Scientists identify new brain circuit in mice that controls body's inflammatory reactions

The brain can direct the immune system to an unexpected degree, capable of detecting, ramping up and tamping down inflammation, shows a new study in mice from researchers at Columbia's Zuckerman Institute.

"The brain is the center of our thoughts, emotions, memories and feelings," said Hao Jin, PhD, a co-first author of the study published online today in Nature. "Thanks to great advances in circuit tracking and single-cell technology, we now know the brain does far more than that. It is monitoring the function of every system in the body."

Future research could identify drugs that can target this newfound brain circuit to help treat a vast range of disorders and diseases in which the immune system goes haywire.

"This new discovery could provide an exciting therapeutic venue to control inflammation and immunity," said Charles S. Zuker, PhD, the study's senior author, a principal investigator at Columbia's Zuckerman Institute and a Howard Hughes Medical Institute investigator.

Recent work from the Zuker lab and other groups is revealing the importance of the body-brain axis, a vital pathway that conveys data between the organs and the brain. For example, Dr. Zuker and his colleagues discovered that sugar and fat entering the gut use the body-brain axis to drive the craving and strong appetite for sugary and fatty foods.

"We found all these ways in which the body is informing the brain about the body's current state," said co-first author Mengtong Li, PhD, a postdoctoral researcher in the Zuker lab. "We wanted to understand how much farther the brain's knowledge and control of the body's biology went."

The scientists looked for connections the brain might have with inflammation and innate immunity, the defense system shared by all animals and the most ancient component of the immune system. Whereas the adaptive immune system remembers previous encounters with intruders to help it resist them if they invade again, the innate immune system attacks anything with common traits of germs. The relative simplicity of innate immunity lets it respond to new insults more quickly than adaptive immunity.

Prior studies in humans revealed that electrically stimulating the vagus nerve -- a bundle of thousands of nerve fibers linking the brain and the body's internal organs -- could reduce the response linked to a specific inflammatory molecule. However, much remained unknown about the nature of this body-brain system: for instance, the generality of the brain's modulation of immunity and the inflammatory response, the selective lines of communication between the body and the brain, the logic of the underlying neural circuit, and the identity of the vagal and brain components that monitor and regulate inflammation.

The Zuker lab turned to a bacterial compound that sets off innate immune responses. The scientists found that giving this molecule to mice activated the caudal nucleus of the solitary tract, or cNST, which is tucked inside the brainstem. The cNST plays a major role in the body-brain axis and is the primary target of the vagus nerve.

The scientists showed that chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal. In contrast, artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold.

"Similar to a thermostat, this newfound brain circuit helps increase or decrease inflammatory responses to keep the body responding in a healthy manner," said Dr. Jin, who started this study as a postdoctoral researcher in Dr. Zuker's lab. Dr. Jin is now a tenure track investigator at the National Institute of Allergy and Infectious Diseases. "In retrospect, it makes sense to have a master arbiter controlling this vital response."

Previous vagus nerve stimulation research in humans suggests the findings go beyond mice. The new research may also be in line with thousands of years of thought on the potential importance of the mind on the body.

"A lot of psychosomatic effects could actually be linked to brain circuits telling your body something," Dr. Jin noted.

The scientists identified the specific groups of neurons in the vagus nerve and in the cNST that help detect and control pro- and anti-inflammatory activity. "This opens up a new window into how the brain monitors and modulates body physiology," said Dr. Zuker, a professor of biochemistry, molecular biophysics and neuroscience at Columbia's Vagelos College of Physicians and Surgeons.

Discovering ways to control this newfound brain circuit may lead to novel therapies for common auto-immune diseases such as rheumatoid arthritis, type I diabetes, multiple sclerosis, neurodegenerative diseases, lupus, inflammatory bowel disease and Crohn's disease, as well as conditions such as long COVID syndrome, immune rejection of transplanted organs, and the potentially deadly outbursts known as cytokine storms that COVID infections can trigger.

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Gut bacteria make neurotransmitters to shape the newborn immune system

Weill Cornell Medicine investigators discovered that unique bacteria colonize the gut shortly after birth and make the neurotransmitter serotonin to educate gut immune cells. This prevents allergic reactions to food and the bacteria themselves during early development.

The preclinical study, published in Science Immunology on Mar. 15, showed that bacteria abundant in the guts of newborns produce serotonin, which promotes the development of immune cells called T-regulatory cells or Tregs. These cells suppress inappropriate immune responses to help prevent autoimmune diseases and dangerous allergic reactions to harmless food items or beneficial gut microbes.

"The gut is now known as the second human brain as it makes over 90 percent of the neurotransmitters in the human body. While neurotransmitters such as serotonin are best known for their roles in brain health, receptors for neurotransmitters are located throughout the human body," explained the study's senior author, Dr. Melody Zeng, an assistant professor of immunology in the Gale and Ira Drukier Institute for Children's Research and the Department of Pediatrics at Weill Cornell Medicine.

Gut Bacteria in Babies Provide a Helping Hand

The researchers observed that the neonatal mouse gut had much higher levels of neurotransmitters, including serotonin, than the adult gut. "So far, almost all studies of gut neurotransmitters were conducted in adult animals or human subjects, where a specific gut cell type called enterochromaffin cells produce neurotransmitters," said Dr. Zeng. "However, we discovered that this isn't the case in the newborn gut where most of the serotonin is made by bacteria that are more abundant in the neonatal gut."

This was also confirmed in babies through a human infant stool biobank that the Zeng lab has established in collaboration with the Neonatal Intensive Care Unit in the NewYork-Presbyterian Alexandra Cohen Hospital for Women and Newborns. These samples were obtained with parental consent and deidentified.

The study results suggest that before the neonatal gut is mature enough to make its own neurotransmitters, unique gut bacteria may supply neurotransmitters that are needed for critical biological functions during early development.

"We found that gut bacteria in young mice not only directly produce serotonin but also decrease an enzyme called monoamine oxidase that normally breaks down serotonin, thus keeping gut serotonin levels high," said the study's lead author Dr. Katherine Sanidad, postdoctoral associate in pediatrics at Weill Cornell Medicine.

The high serotonin levels shift the balance of immune cells by increasing the number of Tregs, which helps prevent the immune system from overreacting and attacking gut bacteria or food antigens. "The neonatal gut needs these serotonin-producing bacteria to keep the immune system in check," Dr. Sanidad added.

Healthy Immune System Helps Later in Life

Dr. Zeng noted that this work underscores the importance of having the right types of beneficial bacteria soon after birth. Babies in developed countries have better access to antibiotics, less exposure to diverse microbes in their clean environments and potentially unhealthy diets that may significantly impact the abundance of serotonin-producing bacteria in their intestines.

As a result, these babies may have fewer Tregs and develop immune reactions to their own gut bacteria, or allergies to food. This may be one reason food allergies have become increasingly common in children, particularly in developed countries. "If educated properly, the immune system in babies would recognize that things like peanuts and eggs are okay, and it doesn't have to attack them," she said. This may also have an impact on developing autoimmune diseases -- when the immune system attacks the body's own healthy cells -- later in life.

The team next plans to look at bacteria in human infant stool samples to measure their production of serotonin, other neurotransmitters and molecules that may help train the immune system to prevent future immune-related diseases, such as allergies, infections and cancer.

"It's essential to understand how the immune system is trained during early life, but this is understudied in newborns and children. Further studies of these developmental periods may hopefully lead us to mitigation approaches to reduce the risk of inflammatory diseases like food allergies and inflammatory bowel disease later in life," Dr. Sanidad said.

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Fiber from crustaceans, insects, mushrooms promotes digestion

Who can forget the stomach-churning moments when "Survivor" contestants forced down crunchy insects, among other unappetizing edibles, for a chance to win $1 million? In daring culinary challenges, the TV show's contestants exhibited gastronomic bravery as viewers watched in discomfort.

Digesting a crunchy critter starts with the audible grinding of its rigid protective covering -- the exoskeleton. Unpalatable as it may sound, the hard cover might be good for the metabolism, according to a new study, in mice, from Washington University School of Medicine in St. Louis.

The researchers, led by Steven Van Dyken, PhD, an assistant professor of pathology & immunology, found in mice that digesting chitin, an abundant dietary fiber in insect exoskeletons and also mushrooms and crustacean shells, engages the immune system. An active immune response was linked to less weight gain, reduced body fat and a resistance to obesity.

"Obesity is an epidemic," Van Dyken said. "What we put into our bodies has a profound effect on our physiology and on how we metabolize food. We're investigating ways to counteract obesity based on what we learn about how the immune system is engaged by diet."

The study is published Sept. 7 in Science.

The immune system is well known for safeguarding the body against various threats, including bacteria, viruses, allergens and even cancer. The researchers found that a particular arm of the immune system also is involved in chitin digestion. Stomach distention after chitin ingestion activates an innate immune response that triggers stomach cells to ramp up production of enzymes, known as chitinases, that break down chitin. Of note, chitin is insoluble -- incapable of being dissolved in liquid -- and thus requires enzymes and harsh acidic conditions to digest.

Do-Hyun Kim, PhD, a postdoctoral research associate and first author on the study, performed the experiments in germ-free mice lacking intestinal bacteria. His results show that chitin activates immune responses in the absence of bacteria.

"We think chitin digestion mainly relies on the host's own chitinases," Van Dyken said. "The stomach cells change their enzymatic output through a process we refer to as adaptation. But it is surprising that this process is happening without microbial input, because bacteria in the gastrointestinal tract are also sources of chitinases that degrade chitin." Van Dyken noted that in mice with intestinal bacteria, dietary chitin altered the bacterial composition in the lower gastrointestinal tract, suggesting that gut bacteria also adapt to chitin-containing food after it leaves the stomach.

The research team found that the greatest impact on obesity in mice occurred when chitin activated the immune system but was not digested. Mice fed a high-fat diet also were given chitin. Some mice lacked the ability to produce chitinases to break down chitin. The mice that ate chitin but couldn't break it down gained the least amount of weight, had the lowest body fat measurements and resisted obesity, compared with mice that didn't eat chitin and with those that did but could break it down.

If the mice could break down chitin, they still benefited metabolically, but they adapted by overproducing chitinases to extract nutrients from chitin.

Van Dyken and his team next plan to follow up on their findings in people, with a goal of determining whether chitin could be added to human diets to help control obesity.

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How being in space impairs astronauts' immune system

A new study led by researchers at Karolinska Institutet in Sweden has examined how T cells of the immune system are affected by weightlessness. The results, which are published in the journal Science Advances, could explain why astronauts' T cells become less active and less effective at fighting infection.

The next steps in the exploration of space are human missions to the moon and to Mars. Space is an extremely hostile environment that poses threats to human health. One such threat is changes to the immune system that occur in astronauts while in space and that persist after their return to Earth. This immune deficiency can leave them more vulnerable to infection and lead to the reactivation of latent viruses in the body.

"If astronauts are to be able to undergo safe space missions, we need to understand how their immune systems are affected and try to find ways to counter harmful changes to it," says study leader Lisa Westerberg, principal researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. "We've now been able to investigate what happens to T cells, which are a key component of the immune system, when exposed to weightless conditions."

In the study, the researchers have tried to simulate weightlessness in space using a method called dry immersion. This involves a custom-made waterbed that tricks the body into thinking it is in a weightless state. The researchers examined T cells in the blood of eight healthy individuals for three weeks of exposure to simulated weightlessness. Blood analyses were performed before the experiment started, at 7, 14 and 21 days after the start, and at 7 days after the experiment ended.

They found that the T cells significantly changed their gene expression -- that is to say, which genes were active and which were not -- after 7 and 14 days of weightlessness and that the cells became more immature in their genetic programme. The greatest effect was seen after 14 days.

"The T cells began to resemble more so-called naïve T cells, which have not yet encountered any intruders. This could mean that they take longer to be activated and thus become less effective at fighting tumour cells and infections. Our results can pave the way for new treatments that reverse these changes to the immune cells' genetic programme," says Carlos Gallardo Dodd, PhD student at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and shared first author with researchers Christian Oertlin and Julien Record at the same department.

After 21 days, the T cells had "adapted" their gene expression to weightlessness so that it had almost returned to normal, but analyses carried out seven days after the experiment ended showed that the cells had regained some of the changes.

The researchers now plan to use Esrange Space Centre's sounding rocket platform in Kiruna, Sweden, to study how T cells behave in weightless conditions and how their function is affected.

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New evidence: Immune system cells in the gut linked to stress-induced depression

In experiments with mice and humans, a team led by Johns Hopkins Medicine researchers says it has identified a particular intestinal immune cell that impacts the gut microbiome, which in turn may affect brain functions linked to stress-induced disorders such as depression. Targeting changes mediated by these immune cells in the gut, with drugs or other therapies, could potentially bring about new ways to treat depression.

The findings of the study were published March 20, 2023 in the journal Nature Immunology.

"The results of our study highlight the previously unrecognized role of intestinal gamma delta T cells (γδ T cells) in modifying psychological stress responses, and the importance of a protein receptor known as dectin-1, found on the surface of immune cells, as a potential therapeutic target for the treatment of stress-induced behaviors," says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's senior author.

Dectin-1 binds to certain antigens, or proteins, to signal immune cells to activate in specific ways. This receptor, the researchers say, may be involved in the microbiome alteration and immune-inflammatory responses in the colon of mice, which suggests that it may be involved in stress responses via γδ T cells in the intestinal immune system.

On the basis of previous studies suggesting that immune inflammatory responses in the gut are related to depression, Kamiya and his team designed experiments to focus on understanding stress-induced behaviors produced by an imbalance in the gut microbiota -- types of microorganisms found in a specific environment, such as bacteria, fungi and viruses.

To this end, the team examined the effects of chronic social defeat stress (CSDS) on the gut microbiota in mice. CSDS is a standard rodent test to study stress-induced disorders such as depression. In a series of experiments, the researchers simulated potential stress inducing environments that could mimic similar responses in human environments. After each exposure, the mice were assessed and classified as stress-resilient (stress did not diminish social interactions) or stress-susceptible (stress increased social avoidance).

Fecal samples were then collected and put through genetic analysis to identify the diversity of bacteria in the gut microbiota of the mice. The analysis showed that the intestinal organisms were less diverse in stress-susceptible mice than in stress-resilient mice. It specifically revealed that there were less Lactobacillus johnsonii (L. johnsonii) -- a type of probiotic, or "good" bacteria -- in stress-susceptible mice compared to stress-resilient mice.

"We found that stress increased the γδ T cells, which in turn increased social avoidance," says Xiaolei Zhu, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's lead author. "However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes."

Looking for potential natural approaches for prevention of depression rooted somehow in the gut, the researchers explored how changes in dectin-1 on CSDS-induced elevation of γδ T cells responded to pachyman. A compound extracted from wild mushrooms, pachyman is used as a natural anti-inflammatory agent and for treating depression in Eastern medicine. For this experiment, mice were fed a dose of pachyman, which was shown in previous research to affect immune function. Data from flow cytometry analysis -- a technology used to measure the physical and chemical characteristics of a population of cells -- provided evidence that dectin-1 binds to pachyman, inhibiting CSDS-induced γδ17 T cell activity and easing social avoidance behavior.

To gain insight into how the alterations in the gut microbiota could impact the human brain, the researchers investigated the makeup of gut organisms in people with major depressive disorder (MDD) compared to people without MDD. From June 2017 to September 2020, 66 participants, ages 20 or older, were recruited at Showa University Karasuyama Hospital, Keio University Hospital and Komagino Hospital in Tokyo, Japan. Of the study participants, 32 had MDD (17 women and 15 men). The other 34 participants (18 women and 16 men) who did not have MDD formed the control group.

Stool samples were collected from all study participants, who had comprehensive evaluations including psychiatric history and standard screening assessments for depression and anxiety. In these assessments, higher scores indicate greater depressive symptoms. Genetic analysis of the stool samples showed no difference in the diversity of intestinal bacteria between the subjects with MDD and the control group. However, the relative abundance of Lactobacillus was inversely related to higher depression and anxiety scores in the MDD group, meaning that the more Lactobacillusfound in the gut, the lower the potential for depression and anxiety, the researchers say.

"Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety," says Kamiya.

The investigators say more research is needed to further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in other cell types along the gut-brain connection under stress conditions.

"These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression," says Kamiya.

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How does the immune system react to altered gravity?

Space travel has always tested the human body by the effects of the new conditions of altered gravity on biological systems. It has long been known that continuous exposure to microgravity conditions human physiology and causes effects that compromise muscular, sensory, endocrine and cardiovascular functions. But is it also risky to be exposed to altered gravity for short periods of time?

Now, a paper published in the journal Acta Astronautica examines the effects on the human immune system of microgravity generated by a parabolic flight. After a short exposure to altered gravity, there were no significant changes in the defensive capacity of blood cells in the volunteers who took part in the study. In addition, the study found no evidence of aggregation processes in erythrocytes -- the cells that transport O2 and CO2 to the cardiovascular system -- after the parabolic flight.

The study was coordinated by Ginés Viscor, professor at the Department of Cell Biology, Physiology and Immunology of the Faculty of Biology of the University of Barcelona, and it included the participation of experts Jordi Petriz, from the Germans Trias i Pujol Research Institute (IGTP), and Antoni Pérez-Poch, from the Technical University of Catalonia-BarcelonaTech (UPC) and the Institute of Space Studies of Catalonia (IEEC), among other authors. The first author of the study is the researcher Abril Gorgori-González (UB). It counted on the support from the Medical Service of the Safety, Health and Environment Office (OSSMA) of the UB, the Aeroclub Barcelona-Sabadell and the company Thermo Fisher Scientific.

Parabolic flights: a simulated gravity laboratory

Space travel is the ideal scenario to study the effect of microgravity on the human body. These trips make it possible to study the consequences of long-term exposure to microgravity on different astronauts simultaneously, but they require a high cost in terms of time, funding and infrastructure. Without leaving the Earth's atmosphere, it is also possible to simulate simulated gravity conditions on different platforms. For example, through parabolic flights in aircraft, which make it possible to study the effect of altered microgravity in the short term -- even for a few seconds -- at an affordable cost.

"Artificial platforms such as parabolic flights in aircraft provide valuable but more limited results, as they only allow the effects of altered gravity to be studied in the short term (seconds or minutes). Therefore, the profiles of physiological changes that can be recreated with parabolic flights are immediate and transitory changes that microgravity generates in the human body," says Ginés Viscor, head of the Adaptive Physiology Group: Exercise, Hypoxia and Health at the UB.

As part of the study, a 20-minute parabolic flight was conducted with the Mudry CAP10 aircraft -- a 2-seat aerobatic training aircraft -- during which fifteen parabolas were performed. "Each parabola allows a period of microgravity to be reached for approximately eight seconds, which is followed and preceded by hypergravity phases of about two seconds," says the researcher Antoni Pérez-Poch, from the Department of Computer Science at the UPC, and lecturer of the School of Engineering of Barcelona East (EEBE) of the UPC and the IEEC.

These parabolic flights with an aerobatic plane -- a pioneering method in the world, developed in Catalonia -- were operated by the Aeroclub Barcelona-Sabadell and are the result of an aeronautical research carried out in collaboration with the UPC. "This innovative technique has a good ratio of time achieved in microgravity compared to the cost of maintenance, which is very favourable compared to the greater use of aircraft, although it also has some limitations (logistical and space). In the case of parabolic flights with a larger aircraft, a more expensive operation that has been used since the beginning of the space race by agencies such as NASA or ESA (European Space Agency), up to 25 seconds per parabola could be achieved," says Pérez-Poch.

Immune function under pressure

The immediate effects of microgravity on the blood system derive from the redistribution of blood volume, blood flow and body fluids to the upper body. "Cardiovascular adaptations consist of an altered cardiovascular response causing abnormalities in body orientation and balance, poor response to orthostatic stress, decreased cardiac function and inadequate cardiovascular response to exercise," says Ginés Viscor.

One of the most vulnerable physiological systems to any change in environmental conditions is the immune system, and this is explained by its great plasticity and responsiveness to internal and external imbalances. In the scientific literature, there are still no conclusive results on the immune response to short exposure in flights with altered gravity, and in some cases the conclusions are even contradictory.

In this study, the team analysed the response of the immune system to short exposure to microgravity based on several parameters: erythrocyte and leukocyte counts, haemoglobin concentration, phagocytic capacity and oxidative metabolism.

"The results reveal that the human blood samples' exposure to altered gravity conditions in parabolic flight did not involve negative effects in relation to samples that were left parallelly on the ground during the experimental study. There are also no significant changes in peripheral blood cell counts," says Jordi Petriz (IGTP).

"Except for the monocytes -- a type of leukocyte -- no significant differences have been observed in the functionality of immune cells in terms of either their oxidative metabolism or their phagocytic capacity," says researcher Abril Gorgori-González (UB). "Hypothetically, if there were changes in the functionality of leukocytes when exposed to an altered gravity, the immune function and defence against external infections or tumour processes would also be compromised."

The team has applied the technique of flow cytometry with acoustic focusing with little manipulation of the volunteers' blood samples. According to the authors, the sample limitation typical of acrobatic flight studies -- with logistical constraints -- does not allow general conclusions to be drawn. Therefore, the goal now is to continue research on the human immune system with other microgravity simulation platforms to study physiological alterations, avoid complications and anticipate risk situations.

Space tourist warning

Space tourism is an activity of great economic interest for some business sectors. However, one of the main differences between space tourists and astronauts is the physical and psychological preparation prior to the trip.

"Altered gravity or the constant lack of gravity is one of several changes in the environment faced by these space travellers. The human body has evolved under the conditions of Earth's gravity and is not adapted to the absence of this attractive force. In space travel, other factors such as ionising radiation, constant noise, isolation, confinement, a total distortion of circadian rhythms and short exposure to extreme temperatures during the return to the atmosphere have to be considered," the experts warn.

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Skipping breakfast may compromise the immune system

Fasting may be detrimental to fighting off infection, and could lead to an increased risk of heart disease, according to a new study by the Icahn School of Medicine at Mount Sinai. The research, which focused on mouse models, is among the first to show that skipping meals triggers a response in the brain that negatively affects immune cells. The results that focus on breakfast were published in the February 23 issue of Immunity, and could lead to a better understanding of how chronic fasting may affect the body long term.

"There is a growing awareness that fasting is healthy, and there is indeed abundant evidence for the benefits of fasting. Our study provides a word of caution as it suggests that there may also be a cost to fasting that carries a health risk," says lead author Filip Swirski, PhD, Director of the Cardiovascular Research Institute at Icahn Mount Sinai. "This is a mechanistic study delving into some of the fundamental biology relevant to fasting. The study shows that there is a conversation between the nervous and immune systems."

Researchers aimed to better understand how fasting -- from a relatively short fast of only a few hours to a more severe fast of 24 hours -- affects the immune system. They analyzed two groups of mice. One group ate breakfast right after waking up (breakfast is their largest meal of the day), and the other group had no breakfast. Researchers collected blood samples in both groups when mice woke up (baseline), then four hours later, and eight hours later.

When examining the blood work, researchers noticed a distinct difference in the fasting group. Specifically, the researchers saw a difference in the number of monocytes, which are white blood cells that are made in the bone marrow and travel through the body, where they play many critical roles, from fighting infections, to heart disease, to cancer.

At baseline, all mice had the same amount of monocytes. But after four hours, monocytes in mice from the fasting group were dramatically affected. Researchers found 90 percent of these cells disappeared from the bloodstream, and the number further declined at eight hours. Meanwhile monocytes in the non-fasting group were unaffected.

In fasting mice, researchers discovered the monocytes traveled back to the bone marrow to hibernate. Concurrently, production of new cells in the bone marrow diminished. The monocytes in the bone marrow -- which typically have a short lifespan -- significantly changed. They survived longer as a consequence of staying in the bone marrow, and aged differently than the monocytes that stayed in the blood.

The researchers continued to fast mice for up to 24 hours, and then reintroduced food. The cells hiding in the bone marrow surged back into the bloodstream within a few hours. This surge led to heightened level of inflammation. Instead of protecting against infection, these altered monocytes were more inflammatory, making the body less resistant to fighting infection.

This study is among the first to make the connection between the brain and these immune cells during fasting. Researchers found that specific regions in the brain controlled the monocyte response during fasting. This study demonstrated that fasting elicits a stress response in the brain -- that's what makes people "hangry" (feeling hungry and angry) -- and this instantly triggers a large-scale migration of these white blood cells from the blood to the bone marrow, and then back to the bloodstream shortly after food is reintroduced.

Dr. Swirski emphasized that while there is also evidence of the metabolic benefits of fasting, this new study is a useful advance in the full understanding of the body's mechanisms.

"The study shows that, on the one hand, fasting reduces the number of circulating monocytes, which one might think is a good thing, as these cells are important components of inflammation. On the other hand, reintroduction of food creates a surge of monocytes flooding back to the blood, which can be problematic. Fasting, therefore regulates this pool in ways that are not always beneficial to the body's capacity to respond to a challenge such as an infection," explains Dr. Swirski. "Because these cells are so important to other diseases like heart disease or cancer, understanding how their function is controlled is critical."

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Using paleogenomics to elucidate 10,000 years of immune system evolution

Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.

In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.

To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia -- a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.

By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under "positive" natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes -- which are responsible for antiviral activity -- and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this "acceleration" in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.

At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to "negative" selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.

Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders -- including Crohn's disease -- became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. "These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases," explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).

The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.

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Sugar molecules as a target in cancer therapy

Cancer cells use sugar molecules on their surface to disable attacks by the body's immune system. Researchers at the University of Basel now report on how this mechanism can be neutralized.

The immune system is actually extremely well equipped to get rid of abnormal cells. As a safety mechanism, special features are built into healthy cells so that the immune system recognizes them, thus preventing a mistaken attack. However, cancer cells sneakily manipulate these safety mechanisms in such a way that the immune system leaves them alone.

Over the past few years, immunotherapies have revolutionized cancer treatment. These include therapies that prevent cancer cells from inhibiting the immune response. This involves blocking what are known as "immune checkpoints" using artificially produced proteins, which allows the immune cells to successfully attack the cancer cells.

"With many tumors, however, there have only been modest levels of success. That's why we're looking for new approaches to engage anti-tumor immune responses more efficiently," explains Professor Heinz Läubli from the Department of Biomedicine at the University of Basel and the University Hospital Basel. In the specialist journal Science Translational Medicine, his team, together with that of recent Nobel laureate Professor Carolyn Bertozzi from Stanford University, reports on a promising new approach. By altering sugar molecules on the surface of cancer cells in mice, the researchers were able to produce a significant increase in anti-tumor immune response.

How immune cells turn traitor

Their focus is on sugar molecules on the surface of the cancer cells, as well as on the cells in their immediate vicinity. These particular sugars, which contain sialic acid, also occur on healthy cells, and are important for cell-to-cell communication. However, tumors boost the proportion of these sugars on their surface.

Certain immune cells called macrophages recognize these sialic acid sugars and inadvertently turn traitor: they give other nearby immune cells the impression that all is well. The research team's experiments on mice have now been able to demonstrate that the sialic acid sugars can be removed, or at least very much reduced, with the help of an enzyme. This means that the macrophages no longer prevent the tumor coming under immunological attack.

A target structure for new therapies

More precise analyses have enabled the researchers to identify in mice exactly which receptor it is on the macrophages that recognizes the sialic acid sugars. If the equivalent receptor could be identified in humans, then that could be another interesting target in the bid to tackle cancer cells with the aid of the patient's own immune system.

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Researchers seek to understand why vaccine responses vary from person to person

While vaccines are one of the most powerful public health tools for protecting against infectious disease, not everybody is conferred the same level of protection. Many factors determine whether an individual responding to vaccination will generate an effective response, including specific biomarkers within a person's immune system, but until now there has been no evidence showing whether these factors were universal across a wide range of vaccines.

New findings from a meta-analysis published in Nature Immunology examine the biological mechanisms responsible for why some people's immune systems respond differently to vaccinations, which could have global implications for the development and administration of vaccines.

As part of a series of studies for The Human Immunology Project Consortium (HIPC), a network of national research institutions studying the range of responses to different infections and vaccinations, Emory researchers analyzed the molecular characteristics of 820 healthy young adults who were immunized with 13 different vaccines to identify specific biomarkers that generate antibody response to vaccines.

The participants were separated into three endotypes, or groups with a common gene expression, based on the level of inflammatory response prior to vaccination -- a high inflammatory group, a low inflammatory group, and a mid-inflammatory group. After studying the immunological changes that occurred in participants following vaccination, researchers found the group that had the highest levels of inflammation prior to vaccine had the strongest antibody response.

"We were surprised because inflammation is usually depicted as something that is bad," says Slim Fourati, PhD, bioinformatic research associate at Emory University and first author on the paper. "These data indicate that some types of inflammation can actually foster a stronger response from a vaccine."

Fourati, Dr. Rafick-Pierre Sekaly, professor and senior author of the paper, and the HIPC team identified specific biomarkers among this group and cellular features that characterized the pre-vaccination inflammatory signature, information that can be used to predict how well an individual will respond to a vaccine.

"With the knowledge we now have about what characteristics of the immune system enable a more robust response, vaccines can be tailored to induce this response and maximize their effectiveness," says Fourati. "But we still have more questions to answer."

More research is needed to determine the cause of this inflammation in otherwise healthy adults. Additionally, Fourati suggests future studies should look at how these biomarkers facilitate vaccine protection in older age groups and among populations who are immunocompromised.

Published simultaneously with three other HIPC studies by researchers at Yale's School of Medicine, Stanford University, University of Cincinnati, Harvard Medical School, and Columbia University Medical Center, these findings can serve to improve vaccine response across all individuals. Better understanding of how various pre-vaccine immune states impact antibody responses opens the possibility of altering these states in more vulnerable individuals. For example, scientists may give patients predicted to have a weaker immune response an adjuvant with the vaccine to trigger the inflammatory genes associated with greater protection.

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The Black Death shaped the evolution of immunity genes, setting the course for how we respond to disease today

An international team of scientists who analyzed centuries-old DNA from victims and survivors of the Black Death pandemic has identified key genetic differences that determined who lived and who died, and how those aspects of our immune systems have continued to evolve since that time.

Researchers from McMaster University, the University of Chicago, the Pasteur Institute and other organizations analyzed and identified genes that protected some against the devastating bubonic plague pandemic that swept through Europe, Asia and Africa nearly 700 years ago. Their study has been published today in the journal Nature.

The same genes that once conferred protection against the Black Death are today associated with an increased susceptibility to autoimmune diseases such as Crohn's and rheumatoid arthritis, the researchers report.

The team focused on a 100-year window before, during and after the Black Death, which reached London in the mid-1300s. It remains the single greatest human mortality event in recorded history, killing upwards of 50 per cent of the people in what were then some of the most densely populated parts of the world.

More than 500 ancient DNA samples were extracted and screened from the remains of individuals who had died before the plague, died from it or survived the Black Death in London, including individuals buried in the East Smithfield plague pits used for mass burials in 1348-9. Additional samples were taken from remains buried in five other locations across Denmark.

Scientists searched for signs of genetic adaptation related to the plague, which is caused by the bacterium Yersinia pestis.

They identified four genes that were under selection, all of which are involved in the production of proteins that defend our systems from invading pathogens and found that versions of those genes, called alleles, either protected or rendered one susceptible to plague.

Individuals with two identical copies of a particular gene, known as ERAP2, survived the pandemic at a much higher rates than those with the opposing set of copies, because the 'good' copies allowed for more efficient neutralization of Y. pestis by immune cells.

"When a pandemic of this nature -- killing 30 to 50 per cent of the population -- occurs, there is bound to be selection for protective alleles in humans, which is to say people susceptible to the circulating pathogen will succumb. Even a slight advantage means the difference between surviving or passing. Of course, those survivors who are of breeding age will pass on their genes," explains evolutionary geneticist Hendrik Poinar, an author of the Nature paper, director of McMaster's Ancient DNA Centre, and a principal investigator with the Michael G. DeGroote Institute for Infectious Disease Research and McMaster's Global Nexus for Pandemics & Biological Threats.

Europeans living at the time of the Black Death were initially very vulnerable because they had had no recent exposure to Yersinia pestis. As waves of the pandemic occurred again and again over the following centuries, mortality rates decreased.

Researchers estimate that people with the ERAP2 protective allele (the good copy of the gene, or trait), were 40 to 50 per cent more likely to survive than those who did not.

"The selective advantage associated with the selected loci are among the strongest ever reported in humans showing how a single pathogen can have such a strong impact to the evolution of the immune system," says human geneticist Luis Barreiro, an author on the paper, and professor in Genetic Medicine at the University of Chicago.

The team reports that over time our immune systems have evolved to respond in different ways to pathogens, to the point that what had once been a protective gene against plague in the Middle Ages is today associated with increased susceptibility to autoimmune diseases. This is the balancing act upon which evolution plays with our genome.

"This highly original work has been possible only through a successful collaboration between very complementary teams working on ancient DNA, on human population genetics and the interaction between live virulent Yersinia pestis and immune cells," says Javier Pizarro-Cerda, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at the Pasteur Institute.

"Understanding the dynamics that have shaped the human immune system is key to understanding how past pandemics, like the plague, contribute to our susceptibility to disease in modern times," says Poinar.

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Brain discovery holds key to boosting body's ability to fight Alzheimer's, MS

UVA Health researchers have discovered a molecule in the brain responsible for orchestrating the immune system's responses to Alzheimer's disease and multiple sclerosis (MS), potentially allowing doctors to supercharge the body's ability to fight those and other devastating neurological diseases.

The molecule the researchers identified, called a kinase, is crucial to both removing plaque buildup associated with Alzheimer's and preventing the debris buildup that causes MS, the researchers found. It does this, the researchers showed, by directing the activity of brain cleaners called microglia. These immune cells were once largely ignored by scientists but have, in recent years, proved vital players in brain health.

UVA's important new findings could one day let doctors augment the activity of microglia to treat or protect patients from Alzheimer's, MS and other neurodegenerative diseases, the researchers report.

"Unfortunately, medical doctors do not currently possess effective treatments to target the root causes of most neurodegenerative diseases, such as Alzheimer's, Parkinson's or ALS [amyotrophic lateral sclerosis, commonly called Lou Gehrig's disease]. In our studies, we have discovered a master controller of the cell type and processes that are required to protect the brain from these disorders," said senior researcher John Lukens, PhD, of the University of Virginia School of Medicine and its Center for Brain Immunology and Glia (BIG), as well as the Carter Immunology Center and the UVA Brain Institute. "Our work further shows that targeting this novel pathway provides a potent strategy to eliminate the toxic culprits that cause memory loss and impaired motor control in neurodegenerative disease."

Toxic Brain Buildup

Many neurodegenerative diseases, including Alzheimer's and MS, are thought to be caused by the brain's inability to cleanse itself of toxic buildup. Recent advances in neuroscience research have shed light on the importance of microglia in removing harmful debris from the brain, but UVA's new discovery offers practical insights into how this cleaning process occurs -- and the dire consequences when it doesn't.

Using a mouse model of Alzheimer's disease, the UVA researchers found that a lack of the molecule they identified, spleen tyrosine kinase, triggered plaque buildup in the brain and caused the mice to suffer memory loss -- like the symptoms seen in humans with Alzheimer's. Further, the neuroscientists were able to reduce the plaque buildup by activating this molecule and microglia in the brain, suggesting a potential treatment approach for human patients, though that would require significantly more research and testing.

"Our work has described a critical element of microglial function during Alzheimer's disease and MS," said researcher Hannah Ennerfelt, the first author of a new scientific paper outlining the findings. "Understanding the underlying biology of these cells during neurodegeneration may allow for scientists and doctors to develop increasingly informed and effective therapeutic interventions."

A lack of the molecule in a mouse model of MS, meanwhile, led to the buildup of damaged myelin, a protective coating on nerve cells. When myelin is damaged, the cells cannot transmit messages properly, causing MS symptoms such as mobility problems and muscle spasms. The UVA researchers conclude in a new scientific paper that the molecule they identified, abbreviated as SYK, is "critically involved" in the crucial removal of myelin debris. "If boosting SYK activity in microglia can decrease the amount of myelin debris in MS lesions, developing new drugs to target SYK could stop the progression of MS and help to reverse the damage," said Elizabeth L. Frost, PhD, a critical researcher on the project. "This is an especially promising option given that most of the currently available drugs for MS treatment dampen adaptive immunity. These immunosuppressive drugs lead to susceptibility to infection and higher risk of potentially fatal side effects like progressive multifocal leukoencephalopathy. Additionally, some forms of MS do not have a strong involvement of the immune system, and therefore there are currently very limited treatment options for those patients."

"Targeting SYK in microglia," she noted, "would circumvent multiple limitations of present-day therapeutics for MS."

Based on their promising results, the researchers report that targeting the molecule to stimulate the brain's immune activity could offer a way to treat not just Alzheimer's and MS but a "spectrum" of neurodegenerative diseases.

"These findings are especially exciting because they point to a treatment avenue in which we could alter the behavior of these native brain cells, microglia, to behave in a more neuroprotective way," said researcher Coco Holliday, a UVA undergraduate working in the Lukens lab. "It could potentially be applied to a variety of different neurological diseases that all share the problem of a buildup of toxic waste in the brain. It's been a very exciting project to be a part of."

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Study demonstrates that ticks weaken skin's immune response

Hitherto, scientists have not fully understood why ticks are such dangerous disease vectors. A research team led by Johanna Strobl and Georg Stary from MedUni Vienna's Department of Dermatology shows that tick saliva inhibits the skin's defence function, thereby increasing the risk of diseases such as tick-borne encephalitis (TBE) or Lyme disease. The study was recently published in the Journal of Clinical Investigation.

The researchers carried out their investigations on skin samples from volunteers and also on models of human skin, mimicking the bite of the most common European tick (Ixodes ricinus). In both cases, the team led by Georg Stary (MedUni Vienna's Department of Dermatology, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases) in collaboration with the research group of Hannes Stockinger (Center for Pathophysiology, Infectiology and Immunology at MedUni Vienna) identified rapidly occurring patterns of immunomodulation. For example, it was found that the function of immune cells, especially T cells, which are important for immunological memory, was disrupted by contact with tick saliva.

Tick saliva modulates immune system

The scientists made similar observations in early stages of model infection by Borrelia burgdorferi, the most common cause of Lyme disease. They found that pre-incubation of Lyme disease-transmitting bacteria (B. burgdorferi spirochetes) with tick salivary gland extracts impedes the accumulation of immune cells in the skin and increases the pathogen burden. "Overall, we found that tick feeding causes profound changes in the skin's immune system inhibiting the local immune response. This means that dangerous pathogens that are introduced into the skin together with tick saliva, can multiply more easily, leading to infection," says Johanna Strobl, lead author of the study, summarising the main research findings.

Climate change increases danger from ticks

Austria is one of the countries with the greatest prevalence of ticks. Nearly every second European tick is infected with pathogens, Lyme disease and tick-borne encephalitis (TBE) being the most common tick-borne diseases. The arachnids become active at a temperature of seven degrees. Due to rising temperatures associated with climate change, ticks now also pose a threat in higher-altitude regions of Austria and well into late autumn.

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Road signs for immune defense cells

Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defence reaction, specialised cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognise that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.

At this point, antigen processing comes into play. The process can be compared to making a road sign. The molecular barcode is "processed" or assembled in the cell -- in the endoplasmic reticulum, to be exact. Special molecules are used in its making, the MHC class I molecules. They are loaded with information about the virus invader in a molecular machine, the peptide loading complex (PLC). This information consists of peptides, fragments of the protein foreign to the body. These fragments also contain epitopes, the molecular segments that elicit a specific immune response. During the loading process, an MHC I-peptide epitope complex thus forms, and this is the road sign that is then transported to the surface of the cell and presented in a readily accessible form to the killer T cells -- we could almost say that it is handed to them on a silver platter. The chaperones, special accessory proteins that assist the correct folding of proteins with complex structures in cells, also play a significant role.

The chaperones that support antigen processing are calreticulin, ERp57, and tapasin. But how do they work together? And how important are they for antigen processing? An answer has now been supplied by a study carried out by Goethe University Frankfurt and the University of Oxford and published in Nature Communications. "With this study, we have achieved a breakthrough in our understanding of cellular quality control," says Professor Robert Tampé, Director of the Institute of Biochemistry at Goethe University Frankfurt. He explains the logic underlying this quality control process as follows: "The MHC I-peptide epitope complex, the road sign, needs to be exceptionally stable, and for quite a long time, because the adaptive immune response does not start instantly. It needs 3 to 5 days to get going." So, the sign must not collapse after one day; that would be disastrous, as the immune defence cells would then fail to detect cells infected by a virus. This would mean that they would not destroy these cells and the virus would be able to continue its spread unhindered. A similar problem would arise if a cell in the body had mutated into a tumour cell: the threat would remain undetected. It is imperative, therefore, that a quality control system is in place.

As the study shows, the chaperones are central process components: they give the road sign the long-term stability it must have by making a strict selection. By rejecting the short-lived virus fragments in the mass of available material, they ensure that only MHC I molecules loaded with the best and most stable peptide epitopes in complex with MHC I are released from the peptide loading complex. The chaperones have different tasks in this selection process that is so important for the adaptive immune response, Tampé says: "Tapasin acts as a catalyst that accelerates the exchange of suboptimal peptide epitopes for optimal epitopes. Calreticulin and ERp57, in contrast, are deployed universally." This concerted approach ensures that only stable MHC I complexes with optimal peptide epitopes reach the cell surface and perform their role of guiding the killer T cells to the infected or mutated cell.

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How breastfeeding offers immune benefits

When infants breastfeed, they receive an immune boost that helps them fight off infectious diseases, according to recent research from Binghamton University Associate Professor of Anthropology Katherine Wander.

She is the lead author of "Tradeoffs in milk immunity affect infant infectious disease risk," published this June in Evolution, Medicine, and Public Health. Co-authors include Masako Fujita from Michigan State University's Anthropology Department, Siobhan Mattison from the University of New Mexico's Anthropology Department and the National Science Foundation; and Frida Mowo, Ireen Kiwelu and Blandina Mmbaga in Tanzania, whose associations include the Kilimanjaro Christian Medical Centre and the Kilimanjaro Clinical Research Institute. Binghamton University graduate students were also part of the research team, with tasks ranging from data collection in Tanzania to data-cleaning and analysis. They include Margaret Duris, Megan Gauck, Tessa Hopt, Katherine Lacy, Angela Foligno, Rebecca Ulloa and Connor Dodge.

For the project, the research team studied almost 100 mother and baby pairs in rural Kilimanjaro. Prolonged breastfeeding is the norm in this population and infectious diseases during infancy are very common, even compared to other areas of East Africa. This makes Kilimanjaro an ideal setting to begin to understand how immune protection from milk might affect infectious disease risk, Wander said.

"You most often hear about the immune system of milk in terms of transferring maternal antibodies to infants via milk -- which is probably very important -- but it seems there's much more going on as well. The immune system of milk is a whole system, capable of mounting immune responses," Wander said. "We're only beginning to understand the full extent and role of the immune system of milk."

Milk and immunity

Mother's milk contains everything needed to mount immune responses, from antibodies to multiple types of immune cells and more. While they originate from the mother's immune system, these components of milk appear to be curated rather than selected at random from the mother's blood, although that mechanism remains poorly understood, Wander explained.

To test the impact of milk's immune system on infant health, the researchers combined a few milliliters of milk with a small amount of bacteria, then placed the mixture in an incubator overnight. They then measured the increase of interleukin-6, an immune cell communication molecule that promotes inflammation. This in-vitro response gives an indication of how the milk's immune system is likely to respond to bacteria encountered in the infant's body -- the gut, for example.

The research team also followed the Tanzanian infants to assess whether those who received milk that mounted stronger immune responses during the in-vitro tests were at lower risk for infectious diseases. That appeared to be the case: infants whose mothers' milk mounted larger responses to Salmonella had fewer infectious diseases, particularly respiratory infections such as pneumonia.

But milk that mounted larger responses to Salmonella also tended to mount stronger responses to a benign strain of E. coli, which is common in the human intestinal tract, and these responses weren't beneficial to infants. Infants who received milk that mounted stronger responses to E. coli were at higher risk for gastrointestinal infections. This may indicate that inappropriate responses by milk's immune system -- for example, to bacteria normally present in the gut -- can be disruptive. Gut bacteria play an important role in preventing diarrhea and other infectious disease, the authors note.

While all immune responses have tradeoffs, the downside of milk -- both immediate and common -- was a surprising discovery.

"With so much at stake, we really expected the immune system of milk to be very finely tuned to protecting infants against infection," Wander said.

Researchers expected to see, at most, negative effects of inappropriate immune responses somewhere down the line, such as in slower growth or less than ideal microbial flora. But differentiating between microbial friend or foe is a tricky business even for adults' mature immune systems, as is eliminating an infection without damaging the person's own tissues. So, the authors say, maybe they shouldn't have been surprised to see these tradeoffs play out in infants, as well.

In addition to reducing risk for respiratory infectious, milk immune responses may help "train" the infant's developing immune system to respond to dangerous bacteria. More research is needed to determine how immune development calibrates to input, such as experience with infectious diseases, microbial flora and the immune system within milk.

"These findings are interesting, but the implications for public health and healthcare will only become clear with additional research," said co-author Mmbaga of the Kilimanjaro Clinical Research Institute. "We need to understand how milk immune responses are affected by things we can design public health programs around, like HIV infection or malnutrition."

This research may have applications that go beyond infancy and breastfeeding. Figuring out how the immune system has evolved to strike a balance between protection and harm could help shed light on health problems from infant diarrhea and pneumonia to autoimmune diseases.

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Hair-raising research: Scientists find surprising link between immune system, hair growth

Salk scientists have uncovered an unexpected molecular target of a common treatment for alopecia, a condition in which a person's immune system attacks their own hair follicles, causing hair loss. The findings, published in Nature Immunology on June 23, 2022, describe how immune cells called regulatory T cells interact with skin cells using a hormone as a messenger to generate new hair follicles and hair growth.

"For the longest time, regulatory T cells have been studied for how they decrease excessive immune reactions in autoimmune diseases," says corresponding author Ye Zheng, associate professor in Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "Now we've identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration completely separate from suppressing immune response."

The scientists didn't begin by studying hair loss. They were interested in researching the roles of regulatory T cells and glucocorticoid hormones in autoimmune diseases. (Glucocorticoid hormones are cholesterol-derived steroid hormones produced by the adrenal gland and other tissues.) They first investigated how these immune components functioned in multiple sclerosis, Crohn's disease and asthma.

They found that glucocorticoids and regulatory T cells did not function together to play a significant role in any of these conditions. So, they thought they'd have more luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors (which respond to glucocorticoid hormones), such as in skin tissue. The scientists induced hair loss in normal mice and mice lacking glucocorticoid receptors in their regulatory T cells.

"After two weeks, we saw a noticeable difference between the mice -- the normal mice grew back their hair, but the mice without glucocorticoid receptors barely could," says first author Zhi Liu, a postdoctoral fellow in the Zheng lab. "It was very striking, and it showed us the right direction for moving forward."

The findings suggested that some sort of communication must be occurring between regulatory T cells and hair follicle stem cells to allow for hair regeneration.

Using a variety of techniques for monitoring multicellular communication, the scientists then investigated how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples. They found that glucocorticoids instruct the regulatory T cells to activate hair follicle stem cells, which leads to hair growth. This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors induce production of the protein TGF-beta3, all within the regulatory T cells. TGF-beta3 then activates the hair follicle stem cells to differentiate into new hair follicles, promoting hair growth. Additional analysis confirmed that this pathway was completely independent of regulatory T cells' ability to maintain immune balance.

However, regulatory T cells don't normally produce TGF-beta3, as they did here. When the scientists scanned databases, they found that this phenomenon occurs in injured muscle and heart tissue, similar to how hair removal simulated a skin tissue injury in this study.

"In acute cases of alopecia, immune cells attack the skin tissue, causing hair loss. The usual remedy is to use glucocorticoids to inhibit the immune reaction in the skin, so they don't keep attacking the hair follicles," says Zheng. "Applying glucocorticoids has the double benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, stimulating the activation of the hair follicle stem cells."

This study revealed that regulatory T cells and glucocorticoid hormones are not just immunosuppressants but also have a regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.

Read more at Science Daily

Tumors partially destroyed with sound don't come back

Noninvasive sound technology developed at the University of Michigan breaks down liver tumors in rats, kills cancer cells and spurs the immune system to prevent further spread -- an advance that could lead to improved cancer outcomes in humans.

By destroying only 50% to 75% of liver tumor volume, the rats' immune systems were able to clear away the rest, with no evidence of recurrence or metastases in more than 80% animals.

"Even if we don't target the entire tumor, we can still cause the tumor to regress and also reduce the risk of future metastasis," said Zhen Xu, professor of biomedical engineering at U-M and corresponding author of the study in Cancers.

Results also showed the treatment stimulated the rats' immune responses, possibly contributing to the eventual regression of the untargeted portion of the tumor and preventing further spread of the cancer.

The treatment, called histotripsy, noninvasively focuses ultrasound waves to mechanically destroy target tissue with millimeter precision. The relatively new technique is currently being used in a human liver cancer trial in the United States and Europe.

In many clinical situations, the entirety of a cancerous tumor cannot be targeted directly in treatments for reasons that include the mass' size, location or stage. To investigate the effects of partially destroying tumors with sound, this latest study targeted only a portion of each mass, leaving behind a viable intact tumor. It also allowed the team, including researchers at Michigan Medicine and the Ann Arbor VA Hospital, to show the approach's effectiveness under less than optimal conditions.

"Histotripsy is a promising option that can overcome the limitations of currently available ablation modalities and provide safe and effective noninvasive liver tumor ablation," said Tejaswi Worlikar, a doctoral student in biomedical engineering. "We hope that our learnings from this study will motivate future preclinical and clinical histotripsy investigations toward the ultimate goal of clinical adoption of histotripsy treatment for liver cancer patients."

Liver cancer ranks among the top 10 causes of cancer related deaths worldwide and in the U.S. Even with multiple treatment options, the prognosis remains poor with five-year survival rates less than 18% in the U.S. The high prevalence of tumor recurrence and metastasis after initial treatment highlights the clinical need for improving outcomes of liver cancer.

Where a typical ultrasound uses sound waves to produce images of the body's interior, U-M engineers have pioneered the use of those waves for treatment. And their technique works without the harmful side effects of current approaches such as radiation and chemotherapy.

"Our transducer, designed and built at U-M, delivers high amplitude microsecond-length ultrasound pulses -- acoustic cavitation -- to focus on the tumor specifically to break it up," Xu said. "Traditional ultrasound devices use lower amplitude pulses for imaging."

The microsecond long pulses from UM's transducer generate microbubbles within the targeted tissues -- bubbles that rapidly expand and collapse. These violent but extremely localized mechanical stresses kill cancer cells and break up the tumor's structure.

Since 2001, Xu's laboratory at U-M has pioneered the use of histotripsy in the fight against cancer, leading to the clinical trial #HOPE4LIVER sponsored by HistoSonics, a U-M spinoff company. More recently, the group's research has produced promising results on histotripsy treatment of brain therapy and immunotherapy.

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New study reveals why HIV remains in human tissue even after antiretroviral therapy

Thanks to antiretroviral therapy, HIV infection is no longer the life sentence it once was. But despite the effectiveness of drugs to manage and treat the virus, it can never be fully eliminated from the human body, lingering in some cells deep in different human tissues where it goes unnoticed by the immune system.

Now, new research by University of Alberta immunologist Shokrollah Elahi reveals a possible answer to the mystery of why infected people can't get rid of HIV altogether.

Elahi and his team found that in HIV patients, killer T cells -- a type of white blood cells responsible for identifying and destroying cells infected with viruses -- have very little to none of a protein called CD73.

Because CD73 is responsible for migration and cell movement into the tissue, the lack of the protein compromises the ability of killer T cells to find and eliminate HIV-infected cells, explained Elahi.

"This mechanism explains one potential reason for why HIV stays in human tissues forever," he said, adding that the research also shows the complexity of HIV infection.

"This provides us the opportunity to come up with potential new treatments that would help killer T cells migrate better to gain access to the infected cells in different tissues."

After identifying the role of CD73 -- a three-year project -- Elahi turned his focus to understanding potential causes for the drastic reduction. He found it is partly due to the chronic inflammation that is common among people living with HIV.

"Following extensive studies, we discovered that chronic inflammation results in increased levels of a type of RNA found in cells and in blood, called microRNAs," he explained. "These are very small types of RNA that can bind to messenger RNAs to block them from making CD73 protein. We found this was causing the CD73 gene to be suppressed."

The team's discovery also helps explain why people with HIV have a lower risk of developing multiple sclerosis, Elahi noted.

"Our findings suggest that reduced or eliminated CD73 can be beneficial in HIV-infected individuals to protect them against MS. Therefore, targeting CD73 could be a novel potential therapeutic marker for MS patients."

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Scientists find new details about how immune system builds long-term memory

Experts in Japan have identified a fundamental part of the immune system's long-term memory, providing a useful new detail in the pursuit to design better vaccines for diseases, ranging from COVID-19 to malaria. The research, published in the Journal of Experimental Medicine, reveals a new role for the enzyme TBK1 in deciding the fate of immune system memory B cells.

The immune system is made of many cell types, but the two types relevant for this University of Tokyo research project are white blood cells called CD4+ follicular helper T cells and B cells. After the body recognizes an infection, the follicular helper T cells release chemical signals that cause immature B cells to learn and remember what pathogens to attack. This process of T-to-B cell signaling and B cell training occurs within a temporary cell structure called the germinal center in organs of the immune system, including the spleen, lymph nodes and tonsils. Memory B cells developed within the germinal center memorize a pathogen the first time it infects you and then if it ever gets into your body again, the mature, trained memory B cells attack it by inducing antibody production before the pathogen can multiply, saving you from feeling sick a second time.

"A goal of vaccination is to produce high-quality memory B cells for long-lasting antibody production," said Project Assistant Professor Michelle S. J. Lee from the UTokyo Institute of Medical Science, first author of the recent publication.

"There are many factors to consider when designing vaccines for long-lasting immunity, so we should not focus only on the germinal center alone. But if you don't have a functional germinal center, then you will be very susceptible to reinfection," said Lee.

However, there is no limit to the number of times you can be bitten by mosquitoes and reinfected by the malaria parasite. Somehow, malaria parasites escape memory B cells. Although children are more likely to die from malaria than adults, some people can become severely ill despite any number of previous malaria infections.

This ability of the parasite to prevent and evade effective B cells is what makes malaria an interesting pathogen for Professor Cevayir Coban, who leads the Division of Malaria Immunology at the UTokyo Institute of Medical Science and is last author of the research paper with Lee and collaborators at Osaka University.

"We want to understand the fundamentals of the natural immune response. Whatever we do should aim to eventually benefit malaria patients," said Coban. "The COVID-19 pandemic brought global attention to infectious diseases and interest in vaccine design, so we have a chance to renew the focus on neglected diseases like malaria," she continued.

Over many years, the scientific community has identified a wide range of roles for the molecule TBK1, an enzyme that can alter the activity of genes or other proteins by adding chemical tags, through a process called phosphorylation. TBK1 has well-known roles in antiviral immunity. However, no research group had connected TBK1 to B cell fate and the germinal center.

Researchers genetically modified mice that had nonfunctional TBK1 genes only in specific types of cells, primarily either B cells or CD4+ T cells. This cell type-specific knockout of TBK1 gives researchers a clearer idea of what a gene with many jobs is doing in different cells of the body. Coban, Lee and their colleagues infected these modified mice and healthy adult mice with the malaria parasite, observed their health, and then examined samples of their spleens and lymph nodes.

Microscopy images revealed that germinal centers only form in mice that have functional TBK1 in their B cells. Mice with no TBK1 in their B cells were more likely to die and died sooner from the malaria infection than their normal peers. Additional experiments showed that the few mice who survived malaria with no TBK1 in their B cells were able to use other types of immune responses, but they can become reinfected.

However, deleting TBK1 only from the CD4+ follicular helper T cells had no effect on the germinal centers or how the mice fared with a malaria infection.

Further analysis confirmed that without TBK1, many proteins in immature B cells had abnormal phosphorylation compared to normal immature B cells. For different genes, abnormal phosphorylation can cause either abnormal increases or decreases in activity. Researchers suspect that in B cells, TBK1 activity acts as an off switch for certain genes, essentially turning off genes that trap the B cells in their immature state.

"This is the first time to show TBK1 is essential in B cells to form the germinal centers and produce high-quality, mature antibodies," said Lee.

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Immune system-stimulating nanoparticle could lead to more powerful vaccines

A common strategy to make vaccines more powerful is to deliver them along with an adjuvant -- a compound that stimulates the immune system to produce a stronger response.

Researchers from MIT, the La Jolla Institute for Immunology, and other institutions have now designed a new nanoparticle adjuvant that may be more potent than others now in use. Studies in mice showed that it significantly improved antibody production following vaccination against HIV, diphtheria, and influenza.

"We started looking at this particular formulation and found that it was incredibly potent, better than almost anything else we had tried," says Darrell Irvine, the Underwood-Prescott Professor with appointments in MIT's departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT's Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.

The researchers now hope to incorporate the adjuvant into an HIV vaccine that is currently being tested in clinical trials, in hopes of improving its performance.

Irvine and Shane Crotty, a professor at the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology, are the senior authors of the study, which appears today in Science Immunology. The lead authors of the paper are Murillo Silva, a former MIT postdoc, and Yu Kato, a staff scientist at the La Jolla Institute.

More powerful vaccines

Although the idea of using adjuvants to boost vaccine effectiveness has been around for decades, there are only a handful of FDA-approved vaccine adjuvants. One is aluminum hydroxide, an aluminum salt that induces inflammation, and another is an oil and water emulsion that is used in flu vaccines. A few years ago, the FDA approved an adjuvant based on saponin, a compound derived from the bark of the Chilean soapbark tree.

Saponin formulated in liposomes is now used as an adjuvant in the shingles vaccine, and saponins are also being used in a cage-like nanoparticle called an immunostimulatory complex (ISCOM) in a Covid-19 vaccine that is currently in clinical trials.

Researchers have shown that saponins promote inflammatory immune responses and stimulate antibody production, but how they do that is unclear. In the new study, the MIT and La Jolla team wanted to figure out how the adjuvant exerts its effects, and to see if they could make it more potent.

They designed a new type of adjuvant that is similar to the ISCOM adjuvant but also incorporates a molecule called MPLA, which is a toll-like receptor agonist. When these molecules bind to toll-like receptors on immune cells, they promote inflammation. The researchers call their new adjuvant SMNP (saponin/MPLA nanoparticles).

"We expected that this could be interesting because saponin and toll-like receptor agonists are both adjuvants that have been studied separately and shown to be very effective," Irvine says.

The researchers tested the adjuvant by injecting it into mice along with a few different antigens, or fragments of viral proteins. These included two HIV antigens, as well as diphtheria and influenza antigens. They compared the adjuvant to several other approved adjuvants and found that the new saponin-based nanoparticle elicited a stronger antibody response than any of the others.

One of the HIV antigens that they used is an HIV envelope protein nanoparticle, which presents many copies of the gp120 antigen that is present on the HIV viral surface. This antigen recently completed initial testing in phase 1 clinical trials. Irvine and Crotty are part of the Consortium for HIV/AIDS Vaccine Development at the Scripps Research Institute, which ran that trial. The researchers now hope to develop a way to manufacture the new adjuvant at large scale so it can be tested along with an HIV envelope trimer in another clinical trial beginning next year. Clinical trials that combine envelope trimers with the traditional vaccine adjuvant aluminum hydroxide are also underway.

"Aluminum hydroxide is safe but not particularly potent, so we hope that (the new adjuvant) would be an interesting alternative to elicit neutralizing antibody responses in people," Irvine says.

Rapid flow

When vaccines are injected into the arm, they travel through lymph vessels to the lymph nodes, where they encounter and activate B cells. The research team found that the new adjuvant speeds up the flow of lymph to the nodes, helping the antigen to get there before it starts to break down. It does this in part by stimulating immune cells called mast cells, which previously were not known to be involved in vaccine responses.

"Getting to the lymph nodes quickly is useful because once you inject the antigen, it starts slowly breaking down. The sooner a B cell can see that antigen, the more likely it's fully intact, so that B cells are targeting the structure as it will be present on the native virus," Irvine says.

Additionally, once the vaccine reaches the lymph nodes, the adjuvant causes a layer of cells called macrophages, which act as a barrier, to die off quickly, making it easier for the antigen to get into the nodes.

Another way that the adjuvant helps boost immune responses is by activating inflammatory cytokines that drive a stronger response. The TLR agonist that the researchers included in the adjuvant is believed to amplify that cytokine response, but the exact mechanism for that is not known yet.

This kind of adjuvant could also be useful for any other kind of subunit vaccine, which consists of fragments of viral proteins or other molecules. In addition to their work on HIV vaccines, the researchers are also working on a potential Covid-19 vaccine, along with J. Christopher Love's lab at the Koch Institute. The new adjuvant also appears to help stimulate T cell activity, which could make it useful as a component of cancer vaccines, which aim to stimulate the body's own T cells to attack tumors.

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