Seasonal immunity: Activity of thousands of genes differs from winter to summer

 

Changing seasons (stock image). Scientists have known for some time that various diseases, including cardiovascular disease, autoimmune diseases such as type 1 diabetes and multiple sclerosis, and psychiatric disorders, display seasonal variation, as does vitamin D metabolism. Credit: © Naj / Fotolia Our immune systems vary with the seasons, according to a study led by the University of Cambridge that could help explain why certain conditions such as heart disease and rheumatoid arthritis are aggravated in winter whilst people tend to be healthier in the summer. The study, published in the journal Nature Communications, shows that the activity of almost a quarter of our genes (5,136 out of 22,822 genes tested) differs according to the time of year, with some more active in winter and others more active in summer. This seasonality also affects our immune cells and the composition of our blood and adipose tissue (fat). Scientists have known for some time that various diseases, including cardiovascular disease, autoimmune diseases such as type 1 diabetes and multiple sclerosis, and psychiatric disorders, display seasonal variation, as does vitamin D metabolism. However, this is the first time that researchers have shown that this may be down to seasonal changes in how our immune systems function. "This is a really surprising -- and serendipitous -- discovery as it relates to how we identify and characterise the effects of the susceptibility genes for type 1 diabetes," says Professor John Todd, Director of the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory. "In some ways, it's obvious -- it helps explain why so many diseases, from heart disease to mental illness, are much worse in the winter months -- but no one had appreciated the extent to which this actually occurred. The implications for how we treat disease like type 1 diabetes, and even how we plan our research studies, could be profound." An international team, led by researchers from the JDRF/Wellcome Trust Diabetes and Inflammation Laboratory in the Department of Medical Genetics, Cambridge Institute for Medical Research, examined samples from over 16,000 people living in both the northern and southern hemispheres, in countries including the UK, USA, Iceland, Australia and The Gambia. These samples included a mixture of blood samples and adipose tissue. The researchers used a variety of techniques to study the samples, including looking at the cell types found in the blood and measuring the level of expression of the individuals' genes -- a gene is said to be 'expressed' when it is active in a particular cell or tissue, usually involving the generation of proteins. They found that the thousands of genes were expressed differently in blood and adipose tissue depending on what time of year the samples were taken. Similarly, they identified seasonal differences in the types of cells found in the blood. Seasonal differences were present across mixed populations in geographically and ethnically diverse locations -- but the seasonal genes displayed opposing patterns in the northern and southern hemispheres. However, the pattern of seasonal activity was not reflected as strongly in Icelandic donors. The researchers speculate that this may be due to the near-24 hour daylight during summer and near-24 hour darkness in winter. One gene of particular interest was ARNTL, which was more active in the summer and less active in the winter. Previous studies have shown that, in mice at least, the gene suppresses inflammation, the body's response to infection; if the gene has the same function in humans, then levels of inflammation will be higher during winter in the northern hemisphere. Inflammation is a risk factor for a range of diseases and hence in winter, those at greatest risk will likely reach the 'threshold' at which the disease becomes a problem much sooner. Drugs that target the mechanisms behind inflammation could offer a way of helping treat these diseases more effectively during the winter periods. A particularly surprising finding was that a set of genes associated to an individual's response to vaccination was more active in winter, suggesting that some vaccination programmes might be more effective if carried out during winter months when the immune system is already 'primed' to respond. During European and Australian winters, they argue, the thresholds required to trigger an immune response may be lower as a direct consequence of our coevolution with infectious organisms, which tend to be more prevalent during winter. Interestingly, people from The Gambia showed distinct seasonal variation in the numbers of immune cells in the blood that correlated with the rainy season (June-October), during which time infectious diseases, particularly mosquito-borne diseases such as malaria, are more rife. "We know that humans adapt to changing environments," says Dr Chris Wallace. "Our paper suggests that human immune systems adapt to show different seasonal variation in equatorial regions with fewer distinct seasons compared to regions at higher and lower latitudes with more pronounced differences between winter and season." It is not clear yet what mechanism maintains the seasonal variation seen in the immune system, though it may be due to environmental cues such as daylight and ambient temperature. Our internal body clock -- known as our circadian rhythm -- is in part coordinated by changes in daylight, which explains why people in jobs that do not fit with the daily cycle, such as factory shift workers or crews on long haul flights, can be affected by poorer health. Professor Todd adds: "Given that our immune systems appear to put us at greater risk of disease related to excessive inflammation in colder, darker months, and given the benefits we already understand from vitamin D, it is perhaps understandable that people want to head off for some 'winter sun' to improve their health and well-being." The research was funded by the Wellcome Trust, the type 1 diabetes charity JDRF and the NIHR Cambridge Biomedical Research Centre. Professor Mike Turner, Head of Infection and Immunobiology at the Wellcome Trust said: "This is an excellent study which provides real evidence supporting the popular belief that we tend to be healthier in the summer. Seasonal variation to this extent is a fascinating find -- the activity of many of our genes, as well as the composition of our blood and fat tissue, varies depending on the seasons. Although we are still unclear of the mechanism that governs this variation, one possible outcome is that treatment for certain diseases could be more effective if tailored to the seasons." Karen Addington, Chief Executive of JDRF in the UK, said: "We have long known there are more diagnoses of type 1 diabetes in winter. This study begins to reveal why. It identifies a biological mechanism we didn't previously know of, which leaves the body seasonally more prone to the autoimmune attack seen in type 1 diabetes. "While we all love winter sun, flying south for the whole of each winter isn't something anyone can practically recommend as a way of preventing type 1 diabetes. But this new insight does open new avenues of research that could help untangle the complex web of genetic and environmental factors behind a diagnosis."

Environment, not genes, dictates human immune variation, study finds

 

Mark Davis and his colleagues have discovered that our environment, not our genes, play a greater factor in shaping the human immune system. A study of twins conducted by Stanford University School of Medicine investigators shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body's primary defense against disease. This is especially true as we age, the study indicates. Much has been made of the role genes play in human health. Stunning advances in gene-sequencing technologies, in concert with their plummeting costs, have turned many scientists' attention to minute variations in the genome -- the entire toolbox of genes carried in virtually every cell in the body -- in the hope of predicting people's future health. Such studies have revealed a genetic contribution to health outcomes. But, with some notable exceptions, very few individual genetic variants contribute much to particular health conditions. "The idea in some circles has been that if you sequence someone's genome, you can tell what diseases they're going have 50 years later," said Mark Davis, PhD, professor of microbiology and immunology and director of Stanford's Institute for Immunity, Transplantation and Infection. But while genomic variation clearly plays a key role in some diseases, he said, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation. "The immune system has to think on its feet," said Davis, senior author of the new study, which will be published Jan. 15 in Cell. Lead authorship is shared by former Stanford postdoctoral scholars Petter Brodin, MD, PhD, and Vladimir Jojic, PhD. Nature versus nurture "Unlike inbred lab mice, people have broadly divergent genetic heritages," said Davis, who is also the Burt and Marion Avery Family Professor. "And when you examine people's immune systems, you often find tremendous differences between them. So we wondered whether this reflects underlying genetic differences or something else. But what we found was that in most cases, including the reaction to a standard influenza vaccine and other types of immune responsiveness, there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver." To determine nature's and nurture's relative contributions, Davis and his colleagues turned to a century-old method of teasing apart environmental and hereditary influences: They compared pairs of monozygotic twins -- best known to most of us as "identical" -- and of dizygotic, or fraternal, twins. Monozygotic twins inherit the same genome. Despite inevitable copying errors when cells divide, which cause tiny genetic divergences to accumulate between monozygotic twins over time, they remain almost 100 percent genetically identical. Dizygotic twins are no more alike genetically than regular siblings, on average sharing 50 percent of their genes. Because both types of twins share the same environment in utero and usually share the same environment in childhood, they make excellent subjects for contrasting hereditary versus environmental influence. About two decades ago, study co-author Gary Swan, PhD, who was then at SRI Inc. and is now a consulting professor of medicine at Stanford, began curating a registry of twins for research purposes. The registry now includes about 2,000 twin pairs. For the new study, the researchers recruited 78 monozygotic-twin pairs and 27 pairs of dizygotic twins from the registry. They drew blood from both members of each twin pair on three separate visits. The Stanford team then applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system components and activities. All samples were sent immediately to Stanford's Human Immune Monitoring Core, which houses the latest immune-sleuthing technology under a single roof. The power of environment Examining differences in the levels and activity states of these components within pairs of monozygotic and dizygotic twins, the Stanford scientists found that in three-quarters of the measurements, nonheritable influences -- such as previous microbial or toxic exposures, vaccinations, diet and dental hygiene -- trumped heritable ones when it came to accounting for differences within a pair of twins. This environmental dominance was more pronounced in older identical twins (age 60 and up) than in younger twins (under age 20). Davis and his associates also observed considerable environmental influence over the quantities of antibodies produced in members of twin pairs who had been vaccinated for influenza in a separate Stanford investigation directed by study co-author Cornelia Dekker, MD, professor of pediatric infectious disease and medical director of the Stanford-Lucile Packard Children's Hospital Vaccine Program. While many previous studies have suggested a powerful genetic component in vaccine responsiveness, Davis noted that those studies typically were performed in very young children who had not yet undergone the decades of environmental exposure that appears to reshape the immune system over time. In a striking example of the immune system's plasticity, the Stanford scientists found that the presence or absence of a single chronic viral infection could have a massive effect on the system's composition and responsiveness. Three out of five people in the USA and as many as nine out of 10 people in the developing world are chronic carriers of cytomegalovirus, which is dangerous in immune-compromised people but otherwise generally benign. In 16 of the 27 monozygotic twin pairs participating in the study, one member of the pair had been exposed to cytomegalovirus but the other had not. For nearly 60 percent of all the features Davis' group measured, cytomegalovirus' presence in one twin and absence in another made a big difference. "Nonheritable influences, particularly microbes, seem to play a huge role in driving immune variation," said Davis. "At least for the first 20 or so years of your life, when your immune system is maturing, this amazing system appears able to adapt to wildly different environmental conditions. A healthy human immune system continually adapts to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more, overshadowing the influences of most heritable factors."

Could Multiple Sclerosis Begin in the Gut?

 

MS researchers are focusing on the content of the gut’s microbiome as a possible contributor to the body’s autoimmune attack on its nervous system

Oct 8, 2014 By Bret Stetka

Mounting evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and, it appears, MS.  Credit: ARS via Wikimedia Commons

Multiple sclerosis (MS) is an electrical disorder, or rather one of impaired myelin, a fatty, insulating substance that better allows electric current to bolt down our neurons and release the neurotransmitters that help run our bodies and brains. Researchers have speculated for some time that the myelin degradation seen in MS is due, at least in part, to autoimmune activity against the nervous system. Recent work presented at the MS Boston 2014 Meeting suggests that this aberrant immune response begins in the gut.

Eighty percent of the human immune system resides in the gastrointestinal tract. Alongside it are the trillions of symbiotic bacteria, fungi and other single-celled organisms that make up our guts’ microbiomes. Normally everyone wins: The microorganisms benefit from a home and a steady food supply; we enjoy the essential assistance they provide in various metabolic and digestive functions. Our microbiomes also help calibrate our immune systems, so our bodies recognize which co-inhabitants should be there and which should not. Yet mounting evidence suggests that when our resident biota are out of balance, they contribute to numerous diseases, including diabetes, rheumatoid arthritis, autism and, it appears, MS by inciting rogue immune activity that can spread throughout the body and brain.

One study presented at the conference, out of Brigham and Women’s Hospital (BWH), reported a single-celled organism called methanobrevibacteriaceae that activates the immune system is enriched in the gastrointestinal tracts of MS patients whereas bacteria that suppress immune activity are depleted. Other work, which resulted from a collaboration among 10 academic researcher centers across the U.S. and Canada, reported significantly altered gut flora in pediatric MS patients while a group of Japanese researchers found that yeast consumption reduced the chances of mice developing an MS-like disease by altering gut flora.

Sushrut Jangi, a staff physician at Beth Israel Deaconess Medical Center in Boston who co-authored the BWH study, thinks that regional dietary influences might even be at play. “The biomes of people living in different areas and who consume Western versus non-Western diets are demonstratively different,” he says. “People who emigrate from non-Western countries, including India, where MS rates are low, consequently develop a high risk of disease in the U.S. One idea to explain this is that the biome may shift from an Indian biome to an American biome,” although there is not yet data to support this theory.

The microbiome theory is gaining so much steam in academia that a coalition of four U.S. research centers called the MS Microbiome Consortium recently formed to investigate the role of gut microorganisms in the disease. The group presented data in Boston showing significantly different gastrointestinal bacterial populations in patients treated with the MS drug glatiramer acetate compared with untreated subjects. How exactly the drug suppresses MS activity is unknown but the findings suggest that perhaps it works in part by altering gut flora and, as a result, suppressing abnormal immune activity. “The gut is well-positioned for an important role in the development of autoimmune disease, including MS.,” says Ilana Katz Sand, an assistant professor of neurology at Mount Sinai Medical Center in New York City and member of the MS Microbiome Consortium. “But important questions remain, such as how MS medications affect the microbiome, how an individual’s microbiome may affect treatment responses, whether particular bacterial species are associated with more severe disease and ultimately whether we can manipulate the microbiome to benefit our patients.”

Katz Sand says that dietary and probiotic approaches to treating MS are worth pursuing, as is a less palatable approach: fecal transplantation. Yet answers in science and medicine are rarely simple, she added, pointing out that in all likelihood MS arises from a complicated confluence of genetic and environmental influences that might ultimately trigger autoimmune activity. Beyond just our gut flora well over 100 genetic variants—many related to immune function—are now known to contribute to the disease as are external factors including vitamin D deficiency (MS is more common at higher latitudes), smoking and increased salt intake.

Further confounding our ability to pinpoint root causes is that our genetic code influences how our bodies and brains respond to these external factors. It could be that both genes and environmental stimuli lead to pathologic microbiomes or that some unfortunate combination of these factors leads to a common autoimmunologic pathway that ravages myelin. “We know the microbiome shapes our immune system and that MS is an immune-mediated disease. We also know that genes influence our microbiomes and immune systems,” says David Hafler, professor of neurology and immunobiology at Yale University School of Medicine who was at the conference but not involved in the microbiome work presented. But there must be nongenetic factors contributing to the disease, too, given that the incidences of MS and other autoimmune disorders are increasing.

“Maybe it’s a lot of little factors like low vitamin D, increased body mass index and increased salt intake,” Hafler says, “but I wouldn’t be surprised if it was one big thing, much like how H. pylori was found to cause ulcers. No one’s identified a clear bug that’s driving MS but I think it’s important we keep looking.”

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Unsuspected aspect of immune regulation revealed: Role of 'B cells'

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B cells (stained green) and regulatory T cells (stained red) in the thymus.

A discovery by Australian immunologists, uncovering an additional role for antibody-making 'B cells', is considered important enough by the American Association of Immunologists to rank it among the top 10% of articles in the latest issue of The Journal of Immunology, off the press today.

The finding by Senior Research Assistant Stacey Walters and Associate Professor Shane Grey, from Sydney's Garvan Institute of Medical Research, shows that B cells also participate in the development of 'regulatory T cells'.

T cells develop in the thymus gland, a soft triangular organ in the chest cavity. From a 'naïve', or undifferentiated, state they are gradually 'educated' to become helpers, or warriors, or regulators.

Until now, the only non-thymic cells known to educate the regulators were dendritic cells, which travel to the thymus to deliver 'antigen', samples of substances toxic to the body. We now know that B cells can do the same thing.

B cells have been thought to specialise only in the production of antibodies. As newfound educators of T cells as well, B cells become much more interesting and complex characters, potentially useful in helping to prevent organ rejection, or control inflammatory bowel disease, or quell autoimmune conditions.

That is because regulatory T cells control how killer T cells behave -- and can effectively prevent the warriors from attacking 'self' tissue, or tissue perceived as foreign. In the case of organ transplantation, several studies have shown that high levels of regulatory T cells can prevent organ rejection.

"Regulatory T cells are critical in the outcome of an immune response -- so anything that in turn regulates them becomes very interesting to immunologists," said Associate Professor Grey.

"Right now there are clinical trials around the world looking to expand populations of these cells in patients. Researchers are also working on ways to grow regulatory cells in the laboratory -- to infuse into patients as therapy."

"Everyone is interested in finding ways to treat autoimmunity and prevent transplant rejection. Expansion of regulatory T cells should help in both cases."

"Our finding suggests it should be possible to set up systems that harness B cells to expand regulatory cells."

The Garvan lab members worked with mice genetically modified to express high levels of 'BAFF', a substance that increases survival of B cells. The higher number of B cells overall allowed researchers to track the activity of B cells in the thymus.

"It has been known for years that some B cells travel to the thymus, but no-one has understood why," said Stacey Walters.

"Our experiments showed clearly that B cells participated in the creation of regulatory T cells -- the more B cells that were in the thymus, the higher the number of regulatory cells generated. That direct correlation raises interesting possibilities."

"One possibility is using BAFF, a non-toxic substance, to ramp up the B cell count of patients before transplant procedures. It will be very interesting to test whether or not that would prevent rejection."

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Story Source:

The above story is based on materials provided by Garvan Institute of Medical Research. Note: Materials may be edited for content and length.

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Journal Reference:

1. S. N. Walters, K. E. Webster, S. Daley, S. T. Grey. A Role for Intrathymic B Cells in the Generation of Natural Regulatory T Cells. The Journal of Immunology, 2014; 193 (1): 170 DOI: 10.4049/%u200Bjimmunol.1302519