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Innate lymphoid cells are a recently discovered family of white blood cells that reside in the skin, gastrointestinal tract, airways and other barrier tissues of the body. Group 2 innate lymphoid cells (ILC2s) have an essential role in protecting these tissues from parasitic infections as well as damage associated with allergic inflammation and asthma, according to a new study led by Weill Cornell Medicine researchers.
The finding resolves a controversy about the possible redundancy of ILC2s with other cells in the body. The study also suggests that a unique set of regulatory networks controlled by neurons in the gut may be viable targets for future drug therapies to combat chronic inflammatory diseases including asthma, allergy and inflammatory bowel disease (IBD).
The study, published Nov. 2 in Nature, shows that although ILC2s have many functional similarities to immune cells called T helper type 2 cells (Th2 cells), the latter cell type cannot adequately compensate for loss of the protective response of ILC2s against parasitic worm infection in the gut as well as gut inflammation. Underscoring the clinical relevance of the study, the researchers found evidence that ILC2s in humans respond in a manner similar to mouse ILC2s.
“This advances our understanding of the complexity of the immune system, and gives us a potential new set of targets for future therapies,” said study senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine.
ILC2s are part of a family of cells, innate lymphoid cells, that were discovered by multiple groups only about 12 years ago. With their strong presence in barrier tissues, innate lymphoid cells are generally considered to serve as sentinels and first responders against various types of infection. But scientists also recognize that ILCs may hold the keys to understanding common inflammatory and autoimmune conditions such as asthma and IBD.
It is thought that both ILC2s and Th2 cells evolved at least in part to defend the body from parasitic worm infections, biting insects and other environmental triggers. When triggered by such challenges, both help marshal what is called a type 2 immune response. These similarities have led researchers to suggest that they are functionally almost the same but ILC2s specialize in earlier, more localized responses, whereas T cells are more blood-borne and mobile, concentrating in multiple tissues where needed. However, in the new study, the researchers found that ILC2s have an essential immune role rather than being redundant as type 2 immune responders.
When ILC2s and Th2 cells are activated by a worm infection, they both produce an anti-worm, tissue-protecting protein called amphiregulin (AREG). To determine if Th2 cells can compensate for loss of this protein from ILC2s, the researchers engineered mice in which AREG production is selectively deleted in ILC2s, but not in Th2 cells. They found that these mice were more susceptible to parasitic worm infection in the gut due to reduced capacity to mount an anti-parasitic immune response, compared with mice with normal ILC2s. The mice lacking ILC2 AREG were also much more susceptible to gut damage from inflammation.
“This finding clarifies that ILC2s are playing the major role in this tissue protective response — without them the response is inadequate,” said study co-first author Dr. Hiroshi Yano, a postdoctoral research associate in the Artis laboratory.
Clarifying the functional importance of a major immune cell type is a significant achievement in basic immunology and the results of the study also suggest clinical applications. The researchers showed that the ILC2 immune response, either to worm infection or inflammatory gut damage, is selectively controlled by a signaling molecule produced by neurons in the gut. Giving the molecule to mice with experimental gut inflammation boosted AREG production in ILC2s and protected the animals from gut damage. Preliminary experiments with gut ILC2s taken from patients with inflammatory bowel disease showed that the molecule could boost the protective response in the human cells as well. These findings suggest that neurons in the gut communicate with ILC2s to generate a protective response that cannot be replaced by other immune cells, thus offering new therapeutic opportunities, Dr. Artis said.
This work was supported in part by the National Institutes of Health (DK126871, AI151599, AI095466, AI095608, AI142213, AR070116, AI172027, DK132244), a WCM Department of Pediatrics Junior Faculty Pilot Award, the Jill Roberts Center Pilot Award for Research in IBD, a Thomas C. King Pulmonary Fellowship, the LEO foundation, Cure for IBD, Jill Roberts Institute, the Sanders Family, and the Rosanne H. Silbermann Foundation.

A type of dietary fiber called inulin, commonly used in health supplements and known to have certain anti-inflammatory properties, can also promote an allergy-related type of inflammation in the lung and gut, and other parts of the body, according to a preclinical study from researchers in the Friedman Center for Nutrition and Inflammation and Jill Roberts Institute for Inflammatory Bowel Disease at Weill Cornell Medicine and in the Boyce Thompson Institute on Cornell’s Ithaca campus.
The study, published Nov. 2 in Nature, found that dietary inulin fiber alters the metabolism of certain gut bacteria, which in turn triggers what scientists call type 2 inflammation in the gut and lungs. This type of inflammation is thought to have evolved in mammals chiefly to defend against parasitic worm (“helminth”) infections, and is also part of normal wound-healing, although its inappropriate activation underlies allergies, asthma and other inflammatory diseases.
“There’s a lot to think about here, but, in general, these findings broaden our understanding of the relationship between diet, immunity, and the normally beneficial microorganisms that constitute our microbiota and colonize our bodies,” said study co-senior author Dr. David Artis, director of the Friedman Center for Nutrition and Inflammation and the Michael Kors Professor of Immunology at Weill Cornell Medicine.
The study’s scientific participants reflect the Friedman Center’s highly cross-collaborative research mission, drawing on expertise in bacterial genetics, biochemistry and immunology at Weill Cornell Medicine in New York City and Cornell’s Ithaca campus. Dr. Chun-Jun Guo, assistant professor of immunology in medicine at Weill Cornell Medicine, and Dr. Frank Schroeder, professor at the Boyce Thompson Institute and in the Department of Chemistry and Chemical Biology in the College of Arts and Sciences on Cornell’s Ithaca campus teamed up with the Artis laboratory to gain a detailed understanding of how an important dietary component affects the microbiome and the immune response. The study’s first author is Dr. Mohammad Arifuzzaman, a postdoctoral researcher in the Artis laboratory.Dr. Artis is also director of the Jill Roberts Institute for Inflammatory Bowel Disease at Weill Cornell Medicine.
Small amounts of inulin are present in a wide variety of fruits and vegetables, including bananas, asparagus, and garlic. It is also frequently concentrated in commonly available high-fiber dietary supplements. Previous studies have found that inulin boosts populations of beneficial gut bacterial species which in turn boost levels of anti-inflammatory immune cells called regulatory T (Treg) cells.
In this new study, the researchers examined inulin’s effects more comprehensively. They gave mice an inulin-based, high-fiber diet for two weeks, and then analyzed the many differences between these mice and mice that had been fed a diet lacking inulin. A major difference was that the inulin diet, while increasing Treg cells, also induced markedly higher levels of white blood cells called eosinophils in the gut and lungs. A high level of eosinophils is a classic sign of type 2 inflammation and is typically seen in the setting of seasonal allergies and asthma.

People in their 20s and 30s who drink moderate to heavy amounts of alcohol may be more likely to have a stroke as young adults than people who drink low amounts or no alcohol, according to a study published in the November 2, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The risk of stroke increased the more years people reported moderate or heavy drinking.
“The rate of stroke among young adults has been increasing over the last few decades, and stroke in young adults causes death and serious disability,” said study author Eue-Keun Choi, MD, PhD, of Seoul National University in the Republic of Korea. “If we could prevent stroke in young adults by reducing alcohol consumption, that could potentially have a substantial impact on the health of individuals and the overall burden of stroke on society.”
The study looked at records from a Korean national health database for people in their 20s and 30s who had four annual health exams. They were asked about alcohol consumption each year. They were followed for an average of six years.
They were asked the number of days per week they drank alcohol and the number of standard drinks per time. People who drank 105 grams or more per week were considered moderate or heavy drinkers. This is equal to 15 ounces per day, or slightly more than one drink per day. A standard drink in the United States contains about 14 grams of alcohol, which is equivalent to 12 ounces of beer, five ounces of wine or 1.5 ounces of liquor.
More than 1.5 million people were included in the study. A total of 3,153 had a stroke during the study.
People who were moderate to heavy drinkers for two or more years of the study were about 20% more likely to have a stroke than people who were light drinkers or did not drink alcohol. Light drinkers were those who drank less than 105 grams per week, or less than 15 ounces per day.
As the number of years of moderate to heavy drinking increased, so did the risk of stroke. People with two years of moderate to heavy drinking had a 19% increased risk, people with three years had a 22% increased risk and people with four years had a 23% increased risk. These results were after researchers accounted for other factors that could affect the risk of stroke, such as high blood pressure, smoking and body mass index.
The association was mainly due to an increased risk of hemorrhagic stroke, or stroke caused by bleeding in the brain.
For any type of stroke, people with four years of moderate to heavy drinking had a stroke rate of 0.51 per 1,000 person-years, compared to 0.48 for three years of drinking, 0.43 for two years, 0.37 for one year and 0.31 for none. Person-years represent both the number of people in the study and the amount of time each person spends in the study.
“Since more than 90% of the burden of stroke overall can be attributed to potentially modifiable risk factors, including alcohol consumption, and since stroke in young adults severely impacts both the individual and society by limiting their activities during their most productive years, reducing alcohol consumption should be emphasized in young adults with heavy drinking habits as part of any strategy to prevent stroke,” Choi said.
A limitation of the study was that only Korean people were included, so the results may not apply to people of other races and ethnicities. In addition, people filled out questionnaires about their alcohol consumption, so they may not have remembered correctly.
The study was supported by the Korea Medical Device Development Fund and the Korea National Research Foundation.
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People who suffer from chronic pain at age 44 are more like to report pain, poor general health, poor mental health outcomes and joblessness in their 50s and 60s, according to a new study published this week in the open-access journal PLOS ONE by David Blanchflower of Dartmouth College, US, and Alex Bryson of University College London, UK.
Chronic pain — pain lasting at least three months — is a serious problem affecting a large number of people: according to the National Academies of Science, Engineering and Medicine, more than 100 million Americans suffer from chronic pain.
In the new work, the researchers studied people enrolled in the National Child Development Survey, a study following all those born in one week in March 1958 in England, Scotland and Wales. The main pain data used were from the Bio-Medical Survey conducted in 2003, when most of the 12,037 respondents were age 44. Additional health data was collected in 2008, 2013 and 2021.
Overall, two-fifths of those in their 40s reported suffering chronic pain. The study pinpointed multiple factors predicting pain at this age, including a person’s father’s social class at birth as well as pain in childhood. Both short-term and chronic pain at age 44 were associated with pain and poor health in later decades of life, with associations strongest for chronic pain. Among those reporting chronic pain at age 44, for example, 84% still reported “very severe” pain at age 50. Chronic pain, but not short-term pain, was also associated with poor mental health outcomes, lower life satisfaction, pessimism about the future, poor sleep and joblessness at age 55. Additionally, the researchers found that pain at age 44 predicts whether a respondent had been infected with COVID-19 in the 2021 survey, at age 62, suggesting that pain is associated with broader health vulnerabilities.
The authors conclude that chronic pain shows persistence across the life-course and is, in part, passed between generations.
The authors add: “Tracking a birth cohort across their life-course we find chronic pain is highly persistent. It is associated with poor mental health outcomes later in life including depression, as well as leading to poorer general health and joblessness. We hope the study highlights the need for academics and policy makers to focus more attention on the problems of chronic pain.”
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A new model for understanding which patients with sepsis, Covid-19 and influenza have immune dysfunction and are more likely to suffer poor outcomes has been developed by researchers at the Wellcome Sanger Institute, the University of Oxford, Queen Mary University, Imperial College and their collaborators.
The study, published 2 November 2022 in Science Translational Medicine, identified 19 genes that predict the way that the body’s immune system responds to sepsis, Covid-19 and influenza infection, and how immune response can go wrong in some individuals. The small number of genes used in the model paves the way for applying precision medicine techniques, such as prioritising individuals for particular interventions, to diseases like sepsis that have proven difficult to diagnose and treat.
Sepsis is caused by an ‘inappropriate’ immune response to infection or injury, which can spread to the whole body. For reasons unknown, in sepsis immune response becomes overactive or underactive and causes damage to healthy cells, rather than just the source of infection. It is difficult to predict who will get sepsis, who will recover and who will have poor outcomes such as post-sepsis syndrome (PSS) and death. Globally, it is estimated that there are around 49 million sepsis cases and 11 million deaths each year.
Despite hundreds of clinical trials aimed at improving sepsis outcomes, there are currently no targeted treatments. Because sepsis can arise from myriad causes it is a highly variable disease, and positive results from some drug trials have not been reproducible in others.
It is thought that a stronger understanding of sepsis at the molecular level, so that patients can be classified according to the particular characteristics of their illness, is the key to greater success in identifying those at risk and developing effective treatments.
In this new study, researchers at the Wellcome Sanger Institute and the University of Oxford set out to develop a gene expression model for understanding which patients with sepsis are more likely to have particular responses and potentially poor outcomes.

A new preclinical study from researchers at The University of Texas MD Anderson Cancer Center and the University of California San Francisco (UCSF) has discovered the underlying cause of gender differences in immunotherapy-associated myocarditis after immune checkpoint inhibitor (ICI) treatment. Their findings point to possible treatment strategies for this side effect, which disproportionately affects female patients.
The study, published today in Science Translational Medicine, demonstrates how life-saving ICI treatment reduces levels of estrogen and important heart-protective proteins, sometimes leading to cardiovascular complications. The results suggest several treatment approaches, including hormone therapies, that could target this endocrine-cardiac-immune pathway without affecting treatment responses.
“Immune checkpoint inhibitors can be life-saving for many patients, but increasing the dose or combining with other therapies also increases the risk for myocarditis, particularly in women,” said co-corresponding author Liuqing Yang, Ph.D., associate professor of Molecular and Cellular Oncology. “With this study, we now understand the mechanisms behind this, and we’ve found several potential ways to reduce this risk without compromising the antitumor effects of treatment.”
Immune checkpoint inhibitors result in durable anti-tumor responses in many patients, but they are associated with an increased risk of cardiovascular toxicities caused by immune cells that infiltrate heart tissue. While this occurs in only about 1% of patients, these side effects can significantly increase the mortality rate in women.
To better understand the mechanisms behind these gender differences, Yang worked with co-corresponding authors Chunru Lin, M.D., Ph.D., associate professor of Molecular and Cellular Oncology at MD Anderson, and Javid Moslehi, M.D., associate professor of Cardio-Oncology and Immunology for the UCSF Heart and Vascular Center.
Checkpoint blockade reduces expression of heart-protective genes, particularly in females
MD Anderson researchers collaborated with Moslehi and his team at UCSF to develop laboratory models of melanoma, breast and colorectal cancer to study ICI-associated myocarditis. Treatment with commonly used ICIs (anti-PD-1 and anti-CTLA-4 antibodies) inhibited tumor growth but also increased immune cell infiltration, particularly in female hearts, causing electrocardiographic abnormalities and systolic dysfunction associated with myocarditis.

Inflammation and increased mucus production are typical symptoms of worm infections and allergies. This immune response involves our innate immune cells, but their exact functions are not yet fully understood. A research team from Charité — Universitätsmedizin Berlin has now shed light on the key tasks that these cells perform. In the study, which has been published in the journal Nature*, the researchers also identify potential therapeutic approaches for the treatment of allergies.
The human immune system is made up of two interconnected branches: the adaptive immune system, which learns something new with every infection and constantly develops over the course of a lifetime, and the innate immune system, which is less specialized but reacts particularly quickly and effectively. The cells of the innate immune system are located in the mucous membranes of the respiratory tract and the intestine, where they form a first line of defense at the point of entry for pathogens. These cells include group 2 innate lymphoid cells (ILC2s for short), which are active in the intestine in the case of parasitic diseases, and in the respiratory tract in the case of allergies.
“Innate lymphoid cells were discovered a decade or so ago and we already know a lot about them, but their exact function in the machinery of the immune system is not yet completely understood,” explains Dr. Christoph Klose, who heads the Emmy Noether Independent Junior Research Group on the regulation of type 2 immune responses by neuropeptides and neurotransmitters at the Institute of Microbiology, Infectious Diseases and Immunology at Charité. “There is a group of adaptive immune cells — namely the T cells — that carry out some similar functions as part of the type 2 immune response, so it was previously thought that the role of ILC2s may be redundant and could be easily taken over by the T cells.”
However, the recently published study has now disproved this theory. Using an animal model and state-of-the-art molecular methods such as single-cell sequencing, which allows scientists to zoom into individual cells and analyze their molecular state, they have shed light on the central functions of ILC2s. “A certain type of immune cells called eosinophils were not able to develop properly when ILC2s were absent,” explains Dr. Klose. “This relationship was previously unknown and came as a big surprise.” Eosinophils are involved in inflammatory processes in the tissue. The scientists also found that ILC2s have a major effect on the ability of epithelial cells to promote mucus production and expel parasites, such as worms, from the body. “The absence of ILC2s was clearly noticeable in our tests examining the immune response to worm infections. There was only limited mucus production in the tissue and the parasites could no longer be combated effectively,” says Dr. Klose, summarizing the results of the study.
In further experiments, the researchers examined the symptoms of allergic asthma and found that these improved when ILC2s were absent. “This could be a starting point for future studies aimed at developing potential allergy therapies,” says Dr. Klose. “With our study, we were able to show that group 2 innate lymphoid cells are essential cogs in the machinery of the immune system and cannot be replaced without compromising the immune response.” In future research projects, Dr. Klose and his team would like to investigate whether the innate lymphoid cells regulate other aspects of the immune response.
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Investigators from Cedars-Sinai Cancer have identified an investigational therapeutic approach that could be effective against treatment-resistant prostate cancer. Results of their Phase II clinical trial, published in the peer-reviewed journal Molecular Therapy, have led to a larger, multicenter trial that will soon be underway.
Cancer of the prostate, a small gland just below the bladder, is the second-leading cause of cancer-related death in men. Many prostate tumors are not aggressive and may require no or minimal treatment. Aggressive tumors are initially treated with surgery or radiation therapy.
In about one-third of patients, the cancer comes back after initial treatment, said Neil Bhowmick, PhD, research scientist at Cedars-Sinai Cancer, professor of Medicine and Biomedical Sciences and senior author of the study. Those patients are usually treated with medications that suppress the actions of testosterone and other androgens — male hormones that help prostate tumors grow.
“Patients do really well until the tumor figures a way around the androgen-suppressing therapy,” Bhowmick said. “One way that it can do this is to cause cells to make only part of the protein that the drug binds to, rendering the drug useless. The partial proteins are called splice variants.”
Through research with human cells and laboratory mice, study first author Bethany Smith, PhD, a project scientist in the Bhowmick Lab, figured out that the cancer cells were signaling to the surrounding supportive cells through a protein called CD105 to make these slice variant proteins. Investigators then conducted a trial in human patients to test a drug that they hoped would keep those partial proteins from forming by inhibiting CD105.
In the trial, nine patients whose tumors were resistant to androgen-blocking therapy continued that therapy but were also given a CD105 inhibitor called carotuximab. Forty percent of those patients experienced progression-free survival, based on radiographic imaging.
“Every single one of the patients in our trial was totally resistant to at least one androgen suppressor, and the normal course of action would be to simply try a different one or chemotherapy, which research has shown generally doesn’t stop tumor growth for more than about three months,” Bhowmick said. “Carotuximab prevented the cancer’s workaround and made the tumor sensitive to androgen-suppressing therapy.”
Importantly, Bhowmick said, carotuximab also appears to prevent androgen receptor splice variants in the supporting cells surrounding tumors, further sensitizing the tumor to the androgen suppressor.
“We found that this therapy may be able to, especially in early cancers, resensitize select patients to androgen suppression. This could allow patients to avoid or delay more toxic interventions such as cytotoxic chemotherapy,” said Edwin Posadas, MD, co-director of the Experimental Therapeutics Program, medical director of the Urologic Oncology Program/Center for Uro-Oncology Research Excellence (CURE), associate professor of Medicine at Cedars-Sinai and a co-author of the study. “We also hope to find ways of predicting which patients are most likely to benefit from this approach by testing blood and tissue samples using next-generation technologies housed at Cedars-Sinai Cancer.”
Study co-author Sungyong You, PhD, director of the Urologic Oncology Bioinformatics Group, pinpointed three biomarkers that could help indicate which patients will respond to this investigational therapy, and the team will validate those markers in a new clinical trial. This will allow future studies to target patients most likely to be helped by this intervention, Bhowmick said.
Funding: The study was supported by Department of Defense grant number W81XWH-17-1-0154 and Veterans Administration grant number I01BX001040.
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The human body is made up of more than a billion cells that join to form the tissues and organs of our bodies. However, cells are dynamic structures that, using different techniques, move through the body to fulfil various functions, such as close wounds or carry nutrients to other tissues.
Understanding how cancer cells move and make decisions in these confined environments is important as 90% of cancer-related deaths involve metastases.
The labs of Dr. Konstantinos Konstantopoulos of Johns Hopkins University and of Dr. Miguel A. Valverde of UPF, together with teams from the USA and Canada have been working together over the past six years to unravel how cancer cells use ion movement through mechanically activated ion channels -stimuli that deform cell membranes- to adapt their movement to different mechanical stresses and environments. The results of this research have been published in two studies in the journals Nature and Nature Communications.
In these two new studies, the scientists asked themselves:
1) how cancer cells polarize ion transport mechanisms in the leading edge and trailing edge of the cells to move through narrow spaces; and
2) how cancer cells optimize movement when fluid viscosity is high.

Scientists have used a mathematical model to reveal how toxic proteins cluster together inside the brain during the early stages of Alzheimer’s.
The researchers, from the University of York’s School of Physics, Engineering and Technology, say the discovery could have important implications for future treatments.
The study revealed that a major class of proteins implicated in Alzheimer’s disease — so called amyloids — condense into objects that resemble liquid droplets, before forming clusters that impact normal brain activity.
Alzheimer’s disease is the most common form of dementia. Over 50 million people worldwide have the disease, and that number is expected to triple by 2050.
On the nanoscale, toxic amyloid proteins inside the brain cluster together around 10-15 years before the first symptoms arise, but the precise way in which they do so has remained unclear. By understanding precisely how the protein clusters form, scientists may be in a far better position to develop targeted drug treatments to block them.
Dr Steve Quinn, an Alzheimer’s Research UK Fellow and Lecturer in Biophysics at the University of York, said: “Understanding the precise molecular-level ways through which amyloid clusters form may help us to design better anti-cluster drugs that combat Alzheimer’s disease at the earliest possible stage.