by clearing out dust, debris and pathogens.
“To date, most trained immunity research has focused on circulating immune cells that arise from the bone marrow,” said lead author Renaud Prével, a postdoctoral fellow at the Meakins-Christie Laboratories at The Institute. “We wanted to explore whether beta-glucan could induce trained immunity in alveolar macrophages, and whether that might be helpful or harmful.”
The researchers exposed mice to beta-glucan, which is known to trigger trained immunity and is found in some health supplements. A week later, the mice were exposed to signals that mimic severe viral or bacterial infections with sepsis-like phenotype. Using high-resolution microCT scans and fluid analysis, they found that mice given beta-glucan developed significantly more severe lung damage compared to the untreated control group.
To confirm the immune cells were causing the damage, researchers removed them from the mice, and the inflammation went away. When they put trained alveolar macrophages into other mice, the inflammation came back. The cells showed signs of immune training, but surprisingly, this didn’t happen through the usual immune pathways. It needed signals from infections and help from other immune cells.
“Our study shows that immune memory in the lungs is more dynamic than previously thought,” said senior author Maziar Divangahi, Professor of Medicine at McGill and Associate Director of the Meakins-Christie Laboratories. “This could help explain why some individuals develop more severe lung inflammation, especially in settings like sepsis.”
PFAS lurks in numerous consumer products – from nonstick cookware and food packaging to stain-resistant fabrics and personal care items. Photo by Cooker King on Unsplash
New research reveals that tiny amounts of per- and polyfluoroalkyl substances (PFAS; widely known as “forever chemicals”) cross the placenta and breast milk to alter infants’ developing immune systems, potentially leaving lasting imprints on their ability to fight disease.
University of Rochester Medical Center (URMC) researchers tracked 200 local healthy mother–baby pairs, measuring common PFAS compounds in maternal blood during pregnancy and then profiling infants’ key T‑cell populations at birth, six months, and one year. By age 12 months, babies whose mothers had higher prenatal PFAS exposure exhibited significantly fewer T follicular helper (Tfh) cells – vital coaches that help B cells produce strong, long‑lasting antibodies – and disproportionately more Th2, Th1, and regulatory T cells (Tregs), each linked to allergies, autoimmunity, or immune suppression when out of balance.
“This is the first study to identify changes in specific immune cells that are in the process of developing at the time of PFAS exposure,” said Kristin Scheible, MD, an associate professor of Pediatrics and Microbiology & Immunology at URMC and lead author of the study, which appears in the journal Environmental Health Perspectives. “Identification of these particular cells and pathways opens up the potential for early monitoring or mitigation strategies for the effects of PFAS exposure, in order to prevent lifelong diseases.”
Implications for vaccines, allergies, and autoimmunity
Tfh cell depletion helps explain previous findings that higher PFAS levels in children correlate with weaker vaccine responses to tetanus, measles, and other routine immunisations. Conversely, the uptick in Th2 and Treg cells can predispose to allergic inflammation or dampened defences, while excess Th1 activity raises concerns about future autoimmune conditions such as juvenile arthritis or type 1 diabetes.
“The cells impacted by PFAS exposure play important roles in fighting infections and establishing long-term memory to vaccines,” said Darline Castro Meléndez, PhD, a researcher in Scheible’s lab and first author of the study. “An imbalance at a time when the immune system is learning how and when to respond can lead to a higher risk of recurrent infections with more severe symptoms that could carry on through their lifetime.”
Minimising PFAS exposure
Although Rochester’s drinking water meets current safety standards, PFAS lurks in numerous consumer products – from nonstick cookware and food packaging to stain-resistant fabrics and personal care items. The study’s mothers had relatively low PFAS blood levels compared to other regions, yet the immune shifts were pronounced even in this small sample.
While not all environmental exposures can be avoided, families can reduce PFAS contact during critical windows of foetal and infant immune development. “Use water filters, minimise cooking in damaged nonstick pans, switch to alternatives like stainless steel or cast iron, and store food in glass or ceramic containers,” said Scheible. “Small steps can help lower the cumulative burden of exposure.”
The team plans a longer follow-up to determine whether these early T‑cell imbalances persist into toddlerhood and whether they translate into more infections, allergies, or autoimmune diseases. Measuring PFAS in infants directly and unravelling the molecular underpinnings of these immune disruptions are key objectives for future research.
A woman with Systemic Lupus Erythematosus. Source: Wikimedia CC0
Chronic inflammation occurs when the immune system is stuck in attack mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health – and their incidence is expected to rise. A new study by investigators from Mass General Brigham identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as infection by a pathogen. Results are published in Nature.
“Chronic inflammatory diseases cause a great deal of suffering and death, but we still have much to learn about what drives chronic inflammation and how to treat it,” said senior author Zhixun Dou, PhD, of the Center for Regenerative Medicine and Krantz Family Center for Cancer Research at Massachusetts General Hospital. “Our findings help us separate chronic and acute inflammation, as well as identify a new target for stopping chronic inflammation that results from aging and disease.”
Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. They confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.
The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.
Further research is needed to validate the therapeutic potential of WSTF restoration in broader settings and to develop specific strategies to target WSTF. Additionally, the findings suggest other similar proteins may be involved in chronic inflammation, opening a promising new avenue for studying and treating inflammation in the future.
When ocrelizumab became the first FDA-approved treatment for early forms of multiple sclerosis (MS) in 2017, it offered patients immense hope. The long-awaited drug is a monoclonal antibody that depletes B cells – the immune cells that drive MS progression. Exactly how ocrelizumab does this, however, remains unclear.
In a new study published in The Journal of Clinical Investigation, Yale scientists begin to answer this question. By using single-cell RNA sequencing, a technique that provides a window into the gene expression in individual cells, the researchers laid out a detailed view of how ocrelizumab achieves its therapeutic effects.
“The surprise was that the drug doesn’t work at all the way we thought it was working,” says David A. Hafler, MD, Professor of Neurology at Yale School of Medicine, who led the study. “We knew what the end result was and that the drug was enormously effective in patients. But what’s driving the drug’s action is a type of white blood cell in the central nervous system. No one would ever hypothesise that.”
The roles of T cells and B cells in multiple sclerosis
B and T cells have closely intertwined roles in the immune system. B cells are critical cells that recognise foreign objects, bind them, and present them to T cells, which then signal other immune cells to take action. But this relationship goes awry in disease.
Scanning electron micrograph of a B cell. Credit: NIH
In MS, abnormally active B cells trigger T cells to attack the myelin sheath, the protective layer of nerve fibres, leading to neurological symptoms, such as loss of vision, muscle weakness, and cognitive impairment. More than two decades ago, Hafler and his team discovered this was due to defects in regulatory T cells, which normally put the brake on immune responses, but when defective, unleash immune cells that mistakenly target the body’s own tissues.
In the early stages of MS, both B and T cells are deemed to be the drivers of the disease. Once the disease progresses to a neurodegenerative stage, other inflammatory processes become more prominent.
“Once you enter the neurodegenerative phase of the disease, it is much more difficult to stop the process,” Hafler says. “What we’ve learned is that the earlier you treat the disease, the better the outcome.”
Ocrelizumab binds to the surface of B cells, leading to their destruction. And especially for people in the early stages of MS, it can be quite effective. “The drug works incredibly well,” Hafler says. But Hafler and his team found that ocrelizumab was doing far more than just controlling B cells.
In the new study, the researchers analysed the blood and cerebrospinal fluid of 18 patients, all of whom had an early-onset form of multiple sclerosis in which patients cycle between periods of disease remission and relapse. The scientists measured the cell type-specific changes in protein expression before and after the patients received six months of ocrelizumab, in an effort to identify immune molecules that might change in response to the drug.
They discovered that the reduction in B cells driven by ocrelizumab led to an increase in the pro-inflammatory molecule TNF-α. This was unexpected because TNF-α has been shown to trigger the immune system and exacerbate inflammation in certain diseases. In fact, medications that block the activity of TNF-α are typically used for treating various autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.
As they looked further, the researchers found that by inducing TNF-α, ocrelizumab led to an increase in a specific type of regulatory T cell. This, in turn, curbed the circulation of T cells that attack the myelin.
“This unpredicted increase in TNF-α shows that ocrelizumab works in a paradoxical way,” says Hafler.
Understanding the cause of multiple sclerosis
One of the current working models of MS suggests that the disease originates from the Epstein-Barr virus. “How the Epstein-Barr virus triggers the disease is a point that we don’t yet understand,” Hafler says. However, there is a strong body of evidence to show that the virus infects B cells. Therefore, understanding how a B cell-depleting drug affects T cell activity may lead to further explanations.
The current finding also explains why a fifth of the genes linked to MS risk involve the TNF pathway and why many of those genetic changes are protective in other diseases, such as inflammatory bowel diseases.
“This shows that biology has a richness to it,” Hafler says. “When these molecules are made, where they’re made, and what cell they’re working on have very different effects.”
Hafler suspects that ocrelizumab might be acting through other mechanisms as well, an inkling that motivates his lab to continue their investigation. “For something to work that well, there must be other things going on,” he says.
The team is now beginning to study the pathogenesis of MS in a large cohort of women who have at least one parent with the disease. By following the genetic evolution of the disease, the scientists are hoping to better understand how B cells change the immune landscape in real time.
“This study is only one piece of the puzzle,” Hafler says. “We’ll continue to look for other pieces.”
