̽��ֱ�� of Cambridge - immunity

Chronic diseases misdiagnosed as psychosomatic can lead to long term damage

cjb250 — Mon, 03 Mar 2025 00:01:07 +0000

A study involving over 3,000 participants – both patients and clinicians – found that these misdiagnoses (sometimes termed “in your head” by patients) were often associated with long term impacts on patients’ physical health and wellbeing and damaged trust in healthcare services.

̽��ֱ��researchers are calling for greater awareness among clinicians of the symptoms of such diseases, which they recognise can be difficult to diagnose, and for more support for patients.

Autoimmune rheumatic diseases such as rheumatoid arthritis, lupus and vasculitis are chronic inflammatory disorders that affect the immune system and can damage organs and tissues throughout the body. They can be very difficult to diagnose as people report a wide range of different symptoms, many of which can be invisible, such as extreme fatigue and depression.

Dr Melanie Sloan from the ̽��ֱ�� of Cambridge led a study exploring patient-reported experiences from two large groups, each of over 1,500 patients, and in-depth interviews with 67 patients and 50 clinicians. ̽��ֱ��results are published today in Rheumatology.

Patients who reported that their autoimmune disease was misdiagnosed as psychosomatic or a mental health condition were more likely to experience higher levels of depression and anxiety, and lower mental wellbeing. For example, one patient with multiple autoimmune diseases said: “One doctor told me I was making myself feel pain and I still can’t forget those words. Telling me I’m doing it to myself has made me very anxious and depressed.”

More than 80% said it had damaged their self-worth and 72% of patients reported that the misdiagnosis still upset them, often even decades later. Misdiagnosed patients also reported lower levels of satisfaction with every aspect of medical care and were more likely to distrust doctors, downplay their symptoms, and avoid healthcare services. As one patient reported, it “has damaged my trust and courage in telling doctors very much. I even stopped taking my immunosuppressive medicine because of those words”.

Following these types of misdiagnoses, patients often then blamed themselves for their condition, as one individual described: “I don’t deserve help because this is a disease I’ve brought on myself. You go back to those initial diagnosis, you’ve always got their voices in your head, saying you’re doing this to yourself. You just can’t ever shake that. I’ve tried so hard.”

One patient described the traumatising response their doctor’s judgement had on them: “When a rheumatologist dismissed me I was already suicidal, this just threw me over the edge. Thankfully I am terrible at killing myself, it’s so much more challenging than you think. But the dreadful dismissiveness of doctors when you have a bizarre collection of symptoms is traumatizing and you start to believe them, that it’s all in your head.”

Dr Melanie Sloan, from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, said: “Although many doctors were intending to be reassuring in suggesting a psychosomatic or psychiatric cause for initially unexplainable symptoms, these types of misdiagnoses can create a multitude of negative feelings and impacts on lives, self-worth and care. These appear to rarely be resolved even after the correct diagnoses. We must do better at helping these patients heal, and in educating clinicians to consider autoimmunity at an earlier stage.”

Clinicians highlighted how hard it was to diagnose autoimmune rheumatic diseases and that there was a high risk of misdiagnosis. Some doctors said they hadn’t really thought about the long-term problems for patients, but others talked about the problems in regaining trust, as one GP from England highlighted: “They lose trust in anything that anyone says…you are trying to convince them that something is OK, and they will say yes but a doctor before said that and was wrong.”

However, there was evidence that this trust can be rebuilt. One patient described having been “badly gaslit by a clinician”, but that when they told the clinician this, “She was shocked and had no idea … She was great. Took it on the chin. Listened and heard. Apologised profusely…For me, the scar of the original encounter was transformed into something much more positive.”

Mike Bosley, autoimmune patient and co-author on the study, said: “We need more clinicians to understand how a misdiagnosis of this sort can result in long-standing mental and emotional harm and in a disastrous loss of trust in doctors. Everyone needs to appreciate that autoimmune conditions can present in these unusual ways, that listening carefully to patients is key to avoiding the long-lasting harm that a mental health or psychosomatic misdiagnosis can cause.”

̽��ֱ��study authors recommend several measures for improving support for patients with autoimmune rheumatological diseases. These are likely to apply for many other groups of patients with chronic diseases that are often misunderstood and initially misdiagnosed.

They propose that clinicians should talk about previous misdiagnoses with patients, discuss and empathise with their patients as to the effects on them, and offer targeted support to reduce the long-term negative impacts. Health services should ensure greater access to psychologists and talking therapies for patients reporting previous misdiagnoses, which may reduce the long-term impact on wellbeing, healthcare behaviours, and patient-doctor relationships. Education may reduce misdiagnoses by encouraging clinicians to consider systemic autoimmunity when they assess patients with multiple, seemingly unconnected, physical and mental health symptoms.

Professor Felix Naughton, from the Lifespan Health Research Centre at the ̽��ֱ�� of East Anglia, said: “Diagnosing autoimmune rheumatic diseases can be challenging, but with better awareness among clinicians of how they present, we can hopefully reduce the risk of misdiagnoses. And while there will unfortunately inevitably still be patients whose condition is not correctly diagnosed, with the correct support in place, we may be able to lessen the impact on them.”

̽��ֱ��research was funded by LUPUS UK and ̽��ֱ��Lupus Trust.

Reference
Sloan, M, et al. “I still can’t forget those words”: mixed methods study of the persisting impacts of psychosomatic and psychiatric misdiagnoses. Rheumatology; 3 Mar 2025; DOI: 10.1093/rheumatology/keaf115

A ‘chasm of misunderstanding and miscommunication’ is often experienced between clinicians and patients, leading to autoimmune diseases such as lupus and vasculitis being wrongly diagnosed as psychiatric or psychosomatic conditions, with a profound and lasting impact on patients, researchers have found.

These types of misdiagnoses can create a multitude of negative feelings and impacts on lives, self-worth and care

Mel Sloan

Annie Spratt

A person laying in a bed under a blanket

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A habitable planet for healthy humans

plc32 — Wed, 13 Dec 2023 17:28:42 +0000

Cambridge Zero symposium gathers researchers to examine the connections between planetary and public health.

Omicron may be significantly better at evading vaccine-induced immunity, but less likely to cause severe disease

cjb250 — Mon, 20 Dec 2021 15:37:40 +0000

As the SARS-CoV-2 virus replicates and spreads, errors in its genetic code can lead to changes in the virus. On 26 November 2021, the World Health Organization designated the variant B.1.1.529, first identified in South Africa, a variant of concern, named Omicron. ̽��ֱ��variant carries a large number of mutations, leading to concern that it will leave vaccines less effective at protecting against infection and illness.

Working in secure conditions, a team led by Professor Ravi Gupta at the Cambridge Institute of Therapeutic Immunology and Infectious Disease, ̽��ֱ�� of Cambridge, created synthetic viruses – known as ‘pseudoviruses’ – that carried key mutations found in the Delta and Omicron strains. They used these to study the virus’s behaviour.

̽��ֱ��team, which included collaborators from Japan, including Dr Kei Sato of the ̽��ֱ�� of Tokyo, has released its data ahead of peer review* because of the urgent need to share information relating to the pandemic, and particularly the new Omicron variant.

Professor Gupta and colleagues tested the pseudoviruses against blood samples donated to the NIHR COVID-19 BioResource. ̽��ֱ��blood samples were from vaccinated individuals who had received two doses of either the AstraZeneca (ChAdOx-1) or Pfizer (BNT162b2) vaccines.

On average, Omicron required around a ten-fold increase in the concentration of serum antibody in order to neutralise the virus, compared to Delta. Of particular concern, antibodies from the majority of individuals who had received two doses of the AstraZeneca vaccine were unable to neutralise the virus. ̽��ֱ��data were confirmed in live virus experiments.

Reassuringly, however, following a third dose of the Pfizer vaccine, both groups saw a significant increase in neutralisation.

Professor Gupta said: “ ̽��ֱ��Omicron variant appears to be much better than Delta at evading neutralising antibodies in individuals who have received just two doses of the vaccine. A third dose ‘booster’ with the Pfizer vaccine was able to overturn this in the short term, though we’d still expect a waning in immunity to occur over time.”

Spike proteins on the surface of SARS-CoV-2 bind to ACE2, a protein receptor found on the surface of cells in the lung. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow the virus to replicate and spread.

To see how effective Omicron is at entering our cells, the team used their pseudoviruses to infect cells in lung organoids – ‘mini-lungs’ that model parts of the lung. Despite having three mutations that were predicted to favour the spike cleavage, the researchers found the Omicron spike protein to be less efficient than the Delta spike at cleaving the ACE2 receptor and entering the lung cells.

In addition, once Omicron had entered the cells, it was also less able than Delta to cause fusion between cells, a phenomenon associated with impaired cell-to-cell spread. Fused cells are often seen in respiratory tissues taken following severe disease. Indeed, when the team used a live Omicron virus and compared it to Delta in a spreading infection experiment using lung cells, Omicron was significantly poorer in replication, confirming the findings regarding impaired entry.

Professor Gupta added: “We speculate that the more efficient the virus is at infecting our cells, the more severe the disease might be. ̽��ֱ��fact that Omicron is not so good at entering lung cells and that it causes fewer fused cells with lower infection levels in the lab suggests this new variant may cause less severe lung-associated disease.

“While further work is needed to corroborate these findings, overall, it suggests that Omicron’s mutations present the virus with a double-edged sword: it’s got better at evading the immune system, but it might have lost some of its ability to cause severe disease.”

However, Professor Gupta urged caution.

“Omicron still represents a major public health challenge. Individuals who have only received two doses of the vaccine – or worse, none at all – are still at significant risk of COVID-19, and some will develop severe disease. ̽��ֱ��sheer number of new cases we are seeing every day reinforces the need for everyone to get their boosters as quickly as possible.”

̽��ֱ��research was supported by Wellcome and the NIHR Cambridge Biomedical Research Centre.

Reference
Meng, B, et al. SARS-CoV-2 Omicron neutralising antibody evasion, replication and cell-cell fusion.

*Update: ̽��ֱ��research has now been peer-reviewed and is published in Nature as Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts tropism and fusogenicity (DOI: 10.1038/s41586-022-04474-x).

̽��ֱ��Omicron variant of SARS-CoV-2 may be significantly better than previous variants at evading vaccine-induced antibodies, according to new research from Cambridge – but preliminary evidence suggests it is less likely to cause severe COVID-19 illness in the lungs.

Omicron’s mutations present the virus with a double-edged sword: it’s got better at evading the immune system, but it might have lost some of its ability to cause severe disease

Ravi Gupta

Naeblys (Getty Images)

SARS-CoV-2 3D rendering

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Opinion: How your body clock helps determine whether you’ll get ill or not

Anonymous — Wed, 17 Aug 2016 10:55:31 +0000

From vitamin C and echinacea to warm clothes and antibacterial soap, there’s no shortage of ideas about how to prevent and manage colds and flu. Unfortunately, many of these are not based on solid scientific evidence. In fact, medical researchers are only starting to unravel the range of factors that affect our susceptibility to getting an infection. Now we have discovered that our body clock plays an important role – making us more prone to get infected at certain times of the day.

It is perhaps easy to forget that we have co-evolved on this planet with micro-organisms, including bacteria, which may be either beneficial or harmful to us. Similarly, viruses cannot copy themselves without help from our cells. Without us, they simply wouldn’t exist.

So what happens when a virus encounters a cell? First, it has to get in through a protective barrier called the cell membrane. Then it has to hijack the interior of the “host” cell to subvert it and divert all resources to copy itself millions of times. Once an army of identical clones is formed, it breaks out of the cell, usually destroying it in the process. Imagine millions of these new viruses then being able to do exactly the same to other cells nearby. ̽��ֱ��cycle goes on, with often rapid amplification of the virus through a tissue, and then through the body.

That’s if the virus had it all its own way … But there is always a battle in play between invading organisms and our bodies. Our immune system counteracts the invading organisms and will invoke mechanisms to stop the virus entering, replicating and spreading. This defence system works at the level of individual cells in the body, but also in specialised tissues of the body that are designed to mount a response to such invasions.

It now turns out that our body clock is also an important gatekeeper of virus infections. ̽��ֱ��body clock is an amazing piece of evolutionary biology. It’s thought that most organisms on our planet have a biological clock that keeps track of the 24-hour day. It can do this by orchestrating chemical reactions and genetic switches that rhythmically control thousands of genes in cells in the cell – turning about 15% of all genes on and off across the day and night.

Timely experiment

So why might viruses care about our body clock? Since our cells are miniature factories, making things that the virus must have to copy itself, the virus is less likely to succeed when the production line is shut down. This is what we tested in the laboratory, by infecting cells and mice at different times of the day. We found that viruses are less able to infect in the late afternoon. In contrast, in the early morning, our cells are hives of biosynthetic activity, at least from the virus’s viewpoint. So, if a virus tries to take over a cell in the early day, it is far more likely to succeed, and spread faster, than if it encounters a rather less favourable climate in the evening.

Perhaps even more interestingly, when the clockwork is disrupted, viruses are more prolific at taking over cells and tissues. Such “clock misalignment” can happen when we do shift work, get jet lagged, or experience the phenomenon of “social jet lag”, which is caused by changes in our sleep schedule on our days off. Therefore, it’s important to know about these interactions because it will undoubtedly help us to find ways to ensure better health for ourselves. For example, since we know shift workers are more likely to get infections, it might be a good idea to give them flu vaccinations.

Perhaps nightclub germs aren’t so threatening after all. *sax/Flickr, CC BY-SA

Knowing about the clock and viruses could also help us to design better public health measures to combat virus spread. You could imagine that during a pandemic limiting exposure during the early daytime could be a small but important intervention to try to prevent viral infection from taking hold. Indeed, a recent study by a team at the ̽��ֱ�� of Birmingham showed that vaccinating people against flu in the morning is more effective than in the evening. This principle could be the same for many unrelated viruses.

̽��ֱ��research could also help us crack a longstanding enigma – why do virus infections like flu happen more commonly in the winter months? It turns out that the very same molecular switch – called Bmal1 – that goes up and down in the day and night also changes according to the seasons, going up in the summer and down in the winter. When we artificially lower Bmal1 levels in mice and cells, the virus is able to infect more. As occurs on a daily basis, the waxing and waning of Bmal1 in our bodies could be a reason why we’re less likely to cope with viruses like flu in the winter.

So, if you’re desperate to avoid catching a flu virus that’s been going around the office, rather than trying to boost your immune system with various vitamins, you may want to try to simply work from home in the mornings.

Akhilesh Reddy, Wellcome Trust Senior Fellow in Clinical Sciences at the Department of Clinical Neurosciences, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Akhilesh Reddy (Department of Clinical Neurosciences) discusses how circadian rhythms can affect whether you get the flu.

Claus Rebler

Sick

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Time of day influences our susceptibility to infection, study finds

cjb250 — Mon, 15 Aug 2016 19:00:21 +0000

When a virus enters our body, it hijacks the machinery and resources in our cells to help it replicate and spread throughout the body. However, the resources on offer fluctuate throughout the day, partly in response to our circadian rhythms – in effect, our body clock. Circadian rhythms control many aspects of our physiology and bodily functions – from our sleep patterns to body temperature, and from our immune systems to the release of hormones. These cycles are controlled by a number of genes, including Bmal1 and Clock.

To test whether our circadian rhythms affect susceptibility to, or progression of, infection, researchers at the Wellcome Trust-Medical Research Council Institute of Metabolic Science, ̽��ֱ�� of Cambridge, compared normal ‘wild type’ mice infected with herpes virus at different times of the day, measuring levels of virus infection and spread. ̽��ֱ��mice lived in a controlled environment where 12 hours were in daylight and 12 hours were dark.

̽��ֱ��researchers found that virus replication in those mice infected at the very start of the day – equivalent to sunrise, when these nocturnal animals start their resting phase – was ten times greater than in mice infected ten hours into the day, when they are transitioning to their active phase. When the researchers repeated the experiment in mice lacking Bmal1, they found high levels of virus replication regardless of the time of infection.

“ ̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection,” explains Professor Akhilesh Reddy, the study’s senior author. “This is consistent with recent studies which have shown that the time of day that the influenza vaccine is administered can influence how effectively it works.”

In addition, the researchers found similar time-of-day variation in virus replication in individual cell cultures, without influence from our immune system. Abolishing cellular circadian rhythms increased both herpes and influenza A virus infection, a dissimilar type of virus – known as an RNA virus – that infects and replicates in a very different way to herpes.

Dr Rachel Edgar, the first author, adds: “Each cell in the body has a biological clock that allows them to keep track of time and anticipate daily changes in our environment. Our results suggest that the clock in every cell determines how successfully a virus replicates. When we disrupted the body clock in either cells or mice, we found that the timing of infection no longer mattered – viral replication was always high. This indicates that shift workers, who work some nights and rest some nights and so have a disrupted body clock, will be more susceptible to viral diseases. If so, then they could be prime candidates for receiving the annual flu vaccines.”

As well as its daily cycle of activity, Bmal1 also undergoes seasonal variation, being less active in the winter months and increasing in summer. ̽��ֱ��researchers speculate that this may help explain why diseases such as influenza are more likely to spread through populations during winter.

Using cell cultures, the researchers also found that herpes viruses manipulate the molecular ‘clockwork’ that controls our circadian rhythms, helping the viruses to progress. This is not the first time that pathogens have been seen to ‘game’ our body clocks: the malaria parasite, for example, is known to synchronise its replication cycle with the host’s circadian rhythm, producing a more successful infection.

“Given that our body clocks appear to play a role in defending us from invading pathogens, their molecular machinery may offer a new, universal drug target to help fight infection,” adds Professor Reddy.

̽��ֱ��research was mostly funded by the Wellcome Trust and the European Research Council.

Reference
Edgar, RS et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. PNAS; e-pub 15 Aug 2016; DOI: 10.1073/pnas.1601895113

We are more susceptible to infection at certain times of the day as our body clock affects the ability of viruses to replicate and spread between cells, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��findings, published today in the Proceedings of the National Academy of Sciences, may help explain why shift workers, whose body clocks are routinely disrupted, are more prone to health problems, including infections and chronic disease.

̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection

Akhilesh Reddy

Alexandra Bilham

Clock

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Too exhausted to fight – and to do harm

cjb250 — Mon, 29 Jun 2015 15:00:31 +0000

Inside our bodies are billions of immune cells known as T cells that protect us from infection, fighting off attacks from invading bacteria and viruses, and also from cancer. One teaspoon full of blood alone is believed to have around 5 million T cells. But these cells can also do harm, mistaking our own cells for invaders and attacking them, leading to autoimmune diseases such as lupus, Crohn’s disease and type 1 diabetes.

Among these T cells are CD8 T cells, the ‘foot soldiers’ that go into battle and kill unwanted invaders. As with any army, in the face of a huge attack they can become ‘exhausted’ – in the case of the immune system, by inhibitory signals – and no longer fight effectively. Whether they become exhausted depends on both the size of the battle (or amount of invading ‘antigen’) and the amount of supporting signals they receive from a second type of cell, known as a CD4 helper T cell. These are the ‘generals’ in the immune system, which coordinate our immune response. Exhaustion can affect the performance of the immune system and allow chronic infections, such as hepatitis C or HIV, to persist.

In research published today in the journal Nature, scientists from the Cambridge Institute for Medical Research looked at patterns of genes that were turned on and off in patients with autoimmune diseases and found similarities with those seen in people with chronic infection, such as hepatitis C, and cancer: in other words, they have shown that the same process of T cell ‘exhaustion’ known to be involved in the immune response to chronic infection and cancer is also important in many autoimmune diseases.

However, the researchers found a key difference: an exhausted immune response toward infection results in worse outcome – the infection persists; for autoinflammatory diseases, the opposite is true – an exhausted immune response results in a milder course of the disease, with fewer relapses.

Dr Eoin McKinney, a Wellcome Trust-Beit Research Fellow from the Department of Medicine at the ̽��ֱ�� of Cambridge, first author of the study, explains: “We know that the way our bodies respond to infection and to autoimmune diseases differs between individuals. In part, we believe this is due to a process known as T cell exhaustion. For effective treatment, we need to exhaust our T cell responses in autoimmune diseases – and hence limit the attack on our body – and to reverse exhaustion when the fight is against unwanted invaders, such as viruses or cancer.”

During chronic infection, blocking the inhibitory signals can restore CD8 cells to begin fighting again and clear chronic infection. ̽��ֱ��researchers were able to show in vitro that, by enhancing the same inhibitory signals, CD8 cells could be made exhausted, which should limit damage to the body that characterises autoimmune disease.

̽��ֱ��team believe their discovery could help doctors better target medicines at patients with autoimmune disease. At the moment, when a patient presents with such a disease for the first time, doctors have no way of predicting what their long-term future holds. Patients whose T cells exhibit signs of exhaustion early in the course of disease have a better long-term outcome, and thus might require less treatment. Conversely those with ‘non-exhausted’ T cells at diagnosis do badly in the long term, and may benefit from more intensive or novel therapy. ̽��ֱ��team at the Department of Medicine has commenced a trial, supported by the Wellcome Trust, that applies this approach to patients with inflammatory bowel disease to see whether it can guide their treatment and improve their clinical outcome.

Professor Ken Smith, lead author of the study and Head of the Department of Medicine, says: “We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion. A focus on T cell exhaustion in cancer has led to a revolution in treatment and a multi-billion dollar industry. We now implicate the same pathways in determining long term patient outcome in autoimmune and inflammatory diseases, which afflict up to one in ten of the population over the course of their lives.”

̽��ֱ��research was supported by the National Institute of Health Research Cambridge Biomedical Research Centre and funded by the Wellcome Trust and the Lupus Research Institute.

Reference
McKinney, EF et al. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature; 29 June 1015

An ‘exhausted’ army of immune cells may not be able to fight off infection, but if its soldiers fight too hard they risk damaging the very body they are meant to be protecting, suggests new research from the ̽��ֱ�� of Cambridge.

We believe the clinical implications of this study could be profound. A test based on the concept is soon to enter the clinic, and we are exploring new treatments for autoimmunity based on manipulating T cell exhaustion

Ken Smith

Wait for the next ride (cropped)

Resting soldiers

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

cjb250 — Tue, 12 May 2015 15:00:00 +0000

̽��ֱ��study, published today 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. ̽��ֱ��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 ̽��ֱ��Gambia. These samples included a mixture of blood samples and adipose tissue.

̽��ֱ��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. ̽��ֱ��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 ̽��ֱ��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 summer.”

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."

̽��ֱ��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.”

Reference
Dopico, XC et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nature Communications; 12 May 2015.

Our immune systems vary with the seasons, according to a study led by the ̽��ֱ�� 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.

In some ways, it’s obvious – it helps explain why so many diseases are much worse in the winter months – but no one had appreciated the extent to which this actually occurred

John Todd

Luke Price

Changing of the seasons

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Sleeping sickness by stealth

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Stealth is a well-known concept in military tactics. Almost since the invention of radar, the hunt began for counter-technologies to hide aircraft and missiles from detection – most successfully by modifying the composition and shape of surfaces to confound detection. In a biological parallel, the African sleeping sickness parasite Trypanosoma brucei also has a stealth-like trick for altering its surface to confound recognition by the human immune system.

Trypanosomes are covered in some 10 million identical proteins called variant surface glycoproteins (VSGs). Although VSGs are well recognised by the immune system, trypanosomes can rapidly and repeatedly change every single one of these coat proteins, just as the rumblings of an immune response against the first coat have begun. In this way, the parasite can effectively ‘disappear’ again and again, deflecting the immune response to something that has essentially become an echo.

A complex mechanism of gene control underlies the process that allows trypanosomes to switch coats. Part of this mechanism has now been revealed in recent research by Cambridge parasitologist Professor Mark Field and colleagues from the USA, UK and Europe.

̽��ֱ��finding has implications for treating African sleeping sickness, one of the ‘neglected tropical diseases’ – those that are caused by infectious agents that are endemic to low-income populations in Africa, Asia and the Americas, where treatment may not be universally available or is poor. Sleeping sickness threatens millions of lives in sub-Saharan countries and, because it also affects cattle, is a major contributor to economic hardship. Currently there is no vaccine.

At the heart of T. brucei’s switching mechanism is a set of genes, possibly as many as 2,000, encoding the VSGs. Only a single VSG gene is active at any one time – ensuring that the coat contains only a single protein. All other VSG genes are inactive or silent.

“ ̽��ֱ��active VSG gene is within a site lying close to the end of the chromosome, while all the silent genes are elsewhere in the parasite genome,” said Field. “When switching occurs, the genes become rearranged and a gene from the silent archive is moved into the expression site. When this one is expressed, new coat proteins are moved to the cell surface to replace the old coat.”

̽��ֱ��researchers have discovered a protein, NUP-1, which helps to maintain the silent archive, as Field described: “ ̽��ֱ��basis of gene silencing is epigenetic. In other words, it’s not written in the DNA per se but is the result of protein ‘decorations’ called chromatin that either block or allow gene expression. NUP-1 is one of the proteins controlling epigenetic gene silencing.”

In multicellular organisms, a key regulator of chromatin remodelling is a protein called lamin, which forms a network across the inner lining of the cell’s nucleus. Until the discovery of NUP-1, an equivalent protein was unknown in plants, fungi or single-celled organisms. NUP-1 not only performs lamin-like functions – suggesting that the mechanism NUP-1 controls is probably an ancient process shared by organisms as diverse as humans and their parasites – but, excitingly, its discovery also opens up new possibilities for eradicating T. brucei by controlling coat switching.

“Without NUP-1, silenced genes are no longer constrained, and increased VSG switching happens,” explained Field. “If we could inactivate NUP-1, the parasite will probably exhaust the VSG repertoire or damage the surface coat so that it’s no longer effective as a barrier. This may finally be one route to penetrating the stealth cloak of Trypanosoma brucei.”

For more information, please contact Louise Walsh at the ̽��ֱ�� of Cambridge Office of External Affairs and Communications.

New research is helping to unveil how the parasite that causes sleeping sickness uses stealth tactics to escape detection by the human immune system.

This may finally be one route to penetrating the stealth cloak of Trypanosoma brucei

Professor Mark Field

Mark Field

Trypanosoma brucei use a changing cloak of VSG coat proteins to confound recognition by the human immune system

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