Posts tagged immune system
Articles and news from the latest research reports.
Month of birth impacts on immune system development
Newborn babies’ immune system development and levels of vitamin D have been found to vary according to their month of birth, according to new research.
The research, from scientists at Queen Mary, University of London and the University of Oxford, provides a potential biological basis as to why an individual’s risk of developing the neurological condition multiple sclerosis (MS) is influenced by their month of birth. It also supports the need for further research into the potential benefits of vitamin D supplementation during pregnancy.
Around 100,000 people in the UK have MS, a disabling neurological condition which results from the body’s own immune system damaging the central nervous system. This interferes with the transmission of messages between the brain and other parts of the body and leads to problems with vision, muscle control, hearing and memory.
The development of MS is believed to be a result of a complex interaction between genes and the environment.
A number of population studies have suggested that the month you are born in can influence your risk of developing MS. This ‘month of birth’ effect is particularly evident in England, where the risk of MS peaks in individuals born in May and drops in those delivered in November. As vitamin D is formed by the skin when it is exposed to sunlight, the ‘month of birth’ effect has been interpreted as evidence of a prenatal role for vitamin D in MS risk.
In this study, samples of cord blood – blood extracted from a newborn baby’s umbilical cord – were taken from 50 babies born in November and 50 born in May between 2009 and 2010 in London.
The blood was analysed to measure levels of vitamin D and levels of autoreactive T-cells. T-cells are white blood cells which play a crucial role in the body’s immune response by identifying and destroying infectious agents, such as viruses. However some T-cells are ‘autoreactive’ and capable of attacking the body’s own cells, triggering autoimmune diseases, and should be eliminated by the immune system during its development. This job of processing T-cells is carried out by the thymus , a specialised organ in the immune system located in the upper chest cavity.
The results showed that the May babies had significantly lower levels of vitamin D (around 20 per cent lower than those born in November) and significantly higher levels (approximately double) of these autoreactive T-cells, compared to the sample of November babies.
Co-author Dr Sreeram Ramagopalan, a lecturer in neuroscience at Barts and The London School of Medicine and Dentistry, part of Queen Mary, said: “By showing that month of birth has a measurable impact on in utero immune system development, this study provides a potential biological explanation for the widely observed “month of birth” effect in MS. Higher levels of autoreactive T-cells, which have the ability to turn on the body, could explain why babies born in May are at a higher risk of developing MS.
“The correlation with vitamin D suggests this could be the driver of this effect. There is a need for long-term studies to assess the effect of vitamin D supplementation in pregnant women and the subsequent impact on immune system development and risk of MS and other autoimmune diseases.”
The research letter is published today in the journal JAMA Neurology.
(Source: qmul.ac.uk)
Comparing mouse and human immune systems
It is a familiar note struck when authors conclude their reports on experiments conducted in mouse models: They suggest caution when translating their findings from mouse to human. A variation of this refrain can be heard when a small molecule that works in mice fails in human clinical trials.
There may be myriad reasons why results differ, and some challenges to the relevance of mouse models to human disease and therapy may be more anecdotal than evidence-driven, scientists say. But the need for better understanding the differences and similarities between human and mouse is clear. Genomic tools and analysis have opened the door to making comprehensive comparisons at a basic level that can inform future research in both mice and humans.
Scientists studying cell differentiation and function in the immune system set out to chart how the mouse and human compare in this area. Tal Shay, a postdoctoral associate in Aviv Regev’s lab at the Broad Institute of Harvard and MIT, led a team from Harvard Medical School, the Broad and Stanford University who compared two large compendia containing transcriptional profiles—how genes are expressed—in human and mouse immune cell types.
The researchers found remarkable consistency between gene expression profiles in the mouse and human immune systems but also some instances of divergence. The majority of gene expression patterns—conservatively estimated at 80 percent—were the same in mouse and human. In addition, they suggest a role for transcriptional regulators that may guide some of the similarities.
Shay and her colleagues reported their findings in PNAS and also deposited their data and analysis in a web portal, which they hope will serve as a reference map for other investigators. Their work is part of the ImmGen Consortium, a collaboration of immunologists and computational biologists generating a complete compendium of gene expression and its regulation in the mouse immune system.
“We wanted to pinpoint where immune system genes and gene expression are different and where you should be very suspicious if something is found in mouse and likely to be translated to human,” said Shay, who is a lead author of the paper. “We thought we might be able to map those places where the comparison is less robust, but we had a very hard time pinpointing convincing differences.”
The researchers had to take extraordinary pains to make sure they were comparing only what was comparable—apples to apples. Not all mouse genes had a corresponding gene in the human data set, or they had more than one: There might be one gene in humans versus five in mice for smell receptors, for example. Sometimes differences were a matter of timing: Genes were activated earlier or later, depending on the species, said David Puyraimond-Zemmour, an HMS graduate student in immunology in the lab of Christophe Benoist and Diane Mathis and a co-author of the PNAS paper.
In all, they found several dozen genes in seven immune cell types that have different expression in 80 human and 137 mouse samples. Their conclusions are based on comparing data from the Differentiation Map—which measures gene expression in about 40 human cell types—and data from ImmGen, which does the same for about 200 mouse cell types. They did further analyses of gene expression when cells were activated in different states, such as responding to infection, based on a data set produced by Ei Wakamatsu and Ting Feng, postdoctoral fellows in the Benoist-Mathis lab. Shay also worked with the Differentiation Map data from the lab of Benjamin Ebert, HMS associate professor of medicine at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and an associate member of the Broad Institute, as well as from the ImmGen Project.
“What we assume most people will be interested in knowing is, if they are working on gene X, whether gene X has the same expression pattern in human and mouse immune systems,” Shay said. “Most lineages have the same expression signature but some genes behave differently and we think it’s important for why some things work in mice but not humans and the other way around.”
Benoist, Morton Grove-Rasmussen Professor of Immunohematology at Harvard Medical School, said the continuing debate about the usefulness of mouse models in understanding humans “is often at the level of the emotional and not necessarily very informed.” Wildly different experimental conditions—hugely varying doses or duration in clinical trials—make comparisons suspect, he said.
Having clear data that scientists can freely access will be useful, said Benoist, who is also a co-author of the PNAS paper.
“The value here is putting up signposts, signaling when the function of a gene in mice may not be relevant to humans,” he said, referring to data and analysis from the work published in PNAS. “Because the differentiation and function of human and mouse lineages are highly related, there is the expectation of conservation, so it is important to know when inter-species inferences may be an issue. Mouse models are far too valuable to be jettisoned for pre-clinical exploration, but it is important to know when caution is needed.”
Separate lives: Neuronal and organismal lifespans decoupled
Replicative aging (also known as replicative senescence) causes mammalian cells to undergo a process of growth arrest dependent on telomeres (the shortening of repeated sequences at the ends of chromosomes). Neurons, on the other hand, are exempt from aging, and so the question of their actual lifespan has remained unanswered. Recently, however, scientists at the University of Pavia and the University of Turin demonstrated that neuronal lifespan is not limited by the organism’s maximum lifespan but, remarkably, continues when transplanted in a longer-living host. The researchers accomplished this by transplanting embryonic mouse cerebellar precursors into the developing brain of longer-living rats, in which the grafted mouse neurons survived for up to three years – twice the average lifespan of the donor mice.
Dr. Lorenzo Magrassi discussed the challenges he and his colleagues, Dr. Ketty Leto and Dr. Ferdinando Rossi, encountered in their research. “Cell transplantation into the developing rat brain is a technique that was originally developed by us and other research groups in the early nineties of the last century,” Magrassi tells Medical Xpress. “In recent years, we improved the protocol that, now standardized, allows reliable implantation rates with good survival rates.” While not all implanted embryos develop into adult animals carrying a viable transplant, Magrassi adds, the percentage of those that do is sufficient to plan a long-term survival experiment involving roughly 100 such successfully-born animals.
In addressing these challenges, Magrassi says that together with the intrinsic bonus of studying cells inside the nervous system, which is immunoprivileged, they transplanted cells before development of the thymus (a specialized organ of the immune system) was complete. The latter can help induce immunological tolerance in the host to the engrafted cells.
One remaining question is if their research can potentially be extended to determine whether or not a maximum lifespan exists for any postmitotic mammalian cells – Including neurons. “Similar techniques can, in principle, be extended to other organs containing perennial cells,” Magrassi notes, “but we don’t have direct experience with injecting cells into organs outside of the central nervous system.” Since the central nervous system is privileged compared to other organs that are more prone to immunological surveillance and attack, a major problem when transferring their experimental paradigm to other organs, he explains, could be an increase in immunological problems.
The scientists say their results suggest that neuronal survival and aging are coincidental but separable processes, thus increasing the hope that extending organismal lifespan by dietary, behavioral, and pharmacologic interventions will not necessarily result in a neuronally depleted brain. “Even after taking into account the obvious species differences, our results in rodents can be extrapolated by analogy to humans and other longer-living species where this sort of experiment is impossible,” Magrassi explains. “Our findings suggest that extending life by extending average organismal lifespan – a hallmark of all technologically advanced societies – will not necessarily result in neuron-impoverished brains well before the longer-living individual dies.” This bodes well for those studying life extension: Their efforts are not intrinsically futile, Magrassi notes, because in the absence of pathology, prolonging life span does not necessarily mean dementia due to widespread loss of neurons, as many people still think. “Roughly speaking,” Magrassi illustrates, “if the average lifespan of humans is now 80 years, our results suggest that at ages up to 160 years our neurons can survive if not hit by specific insults.
That said, however, Magrassi acknowledges that neuronal death is not the only effect of normal aging in the brain. “For example,” he illustrates, “cerebellar neurons – which in term of synaptic loss behave like the majority of neurons in the brain – show a substantial loss of dendritic branches, spines and synapses in normal aging. In our research, we studied transplanted mouse Purkinje cells to determine if their spine density decreased with time at the same rate of Purkinje cells in the mouse or in the rat.” Purkinje cells are large GABAergic (that is, gamma-Aminobutyric acid-producing) neurons, with many branching extensions, found in the cortex of the cerebellum. “The results of our experiments indicate that age-related progressive spine loss of grafted mouse Purkinje cells follows a slower pace, typical of the longer living rat, thus reaching absolute levels of spine loss comparable to those observed in aged mice at much longer survival times that are typical of the rat.”
Moreover, Magrassi adds that their experiments clearly show that by escaping immunological rejection, transplanted neurons can survive undisturbed for the entire life of the host. “This has implications for the ongoing discussion of the detrimental effects of immune attacks on transplanted neural cells for therapeutic purposes,”
Moving forward, in order to screen for intra- and extracellular changes that could be responsible for the long term survival of the mouse cells transplanted into rat brains – as well as the slowdown of dendritic spine loss – the team is planning to perform host and transplanted cell microdissection followed by a proteomic approach. “If we discover what factor or factors cause those changes,” Magrassi points out, “we could hopefully then develop more efficient drugs for treating all pathological neurodegenerative conditions in which neurons start to lose synaptic contacts and die well before organismal death – for example, dementia, memory loss and cognitive impairment. Of course,” he adds, “this work is still in progress and the results are preliminary.”
In addition, the scientists are currently testing xenotransplantation using different transgenic mouse strains with altered aging pathways as donors to characterize the pathways that led to their results.
Magrassi sees other areas of research that might benefit from their study. “Knowing that neuronal aging in rodents is not a cell-autonomous process is important not only for neuroscience,” he concludes. “It also has implications for evolutionary biology and epidemiology.”
(Source: medicalxpress.com)
Hunger-spiking neurons could help control autoimmune diseases
Neurons that control hunger in the central nervous system also regulate immune cell functions, implicating eating behavior as a defense against infections and autoimmune disease development, Yale School of Medicine researchers have found in a new study published in the Proceedings of the National Academies of Sciences (PNAS).
Autoimmune diseases have been on a steady rise in the United States. These illnesses develop when the body’s immune system turns on itself and begins attacking its own tissues. The interactions between different kinds of T cells are at the heart of fighting infections, but they have also been linked to autoimmune disorders.
“We’ve found that if appetite-promoting AgRP neurons are chronically suppressed, leading to decreased appetite and a leaner body weight, T cells are more likely to promote inflammation-like processes enabling autoimmune responses that could lead to diseases like multiple sclerosis,” said lead author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.
“If we can control this mechanism by adjusting eating behavior and the kinds of food consumed, it could lead to new avenues for treating autoimmune diseases,” he added.
Horvath and his research team conducted their study in two sets of transgenic mice. In one set, they knocked out Sirt1, a signaling molecule that controls the hunger-promoting neuron AgRP in the hypothalamus. These Sirt1-deficient mice had decreased regulatory T cell function and enhanced effector T cell activity, leading to their increased vulnerability in an animal model of multiple sclerosis.
“This study highlights the important regulatory role of the neurons that control appetite in peripheral immune functions,” said Horvath. “AgRP neurons represent an important site of action for the body’s immune responses.”
The team’s data support the idea that achieving weight loss through the use of drugs that promote a feeling of fullness “could have unwanted effects on the spread of autoimmune disorders,” he notes.
Can Boosting Immunity Make You Smarter?
After spending a few days in bed with the flu, you may have felt a bit stupid. It is a common sensation, that your sickness is slowing down your brain. At first blush, though, it doesn’t make much sense. For one thing, flu viruses infect the lining of the airways, not the neurons in our brains. For another, the brain is walled off from the rest of the body by a series of microscopic defenses collectively known as the blood-brain barrier. It blocks most viruses and bacteria while allowing essential molecules like glucose to slip through. What ails the body, in other words, shouldn’t interfere with our thinking.
But over the past decade, Jonathan Kipnis, a neuroimmunologist in the University of Virginia School of Medicine’s department of neuroscience, has discovered a possible link, a modern twist on the age-old notion of the body-mind connection. His research suggests that the immune system engages the brain in an intricate dialogue that can influence our thought processes, coaxing our brains to work at their best.
You might not be able to pick your fingerprint out of an inky lineup, but your brain knows what you smell like. For the first time, scientists have shown that people recognize their own scent based on their particular combination of major histocompatibility complex (MHC) proteins, molecules similar to those used by animals to choose their mates. The discovery suggests that humans can also exploit the molecules to differentiate between people.
"This is definitely new and exciting," says Frank Zufall, a neurobiologist at Saarland University’s School of Medicine in Homburg, Germany, who was not involved in the work. "This type of experiment had never been done on humans before."
MHC peptides are found on the surface of almost all cells in the human body, helping inform the immune system that the cells are ours. Because a given combination of MHC peptides—called an MHC type—is unique to a person, they can help the body recognize invading pathogens and foreign cells. Over the past 2 decades, scientists have discovered that the molecules also foster communication between animals, including mice and fish. Stickleback fish, for example, choose mates with different MHC types than their own. Then, in 1995, researchers conducted the now famous “sweaty T-shirt study,” which concluded that women prefer the smell of men who have different MHC genes than themselves. But no studies had shown a clear-cut physiological response to MHC proteins.
In the new work, Thomas Boehm, a biologist at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, and colleagues first tested whether women can recognize lab-made MHC proteins resembling their own. After showering, 22 women applied two different solutions to their armpits and decided which odor they liked better. The experiment was repeated two to six times for each participant. Women preferred to wear a synthetic scent containing their own MHC proteins, but only if they were nonsmokers and didn’t have a cold. The study did not determine which scents women preferred on other people, but past studies on perfume have shown that individuals prefer different smells on themselves than on others.
The researchers wanted to know whether the preferences were truly rooted in the brain’s response to the proteins. So next, they used functional magnetic resonance imaging to measure changes in the brains of 19 different women when they smelled the various solutions, in aerosol form puffed toward their noses. “Sure enough, there again was a clear difference between the response to self and non-self peptides,” Boehm says. “There was a particular region of the brain that was only activated by peptides resembling a person’s own MHC molecules.” The brain had a similar response to all non-self MHC combinations, suggesting that any preference for how other people smell is a preference for non-self, not for particular MHC types.
(Image: Getty)
Leprosy Bacteria Turn Nerve System Cells into Stem Cells
The study, carried out in mice, found that in the early stages of infection, M. leprae were able to protect themselves from the body’s immune system by hiding in the Schwann cells. Once the infection was fully established, the bacteria were able to convert the Schwann cells to become like stem cells.
Like typical stem cells, these cells were pluripotent, meaning they could then become other cell types, for instance muscle cells. This enabled M. leprae to spread to tissues in the body.
The study, published in the journal Cell, also shows that the bacteria-generated stem cells have unexpected characteristic. They can secrete specialized proteins – called chemokines – that attract immune cells, which in turn pick up the bacteria and spread the infection.
“We have found a new weapon in a bacteria’s armory that enables them to spread effectively in the body by converting infected cells to stem cells. Greater understanding of how this occurs could help research to diagnose bacterial infectious diseases, such as leprosy, much earlier,” said study lead author Prof Anura Rambukkana, Medical Research Council Center for Regenerative Medicine at the University of Edinburgh.
“This is very intriguing as it is the first time that we have seen that functional adult tissue cells can be reprogrammed into stem cells by natural bacterial infection, which also does not carry the risk of creating tumorous cells. Potentially you could use the bacteria to change the flexibility of cells, turning them into stem cells and then use the standard antibiotics to kill the bacteria completely so that the cells could then be transplanted safely to tissue that has been damaged by degenerative disease.”
Dr Rob Buckle, Head of Regenerative Medicine at the Medical Research Council Center for Regenerative Medicine at the University of Edinburgh, said: “this ground-breaking new research shows that bacteria are able to sneak under the radar of the immune system by hijacking a naturally occurring mechanism to ‘reprogramme’ cells to make them look and behave like stem cells. This discovery is important not just for our understanding and treatment of bacterial disease, but for the rapidly progressing field of regenerative medicine. In future, this knowledge may help scientists to improve the safety and utility of lab-produced pluripotent stem cells and help drive the development of new regenerative therapies for a range of human diseases, which are currently impossible to treat.”
The scientists believe mechanisms used by leprosy bacteria could exist in other infectious diseases. Knowledge of this newly discovered tactic used by bacteria to spread infection could help research to improve treatments and earlier diagnosis of infectious diseases.
Simulated Mars Mission Reveals Body’s Sodium Rhythms
Clinical pharmacologist Jens Titze, M.D., knew he had a one-of-a-kind scientific opportunity: the Russians were going to simulate a flight to Mars, and he was invited to study the participating cosmonauts.
Titze, now an associate professor of Medicine at Vanderbilt University, wanted to explore long-term sodium balance in humans. He didn’t believe the textbook view – that the salt we eat is rapidly excreted in urine to maintain relatively constant body sodium levels. The “Mars500” simulation gave him the chance to keep salt intake constant and monitor urine sodium levels in humans over a long period of time.
Now, in the Jan. 8 issue of Cell Metabolism, Titze and his colleagues report that – in contrast to the prevailing dogma – sodium levels fluctuate rhythmically with 7-day and monthly cycles. The findings, which demonstrate that sodium is stored in the body, have implications for blood pressure control, hypertension and salt-associated cardiovascular risk.
Titze’s interest in sodium balance was sparked by human space flight simulation studies he conducted in the 1990s that showed rhythmic variations in sodium urine excretion.
“It was so clear to me that sodium must be stored in the body, but no one wanted to hear about that because it was so different from the textbook view,” he said.
He and his team persisted with animal studies and demonstrated that the skin stores sodium and that the immune system regulates sodium release from the skin.
In 2005, planning began for Mars500 – a collaboration between Russia, the European Union and China to prepare for manned spaceflight to Mars. Mars500 was conducted at a research facility in Moscow between 2007 and 2011 in three phases: a 15-day phase to test the equipment, a 105-day phase, and a 520-day phase to simulate a full-length manned mission.
Crews of healthy male cosmonauts volunteered to live and work in an enclosed habitat of sealed interconnecting modules, as if they were on an international space station. Titze and his colleagues organized the food for the mission and secured commitments from the participants to consume all of the food and to collect all urine each day. They studied twelve men: six for the full 105-day phase of the program, and six for the first 205 days of the 520-day phase.
“It was the participants’ stamina to precisely adhere to the daily menu plans and to accurately collect their urine for months that allowed scientific discovery,” Titze said. The researchers found that nearly all (95 percent) of the ingested salt was excreted in the urine, but not on a daily basis. Instead, at constant salt intake, sodium excretion fluctuated with a weekly rhythm, resulting in sodium storage. The levels of the hormones aldosterone (a regulator of sodium excretion) and cortisol (no known major role in sodium balance) also fluctuated weekly.
Changes in total body sodium levels fluctuated on monthly and longer cycles, Titze said. Sodium storage on this longer cycle was independent of salt intake and did not include weight gain, supporting the idea that sodium is stored without accompanying increases in water.
The findings suggest that current medical practice and studies that rely on 24-hour urine samples to determine salt intake are not accurate, he said. “We understand now that there are 7-day and monthly sodium clocks that are ticking, so a one-day snapshot shouldn’t be used to determine salt intake.”
Using newly developed magnetic resonance imaging (MRI) technologies to view sodium, Titze and his colleagues have found that humans store sodium in skin (as they found in their animal studies) and in muscle.
The investigators suspect that genes related to the circadian “clock” genes, which regulate daily rhythms, may be involved in sodium storage and release. “We find these long rhythms of sodium storage in the body particularly intriguing,” Titze said. “The observations open up entirely new avenues for research.”
Autoimmune disease – retraining white blood cells
How can the immune system be reprogrammed once it goes on the attack against its own body? EPFL scientists retrained T-cells involved in type I diabetes, a common autoimmune disease. Using a modified protein, they precisely targeted the white blood cells (T-lymphocytes, or T-cells) that were attacking pancreatic cells and causing the disease. When tested on laboratory mice, the therapy eliminated all signs of the pathology. This same method could be a very promising avenue for treating multiple sclerosis as well. The scientists have just launched a start-up company, Anokion SA, on the Lausanne campus, and are planning to conduct clinical trials within the next two years. Their discovery has been published in the journal PNAS (Proceedings of the National Academy of Science).
To retrain the rebellious white blood cells, the researchers began with a relatively simple observation: every day, thousands of our cells die. Each time a cell bites the dust, it sends out a message to the immune system. If the death is caused by trauma, such as an inflammation, the message tends to stimulate white blood cells to become aggressive. But if the cell dies a programmed death at the end of its natural life cycle, it sends out a soothing signal.
In the human body there is a type of cell that dies off en masse, on the order of 200 billion per day – red blood cells. Each of these programmed deaths sends a soothing message to the immune system. The scientists took advantage of this situation, and attached the pancreatic protein targeted by T-cells in type I diabetes to red blood cells.
"Our idea was that by associating the protein under attack to a soothing event, like the programmed death of red blood cells, we would reduce the intensity of the immune response," explains Jeffrey Hubbell, co-author of the study. To do this, the researchers had to do some clever bioengineering and equip the protein with a tiny, molecular scale hook, that is able to attach itself to a red blood cell. Billions of these were manufactured and then simply injected into the body.
Complete eradication of diabetes symptoms
As these billions of red blood cells died their programmed death, they released two signals: the artificially attached pancreatic protein, and the soothing signal. The association of these two elements, like Pavlov’s dog, who associates the ringing of a bell with a good or bad outcome, essentially retrained the T lymphocytes to stop attacking the pancreatic cells. “It was a total success. We were able to eliminate the immune response in type I diabetes in mice,” explains Hubbell.
Minimizing risks and side effects
Co-author Stephan Kontos adds that the great advantage of this approach is its extreme precision. “Our method carries very little risk and shouldn’t introduce significant side effects, in the sense that we are not targeting the entire immune system, but just the specific kind of T-cells involved in the disease.”
The scientists are planning to conduct clinical trials in 2014, at the earliest. To demonstrate the potential of their method, they plan to first test applications that would counteract the immune response to a drug known for its effectiveness against gout. “We chose to begin with this application before we tackled diabetes or multiple sclerosis, since we knew and were in control of all the parameters,” explains Hubbell.
Currently, the researchers are also testing the potential of this method in treating multiple sclerosis. In this disease, T-cells destroy myelin cells, which form a protective sheath around nerve fibers. They are also studying the potential of their method with another kind of white blood cell, B-lymphocytes, that are involved in many other autoimmune diseases.
(Source: eurekalert.org)
Brain displays an intrinsic mechanism for fighting infection
White blood cells have long reigned as the heroes of the immune system. When an infection strikes, the cells, produced in bone marrow, race through the blood to fight off the pathogen. But new research is emerging that individual organs can also play a role in immune system defense, essentially being their own hero. In a study examining a rare and deadly brain infection, scientists at The Rockefeller University have found that the brain cells of healthy people likely produce their own immune system molecules, demonstrating an “intrinsic immunity” that is crucial for stopping an infection.
Shen-Ying Zhang, a clinical scholar in the St. Giles Laboratory of Human Genetics of Infectious Diseases, has been studying children with Herpes simplex encephalitis, a life-threatening brain infection from the herpes virus, HSV-1, that can cause significant brain damage. The scientists already knew from previous work that children with this encephalitis have a genetic defect that impairs the function of an immune system receptor — toll-like receptor 3 (TLR3) — in the brain. For this study they wanted to see how the defect in TLR3 was hampering the brain’s ability to fight the herpes infection.
When TLR3 detects a pathogen it triggers an immune response causing the release of proteins called interferons to sound the alarm and “interfere” with the pathogen’s replication. It’s most commonly associated with white blood cells, found throughout the body, but here the researchers were examining the receptor’s presence on neurons and other brain cells.
“One interesting thing about these patients is that they didn’t have any of the other, more common herpes symptoms. They didn’t have an infection on their skin or their mouths, just in their brains. We therefore hypothesized that the TLR3 response must be specifically responsible for keeping the herpes virus from infecting the brain and not necessary in other parts of the body,” says Zhang.
The lab, headed by Jean-Laurent Casanova, collaborated with scientists at Harvard Medical School and Memorial Sloan-Kettering Cancer Institute to create induced pluripotent stem cells. Made from the patients’ own tissue, the stem cells were developed into central nervous system cells that carried the patients’ genetic defects. Zhang exposed the cells to HSV-1 and to synthetic double-stranded RNA, which mimics a byproduct of the virus that spurs the toll-like receptors into action. By measuring levels of interferon, Zhang showed that the patients’ TLR3 response was indeed faulty; their cells weren’t making these important immune system proteins, leaving them unable to fight off the infection.
Zhang also exposed the patients’ blood cells to the virus and found that the TLR3 defect was not an issue there as it was in the brain — interferons were released by other means.
Because the toll-like receptors on neurons proved to be vital in preventing the encephalitis infection, the researchers concluded that brain cells use it as an in-house mechanism to fight infection, rather than relying on white blood cells. When its function was impaired, patients couldn’t get better.
“This is evidence of an intrinsic immunity, a newly-discovered function of the immune system,” says Zhang. “It’s likely that other organs also have their own specific tools for fighting infection.”
The researchers are putting together a pilot study to test an interferon-based treatment in patients with the encephalitis, believing it will help speed recovery and increase the survival rate when used alongside antiviral drugs. They’ll also explore whether the brain displays an intrinsic immunity to other types of viral infection.