Category Archives: Immunology

Immunology

Rimjhim Agarwal selected as Major Symposium speaker at the American Association of Immunologists … – La Jolla Institute for Immunology

Rimjhim Agarwal, a UC San Diego Graduate Student and member of LJIs Weiskopf Lab (Image credit: La Jolla Institute for Immunology)

LA JOLLA, CALa Jolla Institute for Immunology (LJI) is pleased to announce the selection of Rimjhim Agarwal, 2024 Tullie and Rickey Families SPARK Awards for Innovations in Immunology (SPARK) winner, as a Major Symposium speaker for the American Association of Immunologists (AAI) IMMUNOLOGY2024 meeting. Agarwal joins 15 additional AAI trainee membersgraduate students and postdoctoral fellowswho were selected from 1,500 abstract submissions.

Agarwal, a UC San Diego Graduate Student and member of LJIs Weiskopf Lab, will present her research on how chikungunya-virus-specific CD4+ T cells are associated with chronic chikungunya viral arthritic disease in humans. Chikungunya virus disease is transmitted by mosquitoes in tropical regions of Africa, Asia, and the Americas. The disease can be fatal, and many survivors are left with chronic, debilitating joint problems.

Almost 25 percent of infected individuals, predominantly women, develop chronic, arthritis-like symptoms, such as joint pain and swelling, said Agarwal in a recent LJI video interview. We dont know the cause of these symptoms, and we dont know why this happens primarily in women.

Agarwal recently won funding from The Rosemary Kraemer Raitt Foundation Trust through LJIs Tullie and Rickey Families SPARK Awards for Innovations in Immunology program to investigate these puzzling symptoms.

Rimjhim Agarwal on what we can learn from studying chikungunya virusand how her research may advance global health. (Filmed by LJI Creative Producer Matthew Ellenbogen)

This year marks the first time AAI has featured trainees in its annual conference Major Symposia. Agarwals talk will be part of the Immune Responses to Chronic Viral, Bacterial, Fungal, and Parasitic Infections Major Symposium, held on May 6. Agarwal will be joined by five faculty-level speakers and one other trainee-level speaker. She will also share her chikungunya virus research in a Poster Session.

AAIs annual meeting features the latest research from some of the brightest minds in the field of immunology, said Loretta Doan, CEO of The American Association of Immunologists. AAI trainee members are making exciting discoveries every day, and we are thrilled to offer this high-profile honor for some of them to share their work with the community.

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The La Jolla Institute for Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. Visit lji.org for more information.

The American Association of Immunologists (AAI) is one of the worlds largest organizations of immunologists and scientists in related disciplines. Our mission is to improve global health and well-being by advancing immunology and elevating public understanding about the immune system. AAI members are responsible for some of the most significant biomedical discoveries of the past century, including the development of life-saving cancer immunotherapies, monoclonal antibodies, transplant technologies, and vaccines. We support scientists across the field of immunology through knowledge dissemination, community building, advocacy, and public outreach.

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Rimjhim Agarwal selected as Major Symposium speaker at the American Association of Immunologists ... - La Jolla Institute for Immunology

Immunology

Seeking new horizons: Where innovators find opportunities in a fast-changing immunology landscape – IQVIA

Unmet need is high in a long list of largely neglected immunological diseases, such as systemic lupus erythematosus, hidradenitis suppurativa, alopecia areata, Sjgren's syndrome, vitiligo, bullous pemphigoid or prurigo nodularis. Their prevalence spans a range from rare diseases with fewer than 200 thousand patients in the US, for example, to relatively more common conditions with a million or more patients, a subset of whom are severe cases most in need of innovative therapies. What they share is having been underserved, with typically limited disease-specific treatment options available to date, leaving many patients with poorly controlled disease. This represents an attractive opportunity for innovators to set an effective, new standard of care.

However, the natural history of these diseases is often less well understood and has led to several setbacks, e.g., in lupus. Nevertheless, innovators are clearly not disheartened, judging by recent pipeline momentum. For example, hidradenitis suppurativa has seen a major inflection point in development activity after many years of an innovation drought and was a key focus at the recent annual meeting of the American Academy of Dermatology (AAD), with several high-profile presentations of mid- to late-stage readouts, including AbbVies IL-1/1 antagonist lutikizumab, Novartis oral BTK inhibitor remibrutinib, and Moonlakes anti-IL-17 nanobody solenokimab.

The overall change in innovation intensity that we are witnessing across underserved immunology diseases is reminiscent of the momentum that transformed todays major autoimmune indications about 10-15 years ago. However, without such epidemiological scale, innovators today must play across multiple of those smaller indications to achieve critical mass in an immunology franchise, e.g., via a portfolio of assets and/or multi-indication assets.

Finding success in less explored immunology indications requires a different approach. Unlike the major, well-established autoimmune conditions such as RA, psoriasis or Crohns disease, smaller indications face unique challenges, for example, often low disease awareness among patients and HCPs, a limited understanding of the burden of illness and its true impact on patients life, immature care pathways, including diagnosis, specialist referral and treatment, leading to under-diagnosis and under-treatment, or convincing payers of the need to treat and for them to cover novel therapies.

Innovators targeting smaller, oft neglected immunology indications therefore must focus on three priorities:

As innovators re-direct their efforts towards historically underserved immunological diseases, long-suffering patients will be the ultimate winners, as the prospect of effective treatment options makes big strides towards becoming reality.

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Seeking new horizons: Where innovators find opportunities in a fast-changing immunology landscape - IQVIA

Immunology

Researchers identify new way to inhibit immune cells that drive allergic asthma – EurekAlert

image:

Activation of ILC2s causes inflammation in mouse lungs (left), but this is reduced by treatment with Yoda1 to stimulate Piezo1 channels (right).

Credit: 2024 Hurrell et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20231835

Researchers at the Keck School of Medicine, University of Southern California, have discovered that a protein called Piezo1 prevents a type of immune cell in the lung from becoming hyperactivated by allergens. The study, to be published March 26 in the Journal of Experimental Medicine (JEM), suggests that switching on Piezo1 could represent a new therapeutic approach to reducing lung inflammation and treating allergic asthma.

Type 2 innate lymphoid cells (also known as ILC2s) are a type of immune cell that resides in the lungs, skin, and other tissues of the body. ILC2s in the lungs become activated in the presence of allergens and produce proinflammatory signals that drive the recruitment of other immune cells into the lungs. Unchecked, this can result in excessive inflammation and a tightening of the airways, making it difficult for asthma patients to properly breathe.

Given the importance of ILC2s in allergic asthma, there is an urgent need to develop novel mechanism-based approaches to target these critical drivers of inflammation in the lungs, says Omid Akbari, Professor of Immunology and Professor of Medicine at USCs Keck School of Medicine.

Akbari and colleagues discovered that, when they are activated by an allergen, ILC2s start to produce a protein called Piezo1 that can limit their activity. Piezo1 forms channels in the outer membranes of cells that open in response to mechanical changes in the cells environment, allowing calcium to enter the cell and change its activity.

Akbaris team found that, in the absence of Piezo1, mouse ILC2s became more active than normal in response to allergenic signals, and the animals developed increased airway inflammation. In contrast, treatment with a drug called Yoda1 that switches on Piezo1 channels reduced the activity of ILC2s, decreased airway inflammation, and alleviated the symptoms of allergen-exposed mice. The groups observations suggest a significant role for Piezo1 channels in ILC2 metabolism, as treatment with Yoda1 reduced ILC2 mitochondrial function and rewired the cells energy source.

Finally, the researchers determined that human ILC2s also produce Piezo1, and so they tested the effects of Yoda1 on mice whose ILC2s had been replaced with human immune cells.

Remarkably, treatment of these humanized mice with Yoda1 reduced airway hyperreactivity and lung inflammation, suggesting that Yoda1 may be used as a therapeutic tool to modulate ILC2 function and alleviate the symptoms associated with ILC2-dependent airway inflammation in humans, Akbari says. Future studies are therefore warranted to delineate the role of Piezo1 channels in human patients with asthma and develop Piezo1-driven therapeutics for the treatment of allergic asthma pathogenesis.

Hurrell et al. 2024. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20231835?PR

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About Journal of Experimental Medicine

Journal of Experimental Medicine (JEM) publishes peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions on research manuscripts are made through collaborative consultation between professional scientific editors and the academic editorial board. Established in 1896, JEM is published by Rockefeller University Press, a department of The Rockefeller University in New York. For more information, visit jem.org.

Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

Follow JEM on Twitter at @JExpMed and @RockUPress.

Journal of Experimental Medicine

Experimental study

Animals

Piezo1 channels restrain ILC2s and regulate the development of airway hyperreactivity

26-Mar-2024

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Researchers identify new way to inhibit immune cells that drive allergic asthma - EurekAlert

Immunology

Measles outbreaks show the risk of under-vaccination | News | Harvard T.H. Chan School of Public Health – HSPH News

March 27, 2024On March 18, the Centers for Disease Control and Prevention issued a health alert warning clinicians and public health officials of a global rise in measles cases. Yonatan Grad, professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health, discusses the highly transmissible disease and what may be driving its resurgence.

Q: What should the public know about measles?

A: The first thing that people should know is that measles is preventable. The measles vaccine is one of our best. One dose is 93% effective and two doses are 97% effective in protecting against infection.

Second, measles is extremely contagiousone of the most contagious pathogens we know of. In a classroom of children who are not protected against measles, a child with measles will infect 12-18 others.

Third, measles can lead to severe health consequences. About 1 in 5 unvaccinated people with measles are hospitalized. About 1 in 20 get pneumonia. About 1 in 1000 get encephalitisinflammation of the brainwhich can result in intellectual disabilities. And about 1 to 3 in 1000 die, most often from measles pneumonia.

Another thing thats not well appreciated is that measles can cause immune amnesia, in that it resets immunity to other diseases. When the vaccine was rolled out, there was not only a decline in measles, but also declines in other childhood infections like chickenpox. Recent work showed how measles infection depletes your antibodies, making you more susceptible to pathogens you had developed protection against. So the benefit of measles vaccination is two-fold: It protects people from measles and helps maintain protection against other childhood illnesses.

Q: Across the U.S. and around the world, were seeing measles cases rise. What might be driving this resurgence?

A: The key issue here is under-vaccination. To protect a community from outbreaks, about 95% of the population needs to have been vaccinated. In some low-income countries, the rates are down around 60-70%, and weve seen large measles outbreaks and measles-related deaths in those areas. Childhood vaccination and preventive health care was disrupted with the COVID-19 pandemic, putting these populations at even greater risk.

In the U.S., where the high rate of vaccination was a tremendous success in reducing measles, anti-vax trends have led to communities becoming more susceptible. Most of the recent U.S. cases have been related to international travel, and then those cases have sparked outbreakslike the ones in the past few months in Philadelphia and Broward County, Florida.

Q: The drop in vaccination rates is alarming. What are some of the cultural and political drivers that are leading people to question vaccines?

A: I dont study cultural and political drivers, so here are a few of my guesses. The level of misinformation and disinformation about vaccines and their safety seems like a huge problem. And as I referred to, the lack of access to health care and vaccines, particularly in low-income countries, is another huge problem. The drop in vaccination rates, where past successful vaccination campaigns have made once familiar diseases very rare, may also get at one of the paradoxes of public health: With a successful public health intervention, over time people forget about a diseases consequences and come to question the need to continue investing in the intervention.

We need to identify communities and populations where vaccination rates are decreasing or are low enough to warrant concern, so we can better understand the drivers at work and effectively respond to them. We need to counter disinformation, providing forums for trusted health advisors. And we need to redouble our global commitment to providing health careand in this case specifically, providing access to vaccinesfor all.

Maya Brownstein

Photos: iStock/Kittisak Kaewchalun; Kent Dayton

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Measles outbreaks show the risk of under-vaccination | News | Harvard T.H. Chan School of Public Health - HSPH News

Immunology

Spring Allergy Season Is Getting Worse. Here’s What to Know. – The New York Times

Spring is here and if youre among the estimated one in four adults in the United States who suffers from seasonal allergies, your sneezing and scratching may have already started.

With climate change affecting temperatures and plant growth, you may need to be on the lookout earlier than ever before. It can be hard to distinguish allergy symptoms from those of a cold, but experts point to a few telltale signs.

Spring allergy seasons are beginning about 20 days earlier than they had, according to an analysis of pollen count data from 60 stations across North America from 1990 to 2018.

That shift can have significant health consequences, said William Anderegg, who is an author of the study and an associate professor of biology at the University of Utah. Other research has shown that very early onset of spring is associated with higher prevalence of allergic rhinitis, also known as hay fever. When people end up sick or in the hospital from uncontrolled allergy symptoms, he said, its because they didnt expect it, and didnt have medications in hand.

The researchers also found that pollen concentrations have risen about 20 percent nationwide since 1990, with Texas and the Midwest having the greatest increases. Warmer temperatures, higher concentrations of carbon dioxide and increased precipitation can all contribute to plants growing bigger and producing more pollen over longer periods of time, Dr. Anderegg said.

Dr. Gailen Marshall, chair of the allergy and immunology department at the University of Mississippi Medical Center, said that when he began practicing nearly 40 years ago, allergy seasons were confined to about eight weeks each. Tree pollen hit in the spring, grass pollen increased in spring and summer and ragweed pollen picked up in late summer and early fall.

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Spring Allergy Season Is Getting Worse. Here's What to Know. - The New York Times

Immunology

Multiple sclerosis has distinct subtypes, study finds, pointing to different treatments – STAT

For years, researchers have been hopeful they could get under the hood of multiple sclerosis. The neurological condition shows up in over 2.5 million people around the world, but it doesnt always look the same. If science could point its light in just the right way, patients might be sorted into disease subgroups, and treated more successfully depending on their kind of MS.

A new study out of Germany gives it a shot, offering up three MS subtypes based on immune markers found in patients blood each group with slightly different disease progression.

The MS connection of the senior author, Heinz Wiendl, could start in his home. His mother had the condition. But thats not really it, he says. He was always fascinated by immunology and neurology, and how MS went from an untreatable disease to a known, druggable condition in less than 40 years.

Hes been in the field for more than half of that time, trying to get a grasp on how the immune system fusses and frays in response to antigens, and how that turns into a difficult chronic condition. MS causes vision problems, fatigue, and weakness or spasms in the arms and legs, among a host of other symptoms. The condition is thought to be more common in women.

Most recently, Wiendl set out to prove a hypothesis hes been building for years: that MS patients have immunological signatures in their blood that match certain versions of the same disease.

With collaborators at a half dozen institutions across Germany, Wiendl, a professor of neurology at the University of Mnster, launched a multi-center cohort study of 500 patients with early-stage MS. Those newly sick people were a right fit because the immunological derailment has happened, but its not yet spread out and diverged, he said. Plus, patients hadnt undergone treatments that changed their immune systems.

And Wiendl, with all his years of research, tried to wipe his mind clean of all presuppositions he had about the disease and go in agnostic. The team assessed the quantity and quality of various immune cell populations, not favoring any in particular. And then they let an algorithm determine whether certain cell populations, or a combination of them, were more prevalent in these MS patients.

Its a little like Lebron James, Wiendl said. If the cameraman is only ever focused on James, the audience will miss what the other players are doing. Sure, the superstar or highly suspect immune cell is captivating, but viewers could miss important plays elsewhere on the court.

If Lebron James in the end happens to make the most goals or baskets, we will find out anyway. But we have not overlooked the others, he said. This is the unsupervised approach the team used.

In the end, there was some superstar-watching: The researchers confirmed that players other researchers had spotted in MS were playing a role in their cohorts, too. But they also found new things, published Wednesday in Science Translational Medicine.

Most notably, Wiendl and his collaborators say they found unique stamps of immunological activation that correspond to specific subgroups, or endophenotypes. And each subgroup identified as E1, E2, and E3 had its own disease trajectory when they followed patients for four years.

E1 patients had alterations in the CD4 T cell compartment, the helper cells that can activate other immune cells, and inflammatory proteins that have been associated with autoimmune disease. This group was associated with earlier structural brain damage, greater disease severity, and higher disability their condition was much worse from the beginning, Wiendl said.

Meanwhile, E2 had differences in natural killer cells, which take down sick cells. And E3 patients had changes to highly toxic CD8 T cells, making it a more inflammatory category. E3 patients had a higher relapse rate within the first year, and more MS lesions that point to issues in the blood-brain barrier. Researchers also found more immune cells in the cerebrospinal fluid of E3 patients (this data was available for about 170 of the patients).

There was some overlap, but Wiendl and his colleagues believe the subtypes are distinct and could help predict how patients disease progresses. They dont know exactly how stable the subtypes are over longer periods of time, or if treatment changes it. But Wiendl said cellular signatures were found over time in the handful of patients who went untreated, including up to nine years within one individual, the authors note in the study.

These differing subgroups could suggest the disease arises through a multitude of immune system pathways. Not only that, Wiendl said, but the groups responded differently to treatments over time potentially a valuable insight for drug developers and clinicians.

For example, the inflammatory E3 group for the most part didnt respond to treatment with interferons, commonly used disease-modifying therapies first approved for MS in 1993. But these patients did improve by taking monoclonal antibodies, such as alemtuzumab (Sanofi Genzymes Lemtrada) and ocrelizumab (Genentechs Ocrevus).

The ability of the endophenotypes to predict a patients future condition needs to be checked by other researchers, and in a different population, said Alberto Ascherio, who led a pivotal study linking MS to previous Epstein-Barr infection and was not involved in the German study. He called the new study interesting for those in the field and said that endophenotypes could, in theory, help to personalize treatment.

But the science isnt there yet, Ascherio added. Personalized medicine in MS is still a fashionable word that is more a marketing pitch than a reality.

Wiendl said he hopes other researchers can use the studys data to test and confirm how well different MS treatments work for patients with these immune signatures, and to find other potential therapies. Wiendl also programmed an app with the data, and said he is developing a test to help others discriminate between the E subgroups. His spinoff company has patented the endophenotypes.

Ideally, one day there will be a simple test to classify patients and help doctors find the most effective treatment, Wiendl said.

We really want to transform patient care and not just open the door, he said.

STATs coverage of chronic health issues is supported by a grant fromBloomberg Philanthropies. Our financial supportersare not involved in any decisions about our journalism.

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Immunology

Researchers identify viable vaccine targets for hepatitis C infections – News-Medical.Net

By studying individuals who spontaneously clear hepatitis C infections, a team of researchers has identified viable vaccine targets for a disease that infects 70 million worldwide with case numbers increasing every year.

It turns out that a quarter of people who become infected with the hepatitis C virus clear the infection on their own without treatment, while the remaining three-quarters of people develop chronic infections that can last for years. The blood-borne disease which causes liver cirrhosis, liver failure and liver cancer is especially prevalent among people who inject drugs.

Direct-acting antivirals developed around a decade ago are 98% effective. But even so, the number of hepatitis C cases has increased year-over-year mainly because early infections are hard to detect, access to treatment is limited and reinfections occur even after treatment.

"That's why there is now a big interest in developing a hepatitis C vaccine," saidAndrew Flyak, assistant professor of microbiology and immunology in the College of Veterinary Medicine and co-corresponding author of the study, "Convergent Evolution and Targeting of Diverse E2 Epitopes by Human Broadly Neutralizing Antibodies are Associated with HCV Clearance," which published March 21 in the journal Immunity. Justin Bailey, associate professor of medicine at Johns Hopkins University, is co-corresponding author.

Our study gives us a glimpse into how certain individuals clear a highly variable infection, and we believe this information can inform a vaccine development."

AndrewFlyak, assistant professor of microbiology and immunology in the College of Veterinary Medicine and co-corresponding author of the study

The study was made possible due to the unique access that Bailey had to samples from people who injected drugs and were at risk of acquiring the virus. This allowed the researchers to track individuals who were hepatitis C negative when they enrolled in the program, and to see upon subsequent clinic visits whether that person acquired the virus. Bailey obtained samples from individuals who cleared the infection on their own and those who developed chronic infection.

Viruses that evolve very rapidly, such as SARS-CoV-2, influenza and hepatitis C, have extraordinary genetic diversity with multiple strains. Combating these types of infections requires special antibodies (blood proteins that recognize pathogens and neutralize them) called broadly neutralizing antibodies (bNAbs), which can neutralize diverse viral variants.

In previous studies, researchers isolated bNAbs from people who were chronically infected with hepatitis C virus. They found that their bNAbs were using a single antibody gene to encode a variable part of the antibody molecule.

"In order to make an antibody, immune systems use multiple sets of different antibody genes, but for whatever reason the immune systems in people with chronic hepatitis C infections used just one variable antibody gene, called VH1-69," Flyak said. Also, most of the bNAbs from these chronically infected donors targeted a specific region of the hepatitis C virus, namely the front layer of the so-called E2 protein. The immune system in chronically infected individuals has failed to clear the virus.

In the current study, the researchers isolated bNAbs from one person who spontaneously cleared three separate infections. This individual's bNAbs revealed important distinctions. First, these bNAbs were genetically diverse, meaning they are encoded by a variety of variable genes, and not just one segment of the VH1-69 gene. Second, bNAbs from this individual targeted three different regions of the virus' E2 protein, the front layer, as well as a back layer and a b-sandwich.

The data suggests that a hepatitis C virus vaccine should elicit bNAbs to all three regions of the E2 protein rather than just one region of the virus, Flyak said.

"If you have a response to multiple regions, you can have a synergistic effect, you get a response that is much stronger than the sum of its parts," he said.

BNAbs from the individual who cleared the infections also revealed evidence of what is called convergent evolution, where different bNAbs have the same mutations but come from different antibody variable genes. "You see the same mutations in two different broadly neutralizing antibodies it means those mutations are important," Flyak said and they increase the breadth of the antibody response to hepatitis C virus.

Members of Flyak's lab used X-ray crystallography to solve the crystal structures of bNAbs in complex with hepatitis C virus' E2 protein and show how bNAb's mutations interact with the E2 protein. "That information can be used to design better vaccine candidates," Flyak said.

In next steps, the team will collaborate with a larger international group to screen multiple vaccine candidates in animals and eventually identify which ones to bring into human clinical trials.

Clinton Ogega, a former graduate student in Bailey's lab, is the paper's first author. Two postdoctoral fellows in Flyak's lab, Marty Schoenle and Xander Wilcox, contributed to the study.

The study was supported by the National Institutes of Health.

Source:

Journal reference:

Ogega, C. O., et al. (2024). Convergent evolution and targeting of diverse E2 epitopes by human broadly neutralizing antibodies are associated with HCV clearance.Immunity. doi.org/10.1016/j.immuni.2024.03.001.

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Immunology

Three research projects awarded funding from the Immunology Institute Pilot Project program – University of Alabama at Birmingham

The program seeks to support and foster multidisciplinary collaborations, especially between UAB clinicians and basic and physician scientists.

The program seeks to support and foster multidisciplinary collaborations, especially between UAB clinicians and basic and physician scientists.The University of Alabama at Birminghams Immunology Institute Pilot Project program has selected three research projects to award funding during its inaugural year.

The three projects awarded include:

The pilot grant program received matching funding from the ONeal Comprehensive Cancer Center at UAB, so the three awarded projects will be funded for one to two years.

The pilot grant program is housed in the Marnix E. Heersink School of Medicines Immunology Institute and serves as a central focal point for coordinating immunologic research across various disciplines. The program seeks to support and foster multidisciplinary collaborations, especially between UAB clinicians and basic and physician scientists.

UAB immunology-focused investigators actively explore the power of the immune system to treat and prevent infectious diseases, transplant organ rejection, autoimmunity, allergy, cancer and numerous inflammatory-based conditions.

Applications for 2025 funding opportunities will open later this fall.

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Three research projects awarded funding from the Immunology Institute Pilot Project program - University of Alabama at Birmingham