Category: Immune System

Categories : Immune System Obstetrics & GynaecologyTags :

Pregnancy Enhances Natural Immunity to Block Severe Flu

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Photo by Anna Hecker on Unsplash

McGill University scientists have discovered that pregnancy may trigger a natural immunity to boost protection against severe flu infection. Contrary to the common belief that pregnancy increases vulnerability to infections, researchers found that it strengthened an immune defence in mice, blocking the Influenza A virus from spreading to the lungs, where it can cause severe infection.

“Our results are surprising because of the current dogma, but it makes sense from an evolutionary perspective,” said co-lead author Dr Maziar Divangahi, Professor in McGill’s Faculty of Medicine and Health Sciences and Senior Scientist at the Research Institute of the McGill University Health Centre (The Institute).

“A mother needs to stay healthy to protect her developing baby, so the immune system adapts to provide stronger defenses. This fascinating response in the nasal cavity is the body’s way of adding an extra layer of protection, which turns on during pregnancy.”

Exploring benefits for pregnancy and beyond

The researchers used a mouse model to observe how a certain type of immune cell activates in the nasal cavity of mice during pregnancy, producing a powerful molecule that boosts the body’s antiviral defenses, especially in the nose and upper airways.

“Influenza A virus remains among the deadliest threats to humanity,” said first author Julia Chronopoulos, who carried out the research while completing her PhD at McGill. “This natural immunity in pregnancy could change the way we think about flu protection for expectant mothers.”

The Public Health Agency of Canada recommends pregnant women and pregnant individuals get the flu vaccine, as they are at high risk of severe illness and complications like preterm birth. The new insights offer promise for more targeted vaccines for influenza, which is among the top 10 leading causes of death in Canada.

“The broader population could also benefit, as our findings suggest the immune response we observed could be replicated beyond pregnancy,” said co-lead author Dr James Martin, Professor in McGill’s Faculty of Medicine and Health Sciences and Senior Scientist at the RI-MUHC. This could mean new nasal vaccines or treatments that increase protective molecules, known as Interleukin-17.

The team’s next focus is on finding ways to reduce lung damage during viral infections like the flu or COVID. Rather than targeting the virus, as previous research has done, they aim to prevent dysregulated immune systems from overreacting, an approach that could lower the risk of serious complications associated with flu infection.

Source: McGill University

Categories : Immune SystemTags :

Immune ‘Brake’ Reveals Drug Targets for Cancer and Autoimmune Disease

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Killer T cells about to destroy a cancer cell. Credit: NIH

Researchers have discovered a genomic ‘brake’ in a subset of immune cells that could help advance immunotherapy for cancer and autoimmune disease. The findings, led by a team at the Peter MacCallum Cancer Centre in collaboration with researchers at the Garvan Institute and Kirby Institute, provide new insights into how the body’s immune defence mechanisms can go awry in these diseases and open a new class of potential drug targets that could activate immune cells in tumour tissue.

The research was published in the journal Immunity.

Discovering an immune brake

Specialised killer T cells are released during an infection, trained to recognise and destroy the threat. When unchecked, these cells can cause autoimmune diseases such as type 1 diabetes or rheumatoid arthritis if they mistakenly attack the body’s own healthy tissues.

The immune system employs a mechanism to prevent autoimmune attacks called ‘tolerance’ – a process that can be exploited by cancer cells to shield them from the body’s natural defences.

“Until now, it was not fully understood how tolerance works at a molecular level. We used advanced sequencing techniques to identify a unique genomic signature in ‘tolerant’ T cells that differentiated them from killer T cells that were activated in response to viral infection,” says Dr Timothy Peters, co-first author from Garvan.

“These precise genome locations have never before been observed and allowed us to track precisely how killer T cells progress through the tolerance pathway, and how specific gene networks enable tolerance to be abused.”

Breakthrough for cancer and autoimmune disease

Dr Ian Parish, who led the research at the Peter MacCallum Cancer Centre said this breakthrough helps to understand why cancer treatments fail and opens the door to developing new treatments in the future.

“Current cancer immunotherapy treatments target the exhaustion phase of the immune response,” he said. “Our research suggests that a second, earlier ‘off-switch’ called tolerance may explain how many cancers resist current immunotherapies by blocking anti-cancer immunity from getting off the ground. We’re excited as these findings can be exploited for new treatments. Our next step is to understand if we can disrupt tolerance and engage the immune system to restart and attack those cancers resistant to treatment.”

Professor Chris Goodnow, Head of the Immunogenomics Lab at Garvan, says this new understanding of T cell tolerance opens up opportunities to develop new drugs that could selectively alter this pathway.

“The discovery of these gene locations provides us with a roadmap for developing future drugs, which could block the tolerance mechanisms to boost cancer-killing ability for immunotherapies. Conversely, for autoimmune diseases, enhancing tolerance could prevent harmful autoimmune attack,” he says.

In next steps, the researchers will focus on understanding how to disrupt the tolerance mechanism and engage the immune system to restart.

“These findings have revealed around 100 new potential targets for drugs to target the tolerance mechanism in T cells, which have until now been largely developed by trial and error,” says Professor Goodnow. “This could lead to a whole new class of treatments for autoimmunity and cancer.”

Professor Chris Goodnow is The Bill and Patricia Ritchie Foundation Chair and Director of the Cellular Genomics Futures Institute, UNSW Sydney. Dr Tim Peters is a Conjoint Lecturer at St Vincent’s Clinical School, UNSW Medicine and Health.

Source: Garvan Institute of Medical Research

Categories : Cancer Immune SystemTags :

Chronic Activation of the Innate Immune System can Unleash Cancer

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Photo by Sangharsh Lohakare on Unsplash

Along with defending against pathogens, the body’s innate immune system helps to protect the stability of our genomes in unexpected ways that have important implications for the development of cancer, researchers at Memorial Sloan Kettering Cancer Center (MSK) are discovering.

In a pair of recent papers, scientists in the lab of molecular biologist John Petrini, PhD, showed that innate immune signaling plays a key role in maintaining genome stability during DNA replication. Furthermore, the researchers showed that chronic activation of these immune pathways can contribute to tumour development in a mouse model of breast cancer.

Not only do the findings add vital insights to our understanding of fundamental human biology, says Dr Petrini, they may also shed new light on tumour initiation and present potential opportunities for new therapies.

“Living organisms have evolved complex pathways to sense, signal, and repair damaged DNA,” he says. “Here we’re learning new things about the role of the innate immune system in responding to that damage – both in the context of cancer and also in human health more generally.”

How Chronic Activation of the Innate Immune System Can Lead to Cancer

The newest paper, led by first author Hexiao Wang, PhD, a postdoctoral fellow in the Petrini Lab, and published in Genes & Development, reveals a connection between innate immune signaling and tumour development in breast tissue. And, Dr Petrini says, the data suggest that when instability arises in the genome, chronic activation of the innate immune system can greatly increase the chances of developing cancer.

The study focused on a protein complex called the Mre11 complex, which plays a pivotal role in maintaining the stability of the genome by sensing and repairing double-strand breaks in DNA.

To study how problems with the Mre11 complex can lead to cancer, the team manipulated copies of the protein in mammary tissue organoids (miniature lab-grown model organs) and then implanted them into laboratory animals.

When oncogenes (genes known to drive cancer) were activated in these mice, tumors arose about 40% of the time, compared with about 5% in their normal counterparts. And the tumors in the mice with mutant Mre11 organoids were highly aggressive.

The research further showed that the mutant Mre11 led to higher activation of interferon-stimulated genes (ISGs). Interferons are signaling molecules that are released by cells in response to viral infections, immune responses, and other cellular stressors.

They also found that the normally tightly controlled packaging of DNA was improperly accessible in these organoids — making it more likely that genes will get expressed, when they otherwise would be inaccessible for transcription.

“We actually saw differences in the expression of more than 5600 genes between the two different groups of mice,” Dr Petrini says.

And strikingly, these profound effects depended on an immune sensor called IFI205.

When the organoids were further manipulated so they would lack IFI205, the packaging of DNA returned almost to normal, and the mice developed cancer at essentially the same rate as normal mice.

“So what we learned is that problems with Mre11 – which can be inherited or develop during life like other mutations – can create an environment where the activation of an oncogene is much more likely to lead to cancer,” Dr Petrini says. “And that the real lynch pin of this cascade is this innate immune sensor, IFI205, which detects that there’s a problem and starts sending out alarm signals. In other words, when problems with Mre11 occur, chronic activation of this innate immune signaling can significantly contribute to the development of cancer.”

New Understandings Could Pave the Way for Future Treatments

The work builds on a previous study, led by Christopher Wardlaw, PhD, a former senior scientist in the Petrini Lab, that appeared in Nature Communications.

That study focused on the role of the Mre11 complex in maintaining genomic integrity. It found that when the Mre11 complex is inactive or deficient, it results in the accumulation of DNA in the cytoplasm of cells and in the activation of innate immune signaling. This research primarily looked at the involvement of ISG15, a protein made by an interferon-stimulating gene, in protecting against replication stress and promoting genomic stability.

“Together, these studies shed new light on how the Mre11 complex works to protect the genome when cells replicate, and how, when it’s not working properly, it can trigger the innate immune system in ways that can promote cancer,” D. Petrini says.

By shedding light on the interrelationships between these complex systems and processes, the researchers hope to identify new strategies to prevent or treat cancer, he adds, such as finding ways to short-circuit the increased DNA accessibility when Mre11 isn’t working properly.

Source: Memorial Sloan Kettering Cancer Center

Categories : COVID Immune SystemTags :

SARS-CoV-2 Hijacks Three Key Proteins in the Complement System

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SARS-CoV-2 viruses (yellow) infecting a human cell (blue). Photo by CDC on Pexels

Researchers at the Medical University of Vienna and the Medical University of Innsbruck discovered that SARS-CoV-2 hijacks three important host proteins that dampen the activity of the complement system, a key component of early antiviral immunity. This significantly impairs viral clearance which may affect the course of both acute COVID infections and post-COVID sequelae. The study was recently published in the journal Emerging Microbes & Infections.

An early and effective immune response is crucial for resolving viral infections and preventing post-infectious complications. The complement system, a pivotal element of antiviral immunity, is a cascade of proteins found in the bloodstream and at mucosal sites, such as the respiratory tract. Activated through three different pathways, complement facilitates the clearance of virus particles by directly inducing their destruction (lysis). To prevent bystander damage to host cells, complement is rapidly inactivated by a set of host molecules referred to as complement regulatory proteins. The new study led by Anna Ohradanova-Repic and colleagues from the Center for Pathophysiology, Infectiology and Immunology at the Medical University of Vienna in collaboration with the team of Heribert Stoiber from the Institute of Virology at the Medical University of Innsbruck shows that SARS-CoV-2 hijacks three of these regulatory proteins, CD55, CD59 and Factor H, and thereby successfully shields itself from complement-mediated lysis.

Hijacking host proteins for effective complement resistance

By propagating SARS-CoV-2 in human cells the researchers discovered that the virus particles acquire the cellular proteins CD55 and CD59. Further experiments showed that SARS-CoV-2 also binds to Factor H, another complement regulatory protein that is primarily found in the bloodstream. Confronting the virus particles with active complement revealed that they are partially resistant to complement-mediated lysis. By removing CD55, CD59 and Factor H from the virus surface or inhibiting their biological functions, the researchers could successfully restore complement-mediated clearance of SARS-CoV-2.

“Through hijacking these three proteins, SARS-CoV-2 can evade all three complement pathways, resulting in reduced or delayed viral clearance by the infected host,” Anna Ohradanova-Repic, the leader of the study explains. Because complement is intricately linked with other components of the immune system, this not only affects virus elimination but can also cause significant inflammation, a core feature of both severe COVID-19 and Long COVID. “Uncovering immune evasion mechanisms that allow the virus to linger within the host for longer, deepen our understanding of the acute and long-term impacts of SARS-CoV-2 infection,” says first author Laura Gebetsberger.

Source: Medical University of Vienna

Categories : COVID Immune SystemTags :

New Discovery Explains How SARS-CoV-2 Evades Anti-viral Immunity

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Image by Fusion Medical on Unsplash

The novel coronavirus SARS-CoV-2 has an enzyme that can counteract a cell’s innate defence mechanism against viruses, explaining why it is more infectious than the previous SARS and MERS-causing viruses. This discovery, from Kobe University, may point the way to the development of more effective drugs against this and possibly similar, future diseases.

When a virus attacks, the body’s immune response has two basic layers of defence: the innate and the adaptive immune systems. While the adaptive immune system grows stronger against a specific pathogen as the body is exposed to it multiple times and which forms the basis of vaccinations, the innate immune system is an assortment of molecular mechanisms that work against a broad range of pathogens at a basic level. The Kobe University virologist SHOJI Ikuo says, “The new coronavirus, however, is so infectious that we wondered what clever mechanisms the virus employs to evade the innate immune system so effectively.”

Shoji’s team previously worked on the immune response to hepatitis viruses and investigated the role of a molecular tag called “ISG15” the innate immune system attaches to the virus’s building blocks. Having learned that the novel coronavirus has an enzyme that is especially effective in removing this tag, he decided to use his team’s expertise to elucidate the effect of the ISG15 tag on the coronavirus and the mechanism of the virus’s countermeasures.

In a paper in the Journal of Virology, the Kobe University-led team is now the first to report that the ISG15 tag gets attached to a specific location on the virus’s nucleocapsid protein, the scaffold that packages the pathogen’s genetic material. For the virus to assemble, many copies of the nucleocapsid protein need to attach to each other, but the ISG15 tag prevents this, which is the mechanism behind the tag’s antiviral action. “However, the novel coronavirus also has an enzyme that can remove the tags from its nucleocapsid, recovering its ability to assemble new viruses and thus overcoming the innate immune response,” explains Shoji.

The novel coronavirus shares many traits with the SARS and MERS viruses, which all belong to the same family of viruses – which also have an enzyme that can remove the ISG15 tag. But their versions are less efficient at it than the one in the novel coronavirus, Shoji’s team found. And in fact, it has been reported recently that the previous viruses’ enzymes have a different primary target. “These results suggest that the novel coronavirus is simply better at evading this aspect of the innate immune system’s defence mechanism, which explains why it is so infectious,” says Shoji.

But understanding just why the novel coronavirus is so effective also points the way to developing more effective treatments. The Kobe University researcher explains: “We may be able to develop new antiviral drugs if we can inhibit the function of the viral enzyme that removes the ISG15 tag. Future therapeutic strategies may also include antiviral agents that directly target the nucleocapsid protein, or a combination of these two approaches.”

Source: Kobe University

Categories : Immune System New Compounds and TreatmentsTags :

“Two for the Price of One” – New Process that Drives Anti-viral Immunity is Discovered

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Scientists at Trinity College Dublin have discovered a new process in the immune system that leads to the production of an important family of anti-viral proteins called interferons. They hope the discovery will now lead to new, effective therapies for people with some autoimmune and infectious diseases.

Reporting in Nature Metabolism, Luke O’Neill, Professor of Biochemistry in the School of Biochemistry and Immunology at Trinity, and his team have found that a natural metabolite called Itaconate can stimulate immune cells to make interferons by blocking an enzyme called SDH. 

Co-lead author, Shane O’Carroll, from Trinity’s School of Biochemistry and Immunology, said: “We have linked the enzyme SDH to the production of interferons in an immune cell type called the macrophage. We hope our work will help the effort to develop better strategies to fight viruses because interferons are major players in how our innate immune system eliminates viruses – including COVID-19.” 

Co-lead author, Christian Peace, from Trinity’s School of Biochemistry and Immunology, added: “Itaconate is a fascinating molecule made by macrophages during infections. It’s already known to suppress damaging inflammation but now we have found how it promotes anti-viral interferons.”

Working with drug companies Eli Lilly and Sitryx Ltd, the next step is to test new therapies  based on Itaconate in various diseases, with some autoimmune diseases and some infectious diseases on the likely list. And the work potentially extends to other disease contexts in which SDH is inhibited, such as cancer, and could reveal a new therapeutic target for SDH-deficient tumours.

Prof O’Neill said: “With Itaconate you get two for the price of one – not only can it block harmful inflammation, but it can also help fight infections. We have discovered important mechanisms for both and the hope now is that patients will benefit from new therapies that exploit Itaconate and its impacts.” 

Clinical trials in patients are set to start next year.  

Source: Trinity College Dublin

Categories : Immune SystemTags :

Rip and Tear: How a Key Immune Protein Defeats Bacterial Membranes

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Illustration of how GBP1 proteins (blue and purple) attach to the membrane of a bacterium (yellow), zoomed in from an image taken with an electron microscope (in grayscale). Credit: Delft University

The protein GBP1 is a vital immune system component which fights against bacteria and parasites by enveloping them in a protein coat, but how the substance manages to do this has remained unknown until now. Researchers from Delft University of Technology report in Nature Structural & Molecular Biology how this protein operates – ripping and tearing until the bacterial membrane is undone. Their findings could aid in the development of medications and therapies for individuals with weakened immune systems.

So-called Guanylate Binding Proteins (GBPs) play a crucial role in our innate immune system, explains biophysicist Arjen Jakobi: “GBPs form the first line of defence against various infectious diseases caused by bacteria and parasites. Examples of such diseases include dysentery, typhoid fever caused by Salmonella bacteria, and tuberculosis. The protein also plays a significant role in the sexually transmitted infection chlamydia as well as in toxoplasmosis, which is particularly dangerous during pregnancy and for unborn children.”

Coat around bacteria

In their publication, Jakobi and his colleagues describe for the first time how the innate immune system fights against bacteria using GBP1 proteins. “The protein surrounds bacteria by forming a sort of coat around them,” explains Tanja Kuhm, PhD candidate in Jakobi’s research group and the lead author of the article. “By pulling this coat tighter, it breaks the membrane of the bacteria – the protective layer surrounding the intruder – after which immune cells can clear the infection.”

Deciphering the defence strategy

To decode the defence strategy of GBPs, the researchers examined how GBP1 proteins bind to bacterial membranes using a cryogenic electron microscope. This allowed them to see the process in great detail down to the molecular level. Jakobi: “We were able to obtain a detailed three-dimensional image of how the protein coat forms. Together with biophysical experiments conducted in Sander Tans’ research group at research institute AMOLF, which enabled us to manipulate the system precisely, we succeeded in deciphering the mechanism of the antibacterial function.”

Medications

According to Jakobi, this research helps us understand better how our body is capable of combating bacterial infections. “If we can grasp this well, and we can specifically activate or deactivate the involved proteins through medication, it may offer opportunities to speed up getting rid of certain infections.”

Source: Delft University

Categories : Immune System Neurodegenerative DiseasesTags :

New Approach to MS ‘Teaches’ Immune Cells not to Attack

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Myelin sheath damage. Credit: Scientific Animations CC4.0

Researchers from have found a potential new way to improve the treatment of multiple sclerosis (MS) using a novel combined therapy. The results, published in the Journal of Clinical Investigation, builds on two harmonised Phase I clinical trials, focusing on the use of Vitamin D3 tolerogenic dendritic cells (VitD3-tolDCs) to regulate the immune response in MS patient.

Multiple Sclerosis (MS) is a long-term disease where the immune system mistakenly attacks the protective myelin sheath around nerve cells. This leads to nerve damage and worsening disability. Current treatments, like immunosuppressants, help reduce these harmful attacks but also weaken the overall immune system, leaving patients vulnerable to infections and cancer. Scientists are now exploring a more targeted therapy using special immune cells, called tolerogenic dendritic cells (tolDCs), from the same patients.

TolDCs can restore immune balance without affecting the body’s natural defences. However, since a hallmark of MS is precisely the dysfunction of the immune system, the effectiveness of these cells for auto transplantation might be compromised. Therefore, it is essential to better understand how the disease affects the starting material for this cellular therapy before it can be applied.

In this study, researchers from Barcelona’s Germans Trias i Pujol Institute and Josep Carreras Leukaemia Research Institute, examined CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-treated tolerogenic dendritic cells (VitD3-tolDCs) from MS patients who had not yet received treatment, as well as from healthy individuals. The clinical trials (NCT02618902 and NCT02903537) are designed to assess the effectiveness of VitD3-tolDCs, which are loaded with myelin antigens to help “teach” the immune system to stop attacking the nervous system. This approach is groundbreaking as it uses a patient’s own immune cells, modified to induce immune tolerance, in an effort to treat the autoimmune nature of MS.

The study, led by Dr Eva Martinez-Cáceres and Dr Esteban Ballestar, with Federico Fondelli as first author, found that the immune cells from MS patients (monocytes, precursors of tolDCs) have a persistent “pro-inflammatory” signature, even after being transformed into VitD3-tolDCs, the actual therapeutic cell type. This signature makes these cells less effective compared to those derived from healthy individuals, missing part of its potential benefits.

Using state-of-the-art research methodologies, the researchers identified a pathway, known as the Aryl Hydrocarbon Receptor (AhR), that is linked to this altered immune response. By using an AhR-modulating drug, the team was able to restore the normal function of VitD3-tolDCs from MS patients, in vitro. Interestingly, Dimethyl Fumarate, an already approved MS drug, was found to mimic the effect of AhR modulation and restore the cells’ full efficacy, with a safer toxic profile.

Finally, studies in MS animal models showed that a combination of VitD3-tolDCs and Dimethyl Fumarate led to better results than using either treatment on its own. This combination therapy significantly reduced symptoms in mice, suggesting enhanced potential for treating human patients.

These results could lead to a new, more potent treatment option for multiple sclerosis, offering hope to the millions of patients worldwide who suffer from this debilitating disease. This study represents a significant step forward in the use of personalised cell therapies for autoimmune diseases, potentially revolutionising how multiple sclerosis is treated.

The team is now preparing to move into Phase II trials to further explore these findings.

Source: Josep Carreras Leukaemia Research Institute

Categories : Immune System Obstetrics & GynaecologyTags :

New Treatment for Pregnancy Loss Caused by Specific Autoantibody

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Photo by SHVETS production

Amongst women who experience recurrent pregnancy loss, around 20% test positive for a specific autoantibody. A Kobe University-led research team now found a treatment using either of two common drugs that drastically increases these women’s chances of carrying to full-term without complications, reporting their findings in Frontiers in Immunology.

Recurrent pregnancy loss is a condition of women who have lost two or more pregnancies for non-obvious reasons. Kobe University obstetrician Tanimura Kenji and his team have previously found that in 20% of these women, they can detect a specific antibody in their blood that targets their own bodies: anti-β2-glycoprotein I/HLA-DR autoantibodies.

Tanimura explains: “There is no known treatment for this particular condition, but the antibodies have a similar target to those that play a role in a different condition that has an established treatment.” Therefore, he wanted to test whether that treatment also works in the cases with the newly discovered antibody.

Tanimura enlisted the help of obstetricians across five hospitals in Japan and over the course of two years analysed the blood of consenting women suffering from recurrent pregnancy loss for the antibodies. If any of these women got pregnant during this time frame, their doctors would offer treatment options also containing those drugs that are effective against the chemically similar condition, specifically, low-dose aspirin or heparin. The research team then observed how many of the women who included these drugs in their treatment had full-term live births or pregnancy complications and compared that to the pregnancy outcomes in women who did not take either of the two drugs.

They report that women who received the treatment were much more likely to have live births (87% did) compared to the ones without treatment (of which only 50% had live births). In addition, amongst the live births, the treatment reduced the likelihood of complications from 50% to 6%. “The sample size was rather small (39 women received the treatment and 8 did not), but the results still clearly show that a treatment with low-dose aspirin or heparin is very effective in preventing pregnancy loss or complications also in women who have these newly discovered self-targeting antibodies,” summarises Tanimura.

Many women who tested positive for the newly discovered self-targeting antibodies also tested positive for the previously known ones. However, the Kobe University-led team found that women who only had the newly discovered antibodies and who received the treatment were even more likely to have a live birth (93%) and, amongst these, none had pregnancy complications.

Looking ahead, Tanimura says: “The newly discovered self-targeting antibody has been demonstrated to be involved also in infertility and recurrent implantation failure, as well as a risk factor for arterial thrombosis in women with systemic rheumatic diseases. I therefore expect that studies about the effectivity of the treatment against a broader range of conditions might produce encouraging results.”

Source: Kobe University

Categories : Immune SystemTags :

Fever Drives Enhanced Activity and Mitochondrial Damage in Immune Cells

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Photo by Kelly Sikkema on Unsplash

Fever temperatures accelerate immune cell metabolism, proliferation and activity, but in a particular subset of T cells, it also causes mitochondrial stress, DNA damage and cell death, Vanderbilt University Medical Center researchers have discovered. 

The findings, published in the journal Science Immunology, offer a mechanistic understanding for how cells respond to heat and could explain how chronic inflammation contributes to the development of cancer. 

The impact of fever temperatures on cells is a relatively understudied area, said Jeff Rathmell, PhD, Professor of Immunobiology and corresponding author of the new study. Most of the existing temperature-related research relates to agriculture and how extreme temperatures impact crops and livestock, he noted. It’s challenging to change the temperature of animal models without causing stress, and cells in the laboratory are generally cultured in incubators that are set at human body temperature: 37°C. 

“Standard body temperature is not actually the temperature for most inflammatory processes, but few have really gone to the trouble to see what happens when you change the temperature,” said Rathmell, who also directs the Vanderbilt Center for Immunobiology. 

Graduate student Darren Heintzman was interested in the impact of fevers for personal reasons: Before he joined the Rathmell lab, his father developed an autoimmune disease and had a constant fever for months on end. 

“I started thinking about what an increased set point temperature like that might do. It was intriguing,” Heintzman said. 

Heintzman cultured immune system T cells at 39°C. He found that heat increased helper T cell metabolism, proliferation and inflammatory effector activity and decreased regulatory T cell suppressive capacity. 

“If you think about a normal response to infection, it makes a lot of sense: You want effector (helper) T cells to be better at responding to the pathogen, and you want suppressor (regulatory) T cells to not suppress the immune response,” Heintzman said. 

But the researchers also made an unexpected discovery: that a certain subset of helper T cells, called Th1 cells, developed mitochondrial stress and DNA damage, and some of them died. The finding was confusing, the researchers said, because Th1 cells are involved in settings where there is often fever, like viral infections. Why would the cells that are needed to fight the infection die? 

The researchers discovered that only a portion of the Th1 cells die, and that the rest undergo an adaptation, change their mitochondria, and become more resistant to stress. 

“There’s a wave of stress, and some of the cells die, but the ones that adapt and survive are better – they proliferate more and make more cytokine (immune signaling molecules),” Rathmell said.

Heintzman was able to define the molecular events of the cell response to fever temperatures. He found that heat rapidly impaired electron transport chain complex 1 (ETC1), a mitochondrial protein complex that generates energy. ETC1 impairment set off signalling mechanisms that led to DNA damage and activation of the tumour suppressor protein p53, which aids DNA repair or triggers cell death to maintain genome integrity. Th1 cells were more sensitive to impaired ETC1 than other T cell subtypes.

 The researchers found Th1 cells with similar changes in sequencing databases for samples from patients with Crohn’s disease and rheumatoid arthritis, adding support to the molecular signaling pathway they defined. 

“We think this response is a fundamental way that cells can sense heat and respond to stress,” Rathmell said. “Temperature varies across tissues and changes all the time, and we don’t really know what it does. If temperature changes shift the way cells are forced to do metabolism because of ETC1, that’s going to have a big impact. This is fundamental textbook kind of stuff.” 

The findings suggest that heat can be mutagenic, when cells that respond with mitochondrial stress don’t properly repair the DNA damage or die. 

“Chronic inflammation with sustained periods of elevated tissue temperatures could explain how some cells become tumorigenic,” Heintzman said, noting that up to 25% of cancers are linked to chronic inflammation. 

“People ask me, ‘Is fever good or bad?’” Rathmell added. “The short answer is: A little bit of fever is good, but a lot of fever is bad. We already knew that, but now we have a mechanism for why it’s bad.” 

Source: Vanderbilt University Medical Center