A European study showed that 92% of patients using the biologic therapy benralizumab could safely reduce inhaled steroid dose and more than 60% could cease entirely. The results, published in The Lancet, could be transformative for severe asthma patients by minimising or eliminating the unpleasant, and often serious, side effects of inhaled steroids.
These include osteoporosis which leads to increased risk of fractures, diabetes and cataracts.
Around 3 to 5% of the 300 million people with asthma worldwide have severe asthma. This leads to daily symptoms of breathlessness, chest tightness and cough, along with repeated asthma attacks which require frequent hospitalisation.
The SHAMAL study was led by Professor David Jackson, head of the Severe Asthma Centre at Guy’s and St Thomas’ and Professor of Respiratory Medicine at King’s College London.
Professor Jackson said: “Biological therapies such as benralizumab have revolutionised severe asthma care in many ways, and the results of this study show for the first time that steroid related harm can be avoided for the majority of patients using this therapy.”
The monoclonal antibody benralizumab targets interleukin-5, reducing eosinophil count, which is elevated in the airway of patients with severe asthma and is critically involved in the development of asthma attacks.
Benralizumab is injected every four to eight weeks.
The SHAMAL study took place across 22 sites in the UK, France, Italy and Germany.
The 208 patients were randomly assigned to taper their high dose inhaled steroid by varying amounts over 32 weeks, followed by a 16 week maintenance period.
Approximately 90% of patients experienced no worsening of asthma symptoms and remained free of any exacerbations throughout the 48 week study.
Similar studies to SHAMAL will be necessary before firm recommendations can be made regarding the safety and efficacy of reducing or eliminating high dose steroid use with other biologic therapies.
Scientists have uncovered a group of T cells that may drive severe asthma, which gather in the lungs and seem most harmful in men who develop asthma in later life. The new research, published in MED, suggests asthma patients with these cells in their lungs may be more likely to have hard-to-treat, and potentially fatal, asthma attacks. These cells do not respond to the usual general therapy for asthma patients.
The scientists, from the University of Southampton and La Jolla Institute for Immunology (LJI), in California, uncovered these T cells, called ‘cytotoxic CD4+ tissue-resident memory T cells’, thanks to volunteers enrolled in the NHS clinic-based WATCH study. It follows hundreds of asthma patients of different ages, sexes, and disease severities. By following patients over many years, and analysing their immune cell populations, researchers are making new connections between asthma symptoms and immune cell activity.
“If you are male and you develop asthma after age 40, there’s a high chance this T cell population is in your lungs,” says LJI Research Assistant Professor Gregory Seumois, who co-led the study with LJI Professor Pandurangan Vijayanand.
“Once you understand the role of cells like these T cells better, you can start to develop treatments that target those cells,” says WATCH study director Dr Ramesh Kurukulaaratchy, Associate Professor at the University of Southampton and researcher at the NIHR Southampton Biomedical Research Centre.
Scientists now hope to learn more about these cells and their role in asthma development in order to develop personalised therapies for asthma patients.
How harmful T cells drive asthma
The ‘memory’ T cells help protect the body from viruses and bacteria it has encountered before, but the same T cell memory is a big problem for asthma patients. Their misguided T cells see harmless molecules, such as pollen, and produce a dangerous inflammatory response.
Men who developed asthma later in life had an overwhelming number of these potentially harmful T cells. Their lungs should have been home to a diverse bunch of CD4+ T cell types but, in this group, more than 65% of their cells were cytotoxic CD4+ tissue-resident memory T cells.
Personalised asthma treatments
Single-cell RNA sequencing by LJI scientists provides a ‘biomarker’ to help detect cytotoxic CD4+ tissue-resident memory T cells in more patients going forward.
Finding this biomarker represents a “paradigm shift” in asthma research, says Dr Kurukulaaratchy. Before now, scientists and clinicians separated asthma patients into just two groups: ‘T2 high’ and T2 low’. In a study published earlier this year, the research team showed the importance of drilling down to identify many more asthma patient subgroups; their analysis reveals that 93% of WATCH subjects with severe asthma were in the T2 high category.
Study co-author Professor Hasan Arshad, Chair in Allergy and Clinical Immunology at the University of Southampton, researcher at the NIHR Southampton Biomedical Research Centre, and Director of The David Hide Asthma and Allergy Research Centre, Isle of Wight says: “We have to think of severe asthma as having different subtypes, and the treatment has to be tailored according to these subtypes because one size does not fit all.”
The researchers now want to use sequencing tools and other techniques to discover additional biomarkers and asthma patient subtypes.
A new study from Aarhus University has shown that young people with mild asthma can experience inflammation and irritation from candles as well as cooking fumes. The results, published in Particle and Fibre Toxicology, suggest that asthma sufferers should try and reduce exposure, for example by opening kitchen windows while cooking.
For this randomised controlled double-blind exposure study, exposed 36 young asthmatics to three different exposures in the climate chambers at Aarhus University. They were exposed to emissions from cooking, emissions from burning candles and finally clean air. Each time, the participants were exposed for five hours under highly controlled conditions. Particles and gases were measured during exposures, and participants reported symptoms related to irritation and general well-being. Biomarkers in relation to airway and systemic inflammatory changes were assessed before exposure, immediately after exposure and again the next morning.
Karin Rosenkilde Laursen, a postdoc at the university’s Department of Public Health and co-author of the study, says:
“Our study shows that indoor air pollution caused by fumes from cooking and burning candles can lead to adverse health effects such as irritation and inflammation in young individuals with mild asthma. Among other things, we’ve found indications of DNA damage and signs of inflammation in the blood.”
When ovens are turned, pans put on the hob, or candles are lit, particulate matter and gases are produced, which can be inhaled. Previous studies have shown that these particles and gases can be detrimental to health. What sets this study apart is that the researchers have focused on the effects on young individuals with mild asthma, aged between 18 and 25, says Karin Rosenkilde Laursen:
“In the study, we observed that even very young individuals with mild asthma can experience discomfort and adverse effects if the room is not adequately ventilated during cooking or when burning candles. Young people are generally fitter and more resilient than older and middle-aged individuals. Therefore, it is concerning that we observed a significant impact from the particles on this particularly young age group.”
But not only people diagnosed with asthma need to keep an eye on the indoor climate, she says.
“Even though the study focused on young asthmatics, its findings are interesting and relevant for all of us. Winter is approaching, a time when we tend to light many candles and perhaps are less likely to open doors and windows while cooking. By prioritising a healthier indoor climate, even when we’re cosying up indoors, we may be able to help reduce the incidence of serious lung and cardiovascular diseases, as well as cancer.”
Karin Rosenkilde Laursen plans to follow up this study with another examining how emissions from cooking and candles affect healthy adults.
Several major childhood allergies may all stem from the gut microbiome gut, according to a new study published in Nature Communications. The research identifies gut microbiome features and early life influences that are associated with children developing any of four common allergies. The study, led by researchers at the University of British Columbia and BC Children’s Hospital, could lead to methods of predicting whether a child will develop allergies, and methods to prevent their development.
“We’re seeing more and more children and families seeking help at the emergency department due to allergies,” said Dr Stuart Turvey, paediatrics professor at UBC and co-senior author on the study, noting that as many as one in three children in Canada have allergies.
The study is one of the first to examine four distinct school-aged paediatric allergies at once: atopic dermatitis, asthma, food allergy and allergic rhinitis. While these allergic diseases each have unique symptoms, the Turvey lab was curious whether they might have a common origin linked to the infant gut microbiota composition.
“These are technically different diagnoses, each with their own list of symptoms, so most researchers tend to study them individually,” says Dr Charisse Petersen, co-senior author on the paper and postdoctoral fellow in the Turvey lab. “But when you look at what is going wrong at a cellular level, they actually have a lot in common.”
For the study, researchers examined clinical assessments from 1115 children who were tracked from birth to age five. Roughly half of the children (523) had no evidence of allergies at any time, while more than half (592) were diagnosed with one or more allergic disorders by an expert physician. The researchers evaluated the children’s microbiomes from stool samples collected at clinical visits at three months and one year of age.
The stool samples revealed a bacterial signature that was associated with the children developing any of the four allergies by five years of age. The bacterial signature is a hallmark of dysbiosis, or an imbalanced gut microbiota, that likely resulted in a compromised intestinal lining and an elevated inflammatory response within the gut.
“Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action,” says Courtney Hoskinson, a PhD candidate at UBC and first author on the paper. “We found a common breakdown in these mechanisms in babies prior to the development of allergies.”
Many factors can shape the infant gut microbiota, including diet, place and delivery method of birth and antibiotics exposure. The researchers examined how these types of influences affected the balance of gut microbiota and the development of allergies.
“There are a lot of potential insights from this robust analysis,” says Dr Turvey. “From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied.”
Now the researchers hope to leverage the findings to inform treatments that correct an imbalanced gut microbiota and could potentially prevent allergies from developing.
“Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime,” says Dr Turvey.
Infants that have a food allergy have an increased risk of asthma and reduced lung function later in childhood, according to a world first study published in the Lancet Child & Adolescent Health.
Food allergy affects 10% of babies and 5% of children and adolescents. The research, led by Murdoch Children’s Research Institute, found that early life food allergy was associated with an increased risk of both asthma and reduced lung growth at six years of age.
Murdoch Children’s Associate Professor Rachel Peters said this was the first study to examine the relationship between challenge-confirmed food allergy in infancy and asthma and poorer lung health later in childhood.
The Melbourne research involved 5276 infants from the HealthNuts study, who underwent skin prick testing to common food allergens, such as peanut and egg, and oral food challenges. At six years, children were followed up with further food allergy and lung function tests.
The study found by six years of age, 13.7% reported a diagnosis of asthma. Babies with a food allergy were almost four times more likely to develop asthma at six years of age, compared to children without a food allergy. The impact was greatest in children whose food allergy persisted to age six as opposed to those who had outgrown their allergy. Children with a food allergy were also more likely to have reduced lung function.
Associate Professor Peters said food allergy in infancy, whether it resolved or not, was linked to poorer respiratory outcomes in children.
“This association is concerning given reduced lung growth in childhood is associated with health problems in adulthood including respiratory and heart conditions,” she said.
“Lung development is related to a child’s height and weight and children with a food allergy can be shorter and lighter compared to their peers without an allergy. This could explain the link between food allergy and lung function. There are also similar immune responses involved in the development of both food allergy and asthma.
“The growth of infants with food allergy should be monitored. We encourage children who are avoiding foods because of their allergy to be under the care of a dietician so that nutrition can be catered for to ensure healthy growth.”
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. Credit: NIAID
One of the adaptive immune system’s most intriguing abilities of the is its memory: upon first contact with antigens, it takes around two weeks to respond, but responses afterwards are much faster, as if the cells ‘remembered’ the antigen. But how is this memory attained? In a recent publication in Science Immunology, a team of researchers examined epigenetic and the structure of DNA for possible clues.
In their research paper, first author Anne Onrust-van Schoonhoven and colleagues compared the response of immune cells that had never been in contact with an antigen (called naïve cells) with cells previously exposed to antigen (memory cells) and sort of knew it. They focused on the differences in the epigenetic control of the cellular machinery and the nuclear architecture of the cells, two mechanisms that could explain the quick activation pattern of memory cells.
While all the cells in an individual have the same genetic information, different cell types access to different parts of the DNA. The term ‘epigenetics’ encompasses the mechanisms that dynamically control this access. The results revealed a particular epigenetic signature in memory T helper (TH)2 cells, resulting in the rapid activation of a crucial set of genes compared to naïve cells. These genes were much more accessible to the cellular machinery, in particular to a family of transcription factors called AP-1. Like athletes before a race, these genes had essentially been ‘warming up’ ever since the cell’s first contact with the antigen.
However, this epigenetic signature was just the tip of the iceberg. It is known that the position of the DNA in the nucleus is not random and reflects the cell’s activation state. The researchers found that, indeed, the 3D distribution of DNA in the nucleus is different between naïve and memory immune cells. Key genes for the early immune response are grouped together and under the influence of the same regulatory regions, called enhancers. Keeping with the racing metaphor, the genes are not only warmed-up, but also gathered together at the starting line.
Although most of the research has focused on healthy cells, the scientific team wondered whether any of the mechanisms found could, when altered, explain actual diseases in which the immune system plays an important role. To address this question, they analysed immune cells from chronic asthma patients and found that the circuits identified as key for an early and strong immune response were overactivated.
The epigenetic control of the immune system is a blossoming field and discoveries like the ones by Dr Stik and colleagues are setting the stage for the next generation of epigenetic drugs and treatments, targeting autoimmune diseases and cancer.
A surprising fact is that bitter taste receptors are found not just in the mouth, but elsewhere including the airways. Activating those receptors dilates up lung passageways, making them a potential target for treating asthma or chronic obstructive pulmonary disease (COPD). Now, researchers report in the Journal of Medicinal Chemistry that they have designed a potent and selective compound that could lead the way to such therapies.
Among the 25 different types of bitter taste receptors, the TAS2R14 subtype is one of the most widely distributed in tissues outside the mouth. Scientists are uncertain about the structure of the receptor, and they haven’t identified the particular compound or “ligand” in the body that activates it. However, a few synthetic compounds, such as the nonsteroidal anti-inflammatory drug (NSAID) flufenamic acid, are known to bind to and activate TAS2R14s. But these compounds aren’t very potent, and they don’t have similar structural features. These difficulties make it challenging to create a better ligand. Nevertheless, Masha Niv, Peter Gmeiner and colleagues used flufenamic acid as a starting point to design and synthesise analogues with improved properties. Next, the team wanted to extend that work to develop a set of even better TAS2R14 ligands.
Building on these earlier findings, the researchers made several new variations. They tested these compounds in a cell-based assay that measures receptor activation. This approach revealed that replacing a phenyl ring with a 2-aminopyrimidine and substituting a tetrazole for a carboxylic acid group was a promising strategy. One of the new ligands was six times more potent than flufenamic acid, meaning less of the compound was needed to produce a similar response as the NSAID. This ligand was also highly selective for TAS2R14 compared to non-bitter taste receptors, which could potentially minimise side effects. The researchers speculate that new compounds will help shed light on the structure, mechanism and physiological function of bitter taste receptors and guide development of drug candidates to target them.
Despite being one of the most common non-communicable diseases globally and there being highly effective treatments for it, asthma is often not well controlled in many low-resource settings, according to a cross-sectional study recently published in the Lancet medical journal.
Closer to home, the Global Asthma Report from 2022 showed that there has been an increase in severe asthma symptoms among adolescents in Cape Town over the last few years. There is little data available for the rest of the country, which makes comparisons with other South African cities very tricky.
‘Disproportionate number of children have severe asthma’
Dr Ahmed Ismail Manjra, a paediatrician and allergologist at the Allergy and Asthma Centre in Durban, tells Spotlight that globally more children than adults have asthma. The centre is in the Life Westville Hospital and provides specialist services to adults and children with asthma or allergic disorders.
“Asthma is quite common in children. It is estimated [globally] that one in ten children have asthma, and in adults, the prevalence is less than in children,” he says. “But the problem is that in South Africa we see a disproportionate number of children with severe asthma. And what has been shown is that over the years the prevalence of asthma is rising, and the severity is rising.” (For more on what asthma is and how it is treated in South Africa’s public sector, see this Spotlight article from December 2022.)
Impact of undiagnosed uncontrolled asthma
The impact of undiagnosed or uncontrolled asthma on children is huge. First, according to Professor Refiloe Masekela, Paediatric Pulmonologist and the Head of Department of Paediatrics and Child Health at the University of KwaZulu-Natal, the symptoms are very noticeable, which can affect children socially. Secondly, a child with undiagnosed asthma will miss school because of their symptoms and be unable to participate in school activities like sport. They will also become less active because exercise may trigger symptoms, which have further effects on their health.
Another implication of uncontrolled asthma, according to Manjra, is poor sleep quality, which can impact a child’s academic performance.
“And in severe asthma without proper treatment, it can lead to recurrent admissions to hospital. This places a burden on the healthcare system, which can be easily prevented by proper management of asthma. And of course, in a small percentage of cases where the asthma is not well controlled, it can also lead to fatality,” he says.
Manjra urges parents to take their children to be checked for asthma if they have recurrent respiratory symptoms.
“The asthma treatment is extremely effective, very safe as well, [and] they have very few side effects. Parents should not be afraid to use asthma treatments to control their children’s asthma,” he says. “Although we don’t have a cure for asthma, we do have medicines that can control it and give better quality of life.”
Asthma trends in children: what the data says
Masekela explains that the data published in the Global Asthma Report is published by the Global Asthma Network (GAN), which consists of a network of centres across the world – including three in South Africa – that contribute data on asthma in their regions every few years.
This data collection effort started with the ISAAC one and ISAAC three studies (International Studies of Asthma and Allergens in Children). The GAN centre in Cape Town contributed data to ISAAC I in 1995 and for ISAAC III data was collected in Cape Town in 2002 and Polokwane in 2004-2005 where adolescents were also included.
According to Masekela, the latest study collecting data on asthma was the Global Asthma Network (GAN) Phase one study, to which the Cape Town centre contributed. Masekela says the data from the ISAAC studies – ISAAC 1 and ISAAC 3 as well as GAN is available in South Africa only for Cape Town.
This means that it is possible to compare trends in childhood asthma in Cape Town over a longer time period, and data from ISAAC 3 can be used to compare Polokwane and Cape Town. But there isn’t current data collected by the GAN to give a clear picture of childhood asthma in the other cities and provinces.
In the 2022 Global Asthma report changes among the prevalence of asthma symptoms – measured as a 12-month prevalence rate of wheezing among adolescents aged 13 to14 – showed that in ISAAC 1, 16% of the around 5 000 adolescents surveyed in Cape Town had symptoms, which increased to 20.3% of just over 5 000 surveys in ISAAC 3 and finally 21.7% of the just under 4 000 adolescents surveyed for the 2022 study.
Masekela says in Cape Town if we look at the period between ISAAC Phase 1 and phase three, there was an increase in the prevalence [of asthma in children], but from the ISAAC 3 to the GAN Phase 1, there has been a stabilisation in the asthma prevalence [among children. “So, it’s very high, it’s over 20%, but it’s stable so it hasn’t been increasing, which it was doing before.”
When comparing data from Polokwane and Cape Town in ISAAC 3, at the time of the study, more children and adolescents in Cape Town had severe asthma than in Polokwane. The prevalence of asthma in children and adolescents was also higher in Cape Town.
Situation is ‘interesting and worrying’
Masekela explains that in many low-and-middle-income countries, those living with asthma don’t have access to the right asthma medications, namely inhalers. What also happens is that when those individuals have access to asthma medications, they are only able to get the reliever inhaler, not the controller inhaler.
People living with asthma need two types of inhalers, a reliever inhaler which brings relief and opens up the chest during an asthma attack and a control medication which is used every day to reduce inflammation in the long run. In order to control asthma adequately, both inhalers need to be used and used correctly.
In South Africa, both types of inhalers are on the Essential Medicines List.
“The story of South Africa is interesting and worrying. We have in our essential medicine list inhalers [both relievers and controllers],” she says. “It should be available. It’s on the essential medicine list for the primary care level. So any person who has asthma in South Africa should have access to that first step of treatments.”
Yet the data from South Africa suggests there is a problem. When looking at the symptoms of asthma among schoolchildren from the GAN phase one study, Masekela says it is worrying because they found that many children in South Africa with asthma symptoms don’t have an asthma diagnosis and of those that do have the diagnosis most only have the reliever inhaler and very few are using both the reliever and the controller inhaler.
“We know that asthma is under-diagnosed and actually the data from Cape Town, as well as Durban, is very similar. You see that 50% of adolescents have severe symptoms, half of them have never got the label – they’ve never been diagnosed as having asthma,” she says.
Under-diagnosed
A possible reason for the under-diagnosis, according to Masekela, is that when a child presents to a clinic with wheezing, the child is treated for something else that might be causing the symptoms and sent home. Then when the child goes back a few weeks or months later with the same symptoms, they are seen by a different doctor or nurse and there isn’t continuity, so the fact that the symptoms are recurrent isn’t picked up on.
Manjra tells Spotlight that asthma can sometimes be difficult to diagnose in small children because its symptoms – wheezing, shortness of breath, tight chest, and coughing – can be caused by a number of other diseases. Wheezing, in particular, can be caused by a number of conditions that can affect children.
“The most common being viral upper respiratory tract infection, particularly with RSV [respiratory syncytial virus] and rhinovirus. And sometimes in young children, it can be extremely difficult to make a correct diagnosis of asthma because there’s overlap between viral-induced wheezing and asthma,” he says.
“However, if the child has an underlying – what we call atopic predisposition – that means if the child has eczema or has allergic rhinitis or food allergy or has [an] inhalant allergy, then the possibility of that child having asthma is very high,” he says.
Other childhood conditions that can cause wheezing in children are TB and inhaling foreign bodies into the lungs.
“So, the diagnosis of asthma in young children is basically made by an exclusion of other causes of wheezing,” he says. “Asthma diagnosis is made over a period of time because, as I’ve mentioned, it’s recurrent wheezing.”
Another problem, according to Masekela, is that those people who do receive a diagnosis of asthma are often not getting the right treatment.
“People who have a label at least should have access to the treatments, but we do see that even in those that have the diagnosis, a lot of them are not using their medicine because they’re getting repeated attacks, they have severe symptoms,” she says. “So, something is not right. Either they are not getting the label, we know that’s happening, or they’re not getting the right treatment.”
This is a bi-directional problem, Masekela says, in that either healthcare workers are not adequately teaching patients how to use both inhalers or patients are relying on the reliever medications despite being taught how to use both.
Manjra says that while inhalers are on the EML, this doesn’t necessarily translate to healthcare facilities having stock. Meaning that there can be stock-out of the medication, but also of the spacers that children need to use with the inhalers.
According to Manjra, children are unable to use inhalers properly with spacers, because the inhaler releases the plume of medication too quickly for the child to be able to breathe it into their lungs. The spacer allows the medication to go into a holding chamber where the child is able to breathe the medication into their lungs in a controlled way, through a special valve.
Better education needed
The solution to the problems of the under-diagnosis of asthma and incorrect inhaler use is better education on all fronts, says Masekela. There needs to be better training among healthcare workers on how to recognise asthma, how to manage it and how to teach patients how to manage it properly.
“We know that there is a system problem about them [children] getting the correct medication, using the correct medication and that all boils down to education of the patient, education of the health workers. And really, overall education in the community about how to handle asthma,” she says.
She adds that patients and the wider community also need to be educated on what asthma is and how to manage it properly and destigmatise it. A good starting place is in schools so that children who are living with asthma and their peers are able to better understand the condition and be more accepting of the use of inhalers.
“It’s important that we then find strategies to get people to understand the need for using these medicines, even when they’re feeling well,” she says.
Sleep deprivation is bad for memorisation, something which still doesn’t deter many med students from late night cramming. Researchers however have discovered that memories learned during sleep deprivation is not necessarily lost, it is just difficult to recall. Publishing in the journal Current Biology, the researchers have found a way to make this ‘hidden knowledge’ accessible again days after studying whilst sleep-deprived using optogenetic approaches and the asthma drug roflumilast.
University of Groningen neuroscientist Robbert Havekes and his team have extensively studied how sleep deprivation affects memory processes. “We previously focused on finding ways to support memory processes during a sleep deprivation episode,” says Havekes. However, in his latest study, his team examined whether amnesia as a result of sleep deprivation was a direct result of information loss, or merely caused by difficulties retrieving information. “Sleep deprivation undermines memory processes, but every student knows that an answer that eluded them during the exam might pop up hours afterwards. In that case, the information was, in fact, stored in the brain, but just difficult to retrieve.”
Priming the hippocampus
To find out, the researchers selectively introduced optogenetic proteins into neurons that are activated during a learning experience, enabling recall of a specific experience by shining a light on the cells. “In our sleep deprivation studies, we applied this approach to neurons in the hippocampus, the area in the brain where spatial information and factual knowledge are stored,” says Havekes.
First, the genetically engineered mice were given a spatial learning task in which they had to learn the location of individual objects, a process heavily reliant on neurons in the hippocampus. The mice then had to perform this same task days later, but this time with one object moved to a new location. The mice that were deprived of sleep for a few hours before the first session failed to detect this spatial change, which suggests that they cannot recall the original object locations. “However, when we reintroduced them to the task after reactivating the hippocampal neurons that initially stored this information with light, they did successfully remember the original locations,” says Havekes. “This shows that the information was stored in the hippocampus during sleep deprivation, but couldn’t be retrieved without the stimulation.”
Memory problems
The molecular pathway set off during the reactivation is also targeted by the drug roflumilast, which is used by patients with asthma or COPD. Havekes says: “When we gave mice that were trained while being sleep deprived roflumilast just before the second test, they remembered, exactly as happened with the direct stimulation of the neurons.” Since roflumilast is approved for use in humans and can enter the brain, this may lead to testing to see if it can recover ‘lost’ memories for humans..
It might be possible to stimulate the memory accessibility in people with age-induced memory problems or early-stage Alzheimer’s disease with roflumilast,” says Havekes. “And maybe we could reactivate specific memories to make them permanently retrievable again, as we successfully did in mice.” If a subject’s neurons are stimulated with the drug while they try and ‘relive’ a memory, or revise information for an exam, this information might be reconsolidated more firmly in the brain. “For now, this is all speculation of course, but time will tell.”
Blocking calcium signalling in immune cells suppresses allergic asthma, but without compromising the immune defence against flu viruses, according to the findings of a new study published in Science Advances.
The researchers showed that, in a mouse model, removing the gene for a certain calcium channel reduced asthmatic lung inflammation caused by house dust mite faeces, a common cause of allergic asthma. Blocking signals sent through this channel, the calcium release-activated calcium (CRAC) channel, with an investigational inhibitor drug had a similar effect.
The study revolved human cells’ use of signalling and switch-flipping ions, mainly calcium. When triggered by viral proteins or allergens, T cells open channels in their outer membranes, allowing calcium in to activate signalling pathways that control cell division and secretion of cytokine molecules.
Past work had found that CRAC channels in T cells regulate their ability to multiply into armies of cells designed to fight infections caused by viruses and other pathogens.
The new study showed that the CRAC channel inhibitor reduced allergic asthma and mucus build-up in mice without undermining their immune system’s ability to fight influenza, a main worry of researchers seeking to tailor immune-suppressing drugs for several applications.
“Our study provides evidence that a new class of drugs that target CRAC channels can be used safely to counter allergic asthma without creating vulnerability to infections,” said senior study author Stefan Feske, MD, a professor at NYU Langone Health. “Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure.”
Allergic asthma, which is the most common form of the disease, is characterised by increased type 2 (T2) inflammation, which involves T helper (Th) 2 cells, the study authors noted. Th2 cells produce cytokines that play important roles in both normal immune defences, and in disease-causing inflammation that occurs in the wrong place and amount. In allergic asthma, cytokines promote the production of IgE antibodies and the recruitment to the lungs of inflammation-causing immune cells called eosinophils, the hallmarks of the disease.
In the new study, the research team found that deletion of the ORAI1 protein in T cells, which makes up the CRAC channel, or treating mice with the CRAC channel inhibitor CM4620, thoroughly suppressed Th2-driven airway inflammation in response to house dust mite allergens.
Treatment with CM4620 significantly reduced airway inflammation when compared to an inactive control substance, with the treated mice also showing much lower levels of Th2 cytokines and related gene expression. Without calcium entering through CRAC channels, T cells are unable to become Th2 cells and produce the cytokines that cause allergic asthma, the authors say.
Conversely, ORAI1 gene deletion, or interfering with CRAC channel function in T cells via the study drug, did not hinder T cell-driven antiviral immunity, as lung inflammation and immune responses were similar in mice with and without ORAI1.
“Our work demonstrates that Th2 cell-mediated airway inflammation is more dependent on CRAC channels than T cell-mediated antiviral immunity in the lung,” said study co-first author Yin-Hu Wang, PhD. “This suggests CRAC channel inhibition as a promising, potential future treatment approach for allergic airway disease.”
