tag:theconversation.com,2011:/africa/topics/immune-cells-6185/articlesImmune cells – The Conversation2024-02-19T13:44:01Ztag:theconversation.com,2011:article/2235282024-02-19T13:44:01Z2024-02-19T13:44:01ZLung cancer: Predicting which patients are at high risk of recurrence to improve outcomes<figure><img src="https://images.theconversation.com/files/575433/original/file-20240205-29-abkjt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chemotherapy is used to treat all lung cancer patients. Yet many would not need such invasive treatment if diagnosis of the risk of recurrence were more refined. A new technology could change all that.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Lung cancer <a href="https://cancer.ca/en/research/cancer-statistics/cancer-statistics-at-a-glance">is responsible for more deaths than breast, colon and prostate cancer combined</a>. </p>
<p>With advancements in lung cancer screening, it is expected that more patients will be diagnosed at earlier stages, enabling them to undergo surgery, the primary treatment modality for early-stage patients.</p>
<p>However, a significant proportion of patients will have a recurrence of their cancer after resection (surgery to remove the tumour). Unfortunately, current clinical guidelines cannot help predict which patients are at risk. Better knowledge of who is at risk has significant implications for systemic therapy selection such as chemotherapy for early-stage lung cancer patients after surgery. </p>
<p>To find solutions to this problem, our research group at McGill University launched a project in collaboration with Université Laval. <a href="https://www.nature.com/articles/s41586-022-05672-3#MOESM1">Preliminary results were published in <em>Nature</em></a>. In our work we discovered that the use of a new imaging technology, along with artificial intelligence, could improve outcomes for cancer patients.</p>
<h2>Too much or too little intervention</h2>
<p>This clinical dilemma has important implications for the choice of treatment, such as chemotherapy. For example, lung cancer patients who are cured by surgery could be spared the toxicity of chemotherapy. Patients at risk of their cancer recurring could benefit from additional therapeutic interventions.</p>
<p>The challenge of predicting recurrence for patients with early-stage lung cancer has important implications for the 31,000 Canadians who are diagnosed with this terrible disease every year.</p>
<h2>Mass cytometry imaging</h2>
<p>To address this clinical problem, we used <a href="https://www.mcgill.ca/gci/facilities/single-cell-imaging-and-mass-cytometry-analysis-platform-scimap">imaging mass cytometry</a> (IMC), a new technology that allows for a comprehensive characterization of the tumour microenvironment. </p>
<p>The tumour microenvironment is a complex ecosystem composed of interactions between tumour cells, immune cells, and various structural cells. IMC can be used to visualize up to 50 markers at the cell surface, significantly more than was previously possible. </p>
<p>This technology makes it possible to identify different types of cells and determine their spatial organization, i.e. how they interact. IMC produces images that can be analyzed to determine the frequency of cell subpopulations, their activation states, the other cell types with which they interact and their organization in cellular communities. </p>
<p>The results of our study, published in <em>Nature</em>, reveal that various cell types can interact in cellular communities, and that communities composed of B cells were strongly associated with prolonged survival in lung cancer patients. Our study highlights that beyond cellular frequency, cellular interactions and spatial organization also correlate strongly with important clinical outcomes such as survival.</p>
<h2>Using artificial intelligence to make better predictions</h2>
<p>Based on our initial results, we hypothesized that important spatial features embedded within IMC images, such as cellular interactions, could be important in predicting clinical outcomes. </p>
<p>Our dataset of 416 patients and over 1.6 million cells provided sufficient power to make predictions using artificial intelligence. We sought to predict which patients with early-stage lung cancer would have a recurrence of their cancer after surgery. </p>
<p>Using 1 mm2 tumour samples, material readily available from surgical resections or biopsies, we used artificial intelligence algorithms together with IMC images to make our predictions. Our algorithm was able to predict with 95 per cent accuracy which patients would experience a cancer recurrence by using the spatial information contained within the images. </p>
<h2>Six markers can make all the difference</h2>
<p>One of the challenges in applying our results in a clinical setting is that IMC is not readily available. Clinical pathologists typically use less complex technologies such as immunofluorescence, which are often limited to three or fewer markers. </p>
<figure class="align-center ">
<img alt="image obtained using immunofluorescence" src="https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/573537/original/file-20240205-17-2oj4zm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Immunofluorescence image of a tumour treated with immunotherapy. This technology is often limited to the use of three or fewer markers at a time.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>To address this challenge, we sought to identify the minimum number of markers needed to make meaningful predictions about recurrence in lung cancer patients after surgery. By using six markers, we obtained an accuracy rate of 93 per cent, a result that is close to the 95 per cent accuracy rate obtained by using 35 markers. </p>
<p>These results suggest that by harnessing the power of artificial intelligence with existing technologies available in hospitals, we may be able to improve the post-surgical clinical management of patients with early-stage lung cancer. Our ultimate goal is to increase cure rates for those at high risk of cancer recurrence, while minimizing toxicity for those who can be cured by surgery.</p><img src="https://counter.theconversation.com/content/223528/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Sorin has received funding from the Fonds de recherche du Québec and Vanier Canada Graduate Scholarships.</span></em></p><p class="fine-print"><em><span>Logan Walsh has received funding from McGill University's Interdisciplinary Infection and Immunity Initiative, the Brain Tumour Funders' Collaborative, the Canadian Institutes of Health Research (CIHR; PJT-162137), the Canada Foundation for Innovation and holds the Rosalind Goodman Research Chair in Lung Cancer.</span></em></p>Treatment for lung cancer patients is the same for everyone, regardless of the risk of recurrence. The use of a new technology could refine diagnosis.Mark Sorin, Étudiant au MD-PhD, chercheur en cancer du poumon, McGill UniversityLogan Walsh, Assistant Professor, Department of Human Genetics, McGill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2152172023-11-20T13:18:45Z2023-11-20T13:18:45ZImmune health is all about balance – an immunologist explains why both too strong and too weak an immune response can lead to illness<figure><img src="https://images.theconversation.com/files/559704/original/file-20231115-15-wutiiv.png?ixlib=rb-1.1.0&rect=0%2C0%2C2044%2C1593&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When immune cells become overactive, your immune system itself can cause disease.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/2oHpNSe">NIAID/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>For immune health, some influencers seem to think the Goldilocks philosophy of “just right” is overrated. Why settle for less immunity when you can have more? Many social media posts push supplements and other life hacks that “boost your immune system” to keep you healthy and fend off illness.</p>
<p>However, these claims are not based on science and what is known about immune function. Healthy immune systems don’t need to be “boosted.” Instead, the immune system works best when it is <a href="https://doi.org/10.1038/ni.2430">perfectly balanced</a>. Scientific experts on the immune system – immunologists – know that too much of an immune reaction could result in allergies, autoimmune disorders or <a href="https://theconversation.com/what-is-inflammation-two-immunologists-explain-how-the-body-responds-to-everything-from-stings-to-vaccination-and-why-it-sometimes-goes-wrong-193503">chronic inflammation</a>. On the flip side, <a href="https://theconversation.com/immunocompromised-people-make-up-nearly-half-of-covid-19-breakthrough-hospitalizations-an-extra-vaccine-dose-may-help-166241">too little of an immune reaction</a> could result in illness or infection.</p>
<p>Your immune system requires a delicate balance to operate properly. When it’s out of balance, your immune system itself can cause disease.</p>
<h2>Cellular balance</h2>
<p>The immune system is the mobile defense system of your body. It is a complex network of cells and organs that work together to protect your body from infection and disease. Your immune cells are continually on patrol, traveling throughout your body looking for infectious invaders and damage. </p>
<p>New immune cells are created in your bone marrow. Certain immune cells – called <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">B and T cells</a> – are the special forces of the immune system, playing an important role in the elimination of infectious invaders. Because of this role, these cells undergo a rigorous boot camp during their development to ensure they will not discharge friendly fire on healthy cells in the body. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/PSRJfaAYkW4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Your immune system is an extensive network of cells and many other components that constantly surveil your body.</span></figcaption>
</figure>
<p>Any <a href="https://doi.org/10.1038/nri.2017.19">B cell</a> or <a href="https://doi.org/10.1146/annurev-immunol-101320-022432">T cell</a> exhibiting activity against the self – or autoreactivity – is killed during training. Millions of newly created B and T cells are killed every day because they fail this training process. If these self-reactive cells escape destruction, they could turn against the body and carry out an inappropriate <a href="https://doi.org/10.1038/ni.3731">autoimmune attack</a>. </p>
<p><a href="https://scholar.google.com/citations?view_op=list_works&hl=en&hl=en&user=PGIEO34AAAAJ">My research</a> investigates how B cells are able to slip past the checkpoints the immune system has in place to guard against autoreactivity. These <a href="https://doi.org/10.1172/jci12462">tolerance checkpoints</a> ensure that autoreactive immune cells are either purged from the body or held in permanent lockdown and unable to engage in inappropriate responses that would target healthy tissue.</p>
<h2>More isn’t necessarily better</h2>
<p>You’ve likely seen advertisements for dietary supplements that promise to “boost immune function.” While this may sound appealing, it is important to keep in mind that the immune system functions best when perfectly balanced.</p>
<p>If the immune system is like a thermostat, turning it up too high results in overactivation and uncontrolled inflammation, while turning it down too low results in a failure to respond to infection and disease. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram of immune activation scale in the shape of a rainbow wedge, with 'vulnerable to infection' at the smaller end, 'sweet spot' in the middle, and 'autoimmunity' at the larger end" src="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=260&fit=crop&dpr=1 600w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=260&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=260&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=326&fit=crop&dpr=1 754w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=326&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/559701/original/file-20231115-23-d6qlle.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=326&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Too much or too little immune activation can lead to illness.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Inflammation_scale.svg">Kevbonham/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Because sustaining <a href="https://www.nature.com/collections/mxwslsscsf">immune balance</a> is critical, tinkering with the immune system through the use of supplements is not a good idea unless you have a clinical deficiency in certain vital nutrients. For people with healthy levels of nutrients, taking supplements could lead to a false sense of security, particularly since the fine print on the back of supplements usually has <a href="https://www.fda.gov/food/information-consumers-using-dietary-supplements/questions-and-answers-dietary-supplements">this disclaimer</a> about their listed benefits: “This statement has not been evaluated by the FDA. Not intended to diagnose, treat, cure, or prevent any disease.”</p>
<p>Eating a <a href="https://www.hsph.harvard.edu/nutritionsource/nutrition-and-immunity/">well-balanced diet</a>, exercising regularly, reducing stress and getting decent sleep, on the other hand, can help your body maintain a functioning and healthy immune system. Although these lifestyle behaviors are not foolproof, they contribute to overall good health and ultimately to a more healthy immune system.</p>
<p>In reality, <a href="https://doi.org/10.1080/07853890.2017.1407035">vaccines are the only safe and effective tool</a> beyond healthy lifestyle behaviors to support your immune system. Vaccines contain harmless forms of pathogens that help to train your immune cells to recognize and fight them. When you come into contact with the real and harmful version of the pathogen out in the wild – whether it’s at a grocery store, social event or school – at a later date, these fully trained immune memory cells will immediately begin to fight and destroy the pathogen, sometimes so quickly that you don’t even realize you’ve been infected.</p>
<p>In a world where people are continually bombarded by the marketing mantra that more is better, rest assured that when it comes to the immune system, maintaining perfect balance is just right.</p><img src="https://counter.theconversation.com/content/215217/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aimee Pugh Bernard is affiliated with Immunize Colorado and Colorado Immunization Advocates as an unpaid board member.</span></em></p>Dietary supplements claim to be able to ‘boost your immune system’ to combat disease. But attaining immune balance through a healthy lifestyle and vaccination is a safer bet to keep in good health.Aimee Pugh Bernard, Assistant Professor of Immunology and Microbiology, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2109472023-08-03T15:01:05Z2023-08-03T15:01:05ZImmune cells that fight cancer become exhausted within hours of first encountering tumors – new research<figure><img src="https://images.theconversation.com/files/540881/original/file-20230802-24657-u8hz8s.png?ixlib=rb-1.1.0&rect=0%2C0%2C538%2C359&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This microscopy image shows a cytotoxic T cell (blue) attacking a cancer cell (green) by releasing toxic chemicals (red).</span> <span class="attribution"><a class="source" href="https://flic.kr/p/wyPJtV">Alex Ritter and Jennifer Lippincott Schwartz and Gillian Griffiths/National Institutes of Health via Flickr</a></span></figcaption></figure><p>A key function of our immune system is to detect and eliminate foreign pathogens such as bacteria and viruses. Immune cells like <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">T cells</a> do this by distinguishing between different types of proteins within cells, which allows them to detect the presence of infection or disease. </p>
<p>A type of T cell called <a href="https://doi.org/10.1038/s41416-020-01048-4">cytotoxic T cells</a> can recognize the mutated proteins on cancer cells and should therefore be able to kill them. However, in most patients, cancer cells grow unchecked despite the presence of T cells.</p>
<p>The current explanation scientists have as to why T cells fail to eliminate cancer cells is because <a href="https://doi.org/10.1038/s41577-019-0221-9">they become “exhausted.”</a> The idea is that T cells initially function well when they first face off against cancer cells, but gradually lose their ability to kill the cancer cells after repeated encounters. </p>
<p>Cancer immunotherapies such as <a href="https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors">immune checkpoint inhibitors</a> and <a href="https://theconversation.com/anti-cancer-car-t-therapy-reengineers-t-cells-to-kill-tumors-and-researchers-are-expanding-the-limited-types-of-cancer-it-can-target-196471">CAR-T cell therapy</a> have shown remarkable promise by inducing long-lasting remission in some patients with otherwise incurable cancers. However, these therapies <a href="https://doi.org/10.1038/s41571-022-00689-z">often fail to induce long-term responses</a> in most patients, and T cell exhaustion is a major culprit.</p>
<p><a href="https://www.philiplab.org/">We are researchers</a> who study ways to harness the immune system to treat cancer. Scientists like us have been working to determine the mechanisms controlling how well T cells function against tumors. In our newly published research, we found that <a href="https://www.nature.com/articles/s41590-023-01578-y">T cells become exhausted within hours</a> after encountering cancer cells.</p>
<figure>
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<figcaption><span class="caption">T cells recognize tumor cells by the specific proteins called antigens they display on their surfaces.</span></figcaption>
</figure>
<h2>Timing T cell exhaustion</h2>
<p>By the time most patients are diagnosed with cancer, their immune system has been interacting with developing cancer cells <a href="https://doi.org/10.1038/nrc3397">for months to years</a>. We wanted to go back earlier in time to figure out what happens when T cells first encounter tumor cells. </p>
<p>To do this, we used mice genetically engineered to develop liver cancers as they age, similarly to how liver cancers develop in people. We introduced trackable cytotoxic T cells that specifically recognize liver cancer cells to analyze the T cells’ function and monitor which of the genes are activated or turned off over time.</p>
<p>We also used these same trackable T cells to study their response in mice infected with the bacteria <em>Listeria</em>. In these mice, we found that the T cells were highly functional and eliminated infected cells. By comparing the differences between dysfunctional T cells from tumors and highly functional T cells from infected mice, we can home in on the genes that code for critical proteins that T cells use to regulate their function.</p>
<p><a href="https://doi.org/10.1038/nature22367">In our previous work</a>, we found that T cells become dysfunctional with dramatically altered genetic structure within five days of encountering cancer cells in mice. We had originally decided to focus on the very earliest time points after T cells encounter cancer cells in mice with liver cancer or metastatic melanoma because we thought there would be fewer genetic changes. That would have allowed us to identify the earliest and most critical regulators of T cell dysfunction. </p>
<p>Instead, we found multiple surprising hallmarks of T cell dysfunction within <a href="https://www.nature.com/articles/s41590-023-01578-y">six to 12 hours</a> after they encountered cancer cells, including thousands of changes in genetic structure and gene expression.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of a human T cell colored blue" src="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/540884/original/file-20230802-19-7xirm8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">T cells play an important role in fighting against disease.</span>
<span class="attribution"><a class="source" href="https://www.nist.gov/image/healthyhumantcelljpg">National Institute of Allergy and Infectious Diseases</a></span>
</figcaption>
</figure>
<p>We analyzed the different regulatory genes and pathways in T cells encountering cancer cells compared to those of T cells encountering infected cells. We found that genes associated with inflammation were highly activated in T cells interacting with infected cells but not in T cells interacting with cancer cells.</p>
<p>Next, we looked at how the initial early changes to the genetic structure of T cells evolved over time. We found that very early DNA changes were stabilized and reinforced with continued exposure to cancer cells, effectively “imprinting” dysfunctional gene expression patterns in the T cells. This meant that when the T cells were removed from the tumors after five days and transferred to tumor-free mice, they still remained dysfunctional.</p>
<h2>Boosting T cell killing</h2>
<p>Altogether, our research suggests that T cells in tumors are not necessarily working hard and getting exhausted. Rather, they are blocked right from the start. This is because the negative signals cancer cells send out to their surrounding environment induce T cell dysfunction, and a lack of positive signals like inflammation results in a failure to kick T cells into high gear.</p>
<p>Our team is now exploring strategies to stimulate inflammatory pathways in T cells encountering cancer cells to make them function as though they are encountering an infection. Our hope is that this will help T cells kill their cancer targets more effectively.</p><img src="https://counter.theconversation.com/content/210947/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>T cells recognize and kill cancer cells but quickly lose their effectiveness. This fast dysfunction may help explain why immunotherapy doesn’t lead to long-term remission for many patients.Mary Philip, Assistant Professor of Medicine and Pathology, Vanderbilt UniversityMichael Rudloff, MD-Ph.D. Candidate in Molecular Pathology and Immunology, Vanderbilt UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2069142023-07-11T12:30:49Z2023-07-11T12:30:49ZImmune cells in the brain may reduce damage during seizures and promote recovery, according to study in mice<figure><img src="https://images.theconversation.com/files/536347/original/file-20230707-29-x9vfl9.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1977%2C1514&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Microglia perform many functions in the brain, and their role in seizures is unclear.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/nerve-cell-conceptual-illustration-royalty-free-illustration/1359390614">KTSDesign/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Seizures are like sudden electrical storms in the brain. Seizure disorders like epilepsy affect <a href="https://www.cureepilepsy.org/for-patients/understanding/basics/what-is-epilepsy/">over 65 million people worldwide</a> and can have profound effects on a person’s quality of life, cognitive function and overall well-being. Prolonged seizures called <a href="https://www.epilepsy.com/complications-risks/emergencies/status-epilepticus">status epilepticus</a> can cause lasting brain damage.</p>
<p>Specialized immune cells in the brain <a href="https://theconversation.com/harnessing-the-brains-immune-cells-to-stave-off-alzheimers-and-other-neurodegenerative-diseases-193606">called microglia</a> are activated during seizures to help clean up the damage. Researchers don’t fully understand exactly how these cells are involved in seizures. Some studies have found that microglia <a href="https://doi.org/10.1002%2Fbrb3.403">promote seizures</a>, while other studies <a href="https://doi.org/10.1016/j.bbi.2020.06.028">show the opposite</a>.</p>
<p>I am a scientist who studies the roles that microglia play in seizures. My colleagues and I at the <a href="https://www.microgleyolab.com">Eyo Lab</a> at the University of Virginia wanted to investigate the possible protective function microglia serve during seizures and how they affect recovery.</p>
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<figcaption><span class="caption">The exact neurobiology of seizures remains unclear.</span></figcaption>
</figure>
<p>We induced seizures in mice using three different methods – chemical, hyperthermic and electrical – and temporarily removed their microglia. In all three cases, we found that <a href="https://doi.org/10.1002/glia.24364">seizures worsened</a> when these cells were absent. Mice without microglia also experienced significant weight loss and decrease in mobility compared with mice with microglia. </p>
<p>Our findings highlight the importance of microglia in safeguarding the brain during seizures and promoting recovery; but they also raise important questions about how these cells provide a protective rather than detrimental effect.</p>
<p>While removing all microglia allowed us to better understand their overall effects on seizures, it meant we were unable to fully assess their contributions in specific brain regions and how they interact with other cells. This is because removing microglia also affects the function of other brain cells. Future studies that more selectively modify microglia or alter their function in a controlled way could help researchers gain a more nuanced understanding of the role these cells play in seizures.</p>
<figure>
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<figcaption><span class="caption">This video shows microglia moving in cell culture.</span></figcaption>
</figure>
<p>Researchers also don’t fully understand what specific molecules and signals microglia use to protect the brain during seizures. How well our findings apply to seizure disorders like epilepsy is also unclear. These knowledge gaps highlight the complexity of seizure disorders and the need for continued study.</p>
<p>Identifying strategies to harness the beneficial functions of microglia can help researchers develop better treatments that prevent long-term brain damage and enhance the quality of life of people with seizure disorders.</p><img src="https://counter.theconversation.com/content/206914/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Synphane Gibbs-Shelton receives funding from the National Institutes of Health.</span></em></p>Seizures are like sudden electrical storms in the brain that can cause lasting damage. A set of immune cells in the brain called microglia may provide protection.Synphane Gibbs-Shelton, Ph.D. Candidate in Pharmacology, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1936062022-12-07T13:43:23Z2022-12-07T13:43:23ZHarnessing the brain’s immune cells to stave off Alzheimer’s and other neurodegenerative diseases<figure><img src="https://images.theconversation.com/files/499323/original/file-20221206-23-z5d85z.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1599%2C1200&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Microglia (colored green) play several essential roles in maintaining brain health and function. </span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg">Gerry Shaw/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p><a href="https://www.fda.gov/news-events/congressional-testimony/path-forward-advancing-treatments-and-cures-neurodegenerative-diseases-07292021">Many neurodegenerative diseases</a>, or conditions that result from the loss of function or death of brain cells, remain largely untreatable. Most available treatments target <a href="https://doi.org/10.1038/d41586-018-05719-4">just one of the multiple processes</a> that can lead to neurodegeneration, which may not be effective in completely addressing disease symptoms or progress, if at all.</p>
<p>But what if researchers harnessed the brain’s inherent capabilities to cleanse and heal itself? My colleagues <a href="https://neurograd.virginia.edu/people/profile/kez9hf">and I</a> in the <a href="https://www.lukenslab.com">Lukens Lab</a> at the University of Virginia believe that the brain’s own immune system may hold the key to neurodegenerative disease treatment. In our <a href="https://doi.org/10.1016/j.cell.2022.09.030">research</a>, we found a protein that could possibly be leveraged to help the brain’s immune cells, or microglia, stave off Alzheimer’s disease.</p>
<h2>Challenges in treating neurodegeneration</h2>
<p>No available treatments for neurodegenerative diseases stop ongoing neurodegeneration while also helping affected areas in the body heal and recuperate.</p>
<p>In terms of failed treatments, Alzheimer’s disease is perhaps the most infamous of neurodegenerative diseases. Affecting <a href="https://www.alz.org/alzheimers-dementia/facts-figures">more than 1 in 9 U.S. adults 65 and older</a>, Alzheimer’s results from brain atrophy with the death of neurons and loss of the connections between them. These casualties contribute to memory and cognitive decline. <a href="https://doi.org/10.1002/alz.12450">Billions of dollars</a> have been funneled into researching treatments for Alzheimer’s, but <a href="https://doi.org/10.1002/trc2.12050">nearly every drug tested to date</a> has failed in clinical trials.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/zTd0-A5yDZI?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Alzheimer’s disease leads to loss of connections between neurons and cell death.</span></figcaption>
</figure>
<p>Another common neurodegenerative disease in need of improved treatment options is <a href="https://www.nationalmssociety.org/What-is-MS/Definition-of-MS">multiple sclerosis</a>. This autoimmune condition is caused by immune cells attacking the protective cover on neurons, known as myelin. Degrading myelin leads to communication difficulties between neurons and their connections with the rest of the body. <a href="https://doi.org/10.1016/j.amjmed.2020.05.049">Current treatments</a> suppress the immune system and can have potentially debilitating side effects. Many of these treatment options fail to address the toxic effects of the myelin debris that accumulate in the nervous system, which can kill cells.</p>
<h2>A new frontier in treating neurodegeneration</h2>
<p>Microglia are <a href="https://doi.org/10.1146/annurev-immunol-051116-052358">immune cells</a> masquerading as brain cells. <a href="https://doi.org/10.1146/annurev-immunol-032713-120240">In mice</a>, microglia originate in the yolk sac of an embryo and then infiltrate the brain early in development. The origins and migration of microglia <a href="https://doi.org/10.3389/fimmu.2018.01014">in people</a> are still under study.</p>
<p>Microglia play important roles in healthy brain function. Like other immune cells, microglia respond rapidly to pathogens and damage. They help to clear injuries and mend afflicted tissue, and can also take an active role in fighting pathogens. Microglia can also regulate brain inflammation, a normal part of the immune response that can cause swelling and damage if left unchecked.</p>
<p>Microglia also support the health of other brain cells. For instance, they can <a href="https://doi.org/10.3389/fncel.2018.00323">release molecules that promote resilience</a>, such as the protein BDNF, which is known to be beneficial for neuron survival and function.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/3AqKU5ktBG4?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Microglia are the often overlooked essential workers of the brain.</span></figcaption>
</figure>
<p>But the keystone feature of microglia are their astounding <a href="https://doi.org/10.3389/fimmu.2019.00790">janitorial skills</a>. Of all brain cell types, microglia possess an exquisite ability to clean up gunk in the brain, including the damaged myelin in multiple sclerosis, pieces of dead cells and amyloid beta, a toxic protein that is a hallmark of Alzheimer’s. They accomplish this by consuming and breaking down debris in their environment, effectively eating up the garbage surrounding them and their neighboring cells. </p>
<p>Given the many essential roles microglia serve to maintain brain function, these cells may possess the capacity to address multiple arms of neurodegeneration-related dysfunction. Moreover, as lifelong residents of the brain, microglia are already educated in the best practices of brain protection. These factors put microglia in the perfect position for researchers to leverage their inherent abilities to protect against neurodegeneration.</p>
<p><a href="https://doi.org/10.1038/s41593-018-0242-x">New data</a> in both animal models and human patients points to a previously underappreciated role microglia also play in the development of neurodegenerative disease. Many genetic risk factors for diseases like <a href="https://doi.org/10.1186/s13024-017-0184-x">Alzheimer’s</a> and <a href="https://doi.org/10.1126/science.aav7188">multiple sclerosis</a> are strongly linked to abnormal microglia function. These findings support an <a href="https://doi.org/10.1038/s41593-018-0242-x">accumulating number of animal studies</a> suggesting that disruptions to microglial function may contribute to neurologic disease onset and severity.</p>
<p>This raises the next logical question: How can researchers harness microglia to protect the nervous system against neurodegeneration? </p>
<h2>Engaging the magic of microglia</h2>
<p>In our lab’s <a href="https://doi.org/10.1016/j.cell.2022.09.030">recent study</a>, we keyed in on a crucial protein called SYK that microglia use to manipulate their response to neurodegeneration. </p>
<p>Our collaborators found that microglia <a href="https://doi.org/10.1016/j.cell.2022.09.033">dial up the activity of SYK</a> when they encounter debris in their environment, such as amyloid beta in Alzheimer’s or myelin debris in multiple sclerosis. When we inhibited SYK function in microglia, we found that twice as much amyloid beta accumulated in Alzheimer’s mouse models and six times as much myelin debris in multiple sclerosis mouse models.</p>
<p>Blocking SYK function in the microglia of Alzheimer’s mouse models also worsened neuronal health, indicated by increasing levels of toxic neuronal proteins and a surge in the number of dying neurons. This correlated with hastened cognitive decline, as the mice failed to learn a spatial memory test. Similarly, impairing SYK in multiple sclerosis mouse models exacerbated motor dysfunction and hindered myelin repair. These findings indicate that microglia use SYK to protect the brain from neurodegeneration. </p>
<p>But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate toward debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in cleanup processes. These jobs support the idea that SYK helps microglia protect the brain by charging them to remove toxic materials.</p>
<p>Finally, we wanted to figure out if we could leverage SYK to create “super microglia” that could help clean up debris before it makes neurodegeneration worse. When we gave mice a drug that boosted SYK function, we found that Alzheimer’s mouse models had lower levels of plaque accumulation in their brains one week after receiving the drug. This finding points to the potential of increasing microglia activity to treat Alzheimer’s disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Light micrograph of microglia cells" src="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=480&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=480&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=480&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=603&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=603&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=603&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Of the many brain cells (shown in black), giving microglia a boost could help them more effectively clean up debris in the brain.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/microglia-silver-carbonate-royalty-free-image/1321565343">Jose Luis Calvo Martin & Jose Enrique Garcia-Mauriño Muzquiz/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<h2>The horizon of microglia treatments</h2>
<p>Future studies will be necessary to see whether creating a super microglia cleanup crew to treat neurodegenerative diseases is beneficial in people. But our results suggest that microglia already play a key role in preventing neurodegenerative diseases by helping to remove toxic waste in the nervous system and promoting the healing of damaged areas. </p>
<p>It’s possible to have too much of a good thing, though. <a href="https://doi.org/10.1038/s41593-018-0242-x">Excessive inflammation</a> driven by microglia could make neurologic disease worse. We believe that equipping microglia with the proper instructions to carry out their beneficial functions without causing further damage could one day help treat and prevent neurodegenerative disease.</p>
<figure class="align-right ">
<img alt="Uncharted Brain, podcast series" src="https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption"></span>
</figcaption>
</figure>
<p><em>Listen to The Conversation’s podcast series <a href="https://theconversation.com/uk/topics/uncharted-brain-decoding-dementia-128903">Uncharted Brain: Decoding Dementia</a> to find out more about the latest research unlocking clues to the ongoing mystery of how dementia works in the brain. Find all episodes via <a href="https://podfollow.com/the-anthill/view">The Anthill podcast</a>.</em></p><img src="https://counter.theconversation.com/content/193606/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>This work was supported by funding from the NIH (1RF1AG071996-01, R01NS106383), The Alzheimer’s Association (ADSF-21-816651), the Cure Alzheimer’s Fund, The Owens Family Foundation, and a Wagner Scholarship</span></em></p>Microglia, immune cells disguised as brain cells, are known as the janitors of the brain. Dialing up their usual duties just enough could provide an avenue to treat neurodegenerative disease.Kristine Zengeler, Ph.D. Candidate in Neuroscience, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1935032022-11-07T13:35:27Z2022-11-07T13:35:27ZWhat is inflammation? Two immunologists explain how the body responds to everything from stings to vaccination and why it sometimes goes wrong<figure><img src="https://images.theconversation.com/files/493585/original/file-20221104-18-efs0p0.jpg?ixlib=rb-1.1.0&rect=107%2C242%2C5883%2C3745&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Insect bites or stings, like the one on this person's hand, are a manifestation of inflammation.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/cropped-hand-with-mosquito-bite-against-white-royalty-free-image/1187314357?phrase=insect%20bite&adppopup=true">Suthep Wongkhad/EyeEm via Getty Images</a></span></figcaption></figure><p>When your body fights off an infection, you develop a fever. If you have arthritis, your joints will hurt. If a bee stings your hand, your hand will swell up and become stiff. These are all manifestations of <a href="https://doi.org/10.1007/s11515-011-1123-9">inflammation</a> occurring in the body.</p>
<p>We are two <a href="https://scholar.google.com/citations?user=jJVj3sUAAAAJ&hl=en&oi=ao">immunologists</a> <a href="https://scholar.google.com/citations?user=af7TahQAAAAJ&hl=en&oi=ao">who study</a> how the immune system reacts <a href="https://pubmed.ncbi.nlm.nih.gov/?term=nagarkatti+p&sort=date">during infections, vaccination and autoimmune diseases</a> where the body starts attacking itself.</p>
<p>While inflammation is commonly associated with the pain of an injury or the many diseases it can cause, it is an important part of the normal immune response. The problems arise when this normally helpful function overreacts or overstays its welcome.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="An image showing many small white cells swarming a larger sphere." src="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=565&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=565&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493374/original/file-20221103-26-eq1cei.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=565&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Inflammation is a process in which antibody-producing cells – like the large beige cell on the left of this image – rush to the site of an infection to attack an invader, such as the flu virus in yellow.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/immune-response-to-a-virus-illustration-royalty-free-illustration/724237117?phrase=antibodies%20infection&adppopup=true">Juan Gaertner/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<h2>What is inflammation?</h2>
<p>Generally speaking, the term inflammation refers to all activities of the immune system that occur where the body is trying to fight off potential or real infections, clear toxic molecules or recover from physical injury. There are <a href="https://doi.org/10.1186%2F1476-9255-1-1">five classic physical signs</a> of acute inflammation: heat, pain, redness, swelling and loss of function. Low-grade inflammation might not even produce noticeable symptoms, but the underlying cellular process is the same.</p>
<p>Take a bee sting, for example. The immune system is like a military unit with a wide range of tools in its arsenal. After sensing the toxins, bacteria and physical damage from the sting, the immune system <a href="https://theconversation.com/coronavirus-b-cells-and-t-cells-explained-141888">deploys various types of immune cells</a> to the site of the sting. These include <a href="https://www.niaid.nih.gov/research/immune-cells">T cells, B cells, macrophages and neutrophils</a>, among other cells.</p>
<p>The <a href="https://www.ncbi.nlm.nih.gov/books/NBK26884/">B cells produce antibodies</a>. Those antibodies can kill any bacteria in the wound and neutralize toxins from the sting. <a href="https://doi.org/10.3389/fimmu.2012.00174">Macrophages and neutrophils engulf bacteria</a> and destroy them. <a href="https://doi.org/10.1038/d41586-021-00367-7">T cells don’t produce antibodies, but kill any virus-infected cell</a> to prevent viral spread. </p>
<p>Additionally, these immune cells produce <a href="https://doi.org/10.1177/1091581815584918">hundreds of types of molecules</a> called cytokines – otherwise known as mediators – that help fight threats and repair harm to the body. But just like in a military attack, inflammation comes with collateral damage.</p>
<p>The mediators that help kill bacteria also kill some healthy cells. Other similar mediating molecules cause blood vessels to leak, leading to accumulation of fluid and influx of more immune cells. </p>
<p>This collateral damage is the reason you develop swelling, redness and pain around a bee sting or after getting a flu shot. Once the immune system clears an infection or foreign invader – whether the toxin in a bee sting or a chemical from the environment – different parts of the inflammatory response take over and help repair the damaged tissue.</p>
<p>After a few days, your body will neutralize the poison from the sting, eliminate any bacteria that got inside and heal any tissue that was harmed. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram of a man showing two airways, one open and the other more constricted." src="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/493375/original/file-20221103-15-myadsi.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Asthma is caused by inflammation that leads to swelling and a narrowing of airways in the lungs, as seen in the right cutaway in this image.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Asthma_(Lungs).png#/media/File:Asthma_(Lungs).png">BruceBlaus/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Inflammation as a cause of disease</h2>
<p>Inflammation is a double-edged sword. It is critical for fighting infections and repairing damaged tissue, but when inflammation occurs for the wrong reasons or <a href="https://theconversation.com/long-covid-how-researchers-are-zeroing-in-on-the-self-targeted-immune-attacks-that-may-lurk-behind-it-169911">becomes chronic</a>, the damage it causes <a href="https://theconversation.com/despite-its-disastrous-effects-covid-19-offers-some-gifts-to-medicine-an-immunology-expert-explains-what-it-can-teach-us-about-autoimmune-disease-174952">can be harmful</a>. </p>
<p><a href="https://doi.org/10.1111/j.1600-065x.2011.01020.x">Allergies</a>, for example, develop when the immune system mistakenly recognizes innocuous substances – like peanuts or pollen – as dangerous. The harm can be minor, like itchy skin, or dangerous if someone’s throat closes up.</p>
<p>Chronic inflammation damages tissues over time and can lead to <a href="https://doi.org/10.1038/s41591-019-0675-0">many noninfectious clinical disorders</a>, including cardiovascular diseases, neurodegenerative disorders, obesity, diabetes and some types of cancers. </p>
<p>The immune system can sometimes mistake one’s own organs and tissues for invaders, leading to inflammation throughout the body or in specific areas. This self-targeted inflammation is what causes the symptoms of <a href="https://doi.org/10.1289/ehp.99107s5661">autoimmune diseases</a> such as lupus and arthritis. </p>
<p>Another cause of chronic inflammation that researchers like us are currently studying is defects in the <a href="https://doi.org/10.3389/fimmu.2016.00160">mechanisms that curtail inflammation</a> after the body clears an infection.</p>
<p>While inflammation mostly plays out at a cellular level in the body, it is far from a simple mechanism that happens in isolation. Stress, diet and nutrition, as well as genetic and environmental factors, have all been shown <a href="https://doi.org/10.3389%2Ffimmu.2020.570083">to regulate inflammation</a> in some way. </p>
<p>There is still a lot to be learned about what leads to harmful forms of inflammation, but a <a href="https://doi.org/10.3390%2Fnu11081933">healthy diet</a> and <a href="https://doi.org/10.1016%2Fj.copsyc.2015.03.007">avoiding stress</a> can go a long way toward helping maintain the delicate balance between a strong immune response and harmful chronic inflammation.</p><img src="https://counter.theconversation.com/content/193503/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Prakash Nagarkatti receives funding from the National Science Foundation and the National Institutes of Health. </span></em></p><p class="fine-print"><em><span>Mitzi Nagarkatti receives funding from the National Institutes of Health.</span></em></p>Inflammation is a complicated and important part of how the immune system responds to threats to the body. But when the inflammatory response goes awry, it can lead to serious problems.Prakash Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaMitzi Nagarkatti, Professor of Pathology, Microbiology and Immunology, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1888992022-09-18T20:15:03Z2022-09-18T20:15:03ZI’ve had COVID and am constantly getting colds. Did COVID harm my immune system? Am I now at risk of other infectious diseases?<figure><img src="https://images.theconversation.com/files/483171/original/file-20220907-24-ekxrkx.jpg?ixlib=rb-1.1.0&rect=2%2C2%2C1914%2C1276&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.pexels.com/photo/photo-of-a-cold-woman-6753163/">Pavel Danilyuk/Pexels</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>So you’ve had COVID and have now recovered. You don’t have ongoing symptoms and luckily, you don’t seem to have developed <a href="https://theconversation.com/long-covid-how-researchers-are-zeroing-in-on-the-self-targeted-immune-attacks-that-may-lurk-behind-it-169911">long COVID</a>. </p>
<p>But what impacts has COVID had on your overall immune system?</p>
<p>It’s early days yet. But growing evidence suggests there are changes to your immune system that may put you at risk of other infectious diseases.</p>
<p>Here’s what we know so far.</p>
<h2>A round of viral infections</h2>
<p>Over this past winter, many of us have had what seemed like a <a href="https://theconversation.com/why-do-i-and-my-kids-get-so-many-colds-and-with-all-this-covid-around-should-we-be-isolating-too-179302">continual round</a> of viral illness. This may have included COVID, <a href="https://www.who.int/health-topics/influenza-seasonal#tab=tab_1">influenza</a> or infection with <a href="https://www.mayoclinic.org/diseases-conditions/respiratory-syncytial-virus/symptoms-causes/syc-20353098">respiratory syncytial virus</a>. We may have recovered from one infection, only to get another.</p>
<p>Then there is the re-emergence of infectious diseases globally such as <a href="https://theconversation.com/we-need-to-talk-about-monkeypox-without-shame-and-blame-188295">monkeypox</a> or <a href="https://theconversation.com/the-latest-polio-cases-have-put-the-world-on-alert-heres-what-this-means-for-australia-and-people-travelling-overseas-188989">polio</a>.</p>
<p>Could these all be connected? Does COVID somehow weaken the immune system to make us more prone to other infectious diseases?</p>
<p>There are <a href="https://www.sciencedirect.com/science/article/pii/B9780128009475000168?via%3Dihub">many reasons</a> for infectious diseases to emerge in new locations, after many decades, or in new populations. So we cannot jump to the conclusion COVID infections have given rise to these and other viral infections.</p>
<p>But evidence is building of the negative impact of COVID on a healthy <em>individual’s</em> immune system, several weeks after symptoms have subsided.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/the-latest-polio-cases-have-put-the-world-on-alert-heres-what-this-means-for-australia-and-people-travelling-overseas-188989">The latest polio cases have put the world on alert. Here's what this means for Australia and people travelling overseas</a>
</strong>
</em>
</p>
<hr>
<h2>What happens when you catch a virus?</h2>
<p>There are three possible outcomes after a viral infection:</p>
<p>1) your immune system clears the infection and you recover (for instance, with <a href="https://www.healthychildren.org/English/health-issues/conditions/ear-nose-throat/Pages/Rhinovirus-Infections.aspx">rhinovirus</a> which causes the common cold)</p>
<p>2) your immune system fights the virus into “latency” and you recover with a virus dormant in our bodies (for instance, <a href="https://www.healthdirect.gov.au/chickenpox">varicella zoster virus</a>, which causes chickenpox) </p>
<p>3) your immune system fights, and despite best efforts the virus remains “chronic”, replicating at very low levels (this can occur for <a href="https://www.who.int/news-room/fact-sheets/detail/hepatitis-c">hepatitis C virus</a>).</p>
<p>Ideally we all want option 1, to clear the virus. In fact, most of us <a href="https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00856-w">clear SARS-CoV-2</a>, the virus that causes COVID. That’s through a complex process, using many different parts of our immune system.</p>
<p>But international evidence suggests changes to our immune cells after SARS-CoV-2 infection may have other impacts. It may affect our ability to fight other viruses, as well as other pathogens, such as bacteria or fungi. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/no-the-extra-hygiene-precautions-were-taking-for-covid-19-wont-weaken-our-immune-systems-143690">No, the extra hygiene precautions we're taking for COVID-19 won't weaken our immune systems</a>
</strong>
</em>
</p>
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<h2>How much do we know?</h2>
<p>An <a href="https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02228-6">Australian study</a> has found SARS-CoV-2 alters the balance of immune cells up to 24 weeks after clearing the infection. </p>
<p>There were changes to the relative numbers and types of immune cells between people who had recovered from COVID compared with healthy people who had not been infected.</p>
<p>This included changes to cells of the <a href="https://www.khanacademy.org/test-prep/mcat/organ-systems/the-immune-system/a/innate-immunity">innate immune system</a> (which provides a non-specific immune response) and the <a href="https://www.ncbi.nlm.nih.gov/books/NBK21070/">adaptive immune system</a> (a specific immune response, targeting a recognised foreign invader).</p>
<p><a href="https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009742">Another study</a> focused specifically on <a href="https://www.immunology.org/public-information/bitesized-immunology/cells/dendritic-cells">dendritic cells</a> – the immune cells that are often considered the body’s “first line of defence”.</p>
<p>Researchers found fewer of these cells circulating after people recovered from COVID. The ones that remained were less able to activate white blood cells known as <a href="https://www.britannica.com/science/T-cell">T-cells</a>, a critical step in activating anti-viral immunity.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Dendritic cells (red) attacking viruses (green)" src="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/483176/original/file-20220907-16-x3asae.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Fewer dendritic cells (red) were circulating after COVID.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/antiviral-immunity-dendritic-cells-binding-viruses-1781314607">Shutterstock</a></span>
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<p>Other studies have found different impacts on T-cells, and other types of white blood cells known as <a href="https://askabiologist.asu.edu/b-cell">B-cells</a> (cells involved in producing antibodies).</p>
<p>After SARS-CoV-2 infection, one study <a href="https://doi.org/10.1172/JCI140491">found evidence</a> many of these cells had been activated and “exhausted”. This suggests the cells are dysfunctional, and might not be able to adequately fight a subsequent infection. In other words, sustained activation of these immune cells after a SARS-CoV-2 infection may have an impact on other inflammatory diseases.</p>
<p><a href="https://www.nature.com/articles/s41392-021-00749-3#citeas">One study</a> found people who had recovered from COVID have changes in different types of B-cells. This included changes in the cells’ metabolism, which may impact how these cells function. Given B-cells are critical for producing antibodies, we’re not quite sure of the precise implications.</p>
<p>Could this influence how our bodies produce antibodies against SARS-CoV-2 should we encounter it again? Or could this impact our ability to produce antibodies against pathogens more broadly – against other viruses, bacteria or fungi? The study did not say.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
</strong>
</em>
</p>
<hr>
<h2>What impact will these changes have?</h2>
<p>One of the main concerns is whether such changes may impact how the immune system responds to other infections, or whether these changes
might worsen or cause other chronic conditions. </p>
<p>So more work needs to be done to understand the long-term impact of SARS-CoV-2 infection on a person’s immune system.</p>
<p>For instance, we still don’t know how long these changes to the immune system last, and if the immune system recovers. We also don’t know if SARS-CoV-2 triggers other chronic illnesses, such as <a href="https://www.healthdirect.gov.au/chronic-fatigue-syndrome-cfs-me">chronic fatigue syndrome</a> (myalgic encephalomyelitis). Research into this is ongoing.</p>
<p>What we do know is that having a healthy immune system and being vaccinated (when a vaccine has been developed) is critically important to have the best chance of fighting any infection.</p><img src="https://counter.theconversation.com/content/188899/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lara Herrero receives funding from NHMRC.</span></em></p>Evidence is growing there are changes to your immune system that may put you at risk of other infectious diseases.Lara Herrero, Research Leader in Virology and Infectious Disease, Griffith UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1869702022-08-04T12:23:36Z2022-08-04T12:23:36ZLong COVID-19 and other chronic respiratory conditions after viral infections may stem from an overactive immune response in the lungs<figure><img src="https://images.theconversation.com/files/477255/original/file-20220802-23-r6z7fj.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2297%2C1292&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The immune system usually stays dormant in the lungs in times of health.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/lung-virus-infection-royalty-free-image/1205199983">wildpixel/iStock via Getty Images</a></span></figcaption></figure><p>Viruses that cause respiratory diseases like the flu and COVID-19 can lead to mild to severe symptoms within the first few weeks of infection. These symptoms typically resolve within a few more weeks, sometimes with the help of treatment if severe. However, some people go on to experience persistent symptoms that last several months to years. Why and how respiratory diseases can develop into chronic conditions like <a href="https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html">long COVID-19</a> are still unclear.</p>
<p>I am a <a href="https://scholar.google.com/citations?hl=en&user=BNGZA1MAAAAJ">doctoral student</a> working in the <a href="https://www.immunology.virginia.edu/Sun/">Sun Lab</a> at the University of Virginia. We study how the immune system sometimes goes awry after fighting off viral infections. We also develop ways to target the immune system to prevent further complications without weakening its ability to protect against future infections. Our <a href="https://doi.org/10.1126/sciimmunol.abm7996">recently published review</a> of the research in this area found that it is becoming clearer that it might not be an active viral infection causing long COVID-19 and similar conditions, but an overactive immune system.</p>
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<figcaption><span class="caption">Long COVID-19 patients can experience persistent respiratory, cognitive and neurological symptoms.</span></figcaption>
</figure>
<h2>The lungs in health and disease</h2>
<p>Keeping your immune system dormant when there isn’t an active infection is essential for your lungs to be able to function optimally. </p>
<p>Your respiratory tract is in constant contact with your external environment, sampling around <a href="https://www.acepnow.com/article/avoid-airway-catastrophes-extremes-minute-ventilation/">5 to 8 liters (1.3 to 2 gallons) of air</a> – and the toxins and microorganisms in it – every minute. Despite continuous exposure to potential pathogens and harmful substances, your body has evolved to <a href="https://doi.org/10.1164/ajrccm.162.supplement_3.15tac6">keep the immune system dormant in the lungs</a>. In fact, allergies and conditions such as asthma are byproducts of an <a href="https://doi.org/10.1513/AnnalsATS.201401-028AW">overactive immune system</a>. These excessive immune responses can cause your airways to constrict and make it difficult to breathe. Some severe cases may require treatment to suppress the immune system. </p>
<p>During an active infection, however, the immune system is absolutely essential. When viruses infect your respiratory tract, immune cells are recruited to your lungs to fight off the infection. Although these cells are crucial to eliminate the virus from your body, their activity often results in collateral damage to your lung tissue. After the virus is removed, your body <a href="https://doi.org/10.1007%2Fs00281-016-0560-6">dampens your immune system</a> to give your lungs a chance to recover.</p>
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<figcaption><span class="caption">An overactive immune system, as in the case of asthma, can damage the lungs.</span></figcaption>
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<p>Over the past decade, researchers have identified a variety of <a href="https://doi.org/10.1016/j.stem.2020.03.009">specialized stem cells in the lungs</a> that can help regenerate damaged tissue. These stem cells can turn into almost all the different types of cells in the lungs depending on the signals they receive from their surrounding environment. <a href="https://doi.org/10.1126/scitranslmed.abo5254">Recent</a> <a href="https://doi.org/10.1016/j.stem.2020.06.020">studies</a> <a href="https://doi.org/10.1016/j.stemcr.2019.02.013">have highlighted</a> the prominent role the immune system plays in providing signals that facilitate lung recovery. But these signals can produce more than one effect. They can not only activate stem cells, but also perpetuate damaging inflammatory processes in the lung. Therefore, your body tightly regulates when, where and how strongly these signals are made in order to prevent further damage.</p>
<p>While the reasons are still unclear, some people are unable to turn off their immune system after infection and <a href="https://doi.org/10.1126/sciimmunol.abk1741">continue to produce tissue-damaging molecules</a> <a href="https://doi.org/10.1038/s41590-021-01113-x">long after</a> the virus has been flushed out. This not only further damages the lungs, but also interferes with regeneration via the lung’s resident stem cells. This phenomenon can result in chronic disease, as seen in several respiratory viral infections including <a href="https://doi.org/10.1016/j.immuni.2022.01.017">COVID-19</a>, <a href="https://doi.org/10.2340/16501977-2694">Middle East Respiratory Syndrome (MERS)</a>, <a href="https://doi.org/10.1056/NEJMoa1211917">respiratory syncytial virus (RSV)</a> and the <a href="https://doi.org/10.1016/j.jaci.2005.06.024">common cold</a>.</p>
<h2>The immune system’s role in chronic disease</h2>
<p>In our review, my colleagues and I found that many <a href="https://doi.org/10.1126/sciimmunol.abm7996">different types of immune cells</a> are involved in the development of chronic disease after respiratory viral infections, including long COVID-19.</p>
<p>Scientists so far have identified one particular type of immune cells, <a href="https://doi.org/10.1126/sciimmunol.abk1741">killer T cells</a>, as potential contributors to chronic disease. Also known as cytotoxic or CD8+ T cells, they specialize in killing infected cells either by interacting directly with them or by producing damaging molecules called cytokines. </p>
<p>Killer T cells are essential to curbing the virus from spreading in the body during an active infection. But their persistence in the lungs after the infection has resolved is linked to extended <a href="https://doi.org/10.1126/sciimmunol.abc4557">reduced respiratory function</a>. Moreover, animal studies have shown that <a href="https://doi.org/10.1126/sciimmunol.abk1741">removing killer T cells from the lungs</a> after infection may improve lung function and tissue repair.</p>
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<figcaption><span class="caption">A legion of immune cells work together to remove invading pathogens.</span></figcaption>
</figure>
<p>Another type of immune cells called monocytes are also involved in fighting respiratory infections, serving among the first responders by producing virus- and tissue-damaging cytokines. Research has found that these cells also <a href="https://doi.org/10.1016/j.immuni.2022.01.017">continue to accumulate</a> in the lungs of long COVID-19 patients and promote a pro-inflammatory environment that can cause further damage.</p>
<p>Understanding the immunological mechanisms underlying long COVID-19 is the first step to addressing a <a href="https://www.kff.org/policy-watch/what-are-the-implications-of-long-covid-for-employment-and-health-coverage/">quickly worsening public health problem</a>. Identifying the subtle differences in how the same immune cells that protect you during an active infection can later become harmful could lead to earlier diagnosis of long COVID-19. Moreover, based on our findings, my team and I believe treatments that target the immune system could be an effective approach to manage long COVID-19 symptoms. We believe that this strategy may turn out to be useful not only for COVID-19, but also for other respiratory viral infections that lead to chronic disease as well.</p><img src="https://counter.theconversation.com/content/186970/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Harish Narasimhan does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>While a strong immune response is essential to fight against viral infection, an immune system that continues to stay active long after the virus has been cleared can lead to lung damage.Harish Narasimhan, PhD Candidate in Immunology, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1756502022-06-10T12:29:55Z2022-06-10T12:29:55ZSepsis still kills 1 in 5 people worldwide – two ICU physicians offer a new approach to stopping it<figure><img src="https://images.theconversation.com/files/467853/original/file-20220608-22-nfife2.jpg?ixlib=rb-1.1.0&rect=59%2C0%2C6540%2C2642&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Sepsis begins with infection by bacteria or a virus. This panoramic ilustration inside a blood vessel shows rod-shaped bacteria, red blood cells and immune cells called leukocytes.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/bacteria-in-blood-illustration-royalty-free-illustration/685024929?adppopup=true">Kateryna Kon/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Can an otherwise healthy young woman die from what starts out as something akin to a common cold? The answer is, <a href="https://www.bbc.com/news/uk-wales-45498914">shockingly, yes</a>, when certain telltale signs of a more serious problem go undetected. </p>
<p>Though many people haven’t even heard of it, sepsis – the body’s extreme response to infection – is <a href="https://www.natlawreview.com/article/sepsis-accounts-1-5-deaths-leading-cause-death-hospitals#">the leading killer of hospitalized patients</a> in the United States. Worldwide, sepsis is responsible <a href="https://doi.org/10.1016/S0140-6736(19)32989-7">for 1 in 5 deaths every year</a>. <a href="https://www.sccm.org/MyICUCare/THRIVE/Post-intensive-Care-Syndrome">Even among those who survive</a>, many will never be able to return to work, and some won’t be able to return home from the hospital, requiring life support or ongoing critical care.</p>
<p>We <a href="https://pre.ccm.pitt.edu/?q=content/rudd-kristina">are two researchers</a> and <a href="https://www.ccm.pitt.edu/node/1211">critical care doctors</a> at the University of Pittsburgh School of Medicine who are working to change the way scientists and doctors think about sepsis. We are interested in understanding and spreading awareness about how sepsis starts and how it can elude even the most astute physicians. </p>
<p>We are also learning more about how community factors are at play and how a better understanding of the communities we all live in could help everyday people and health care workers alike recognize and stop this deadly disease.</p>
<h2>What is sepsis?</h2>
<p>Sepsis is a medical emergency that begins with an infection – perhaps even a mild infection. Upon detecting bacteria or a virus, your body releases a choreographed cascade of chemicals into the bloodstream. This chemical alert beckons <a href="https://theconversation.com/how-long-does-protective-immunity-against-covid-19-last-after-infection-or-vaccination-two-immunologists-explain-177309">an artillery of immune cells</a> that work in concert to fight the bug. </p>
<p>When this system works well, your body clears the infection and you get better. But when the system doesn’t work well, sepsis can ensue.</p>
<p>The onset of sepsis occurs when your immune cells pivot from fighting the infection to fighting your own tissues and organs. This reaction can be similar to an autoimmune response, a condition in which <a href="https://medlineplus.gov/autoimmunediseases.html">the body’s immune system turns on itself</a>. Many people are familiar with chronic autoimmune diseases such as <a href="https://www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html#">rheumatoid arthritis</a> or <a href="https://www.mayoclinic.org/diseases-conditions/crohns-disease/symptoms-causes/syc-20353304#">Crohn’s disease</a>, but sometimes this type of autoimmune response can occur even in healthy people. </p>
<p>When sepsis occurs, the immune system can commonly injure the heart, lungs, kidneys or blood cells, among other important body systems. Inflammation in the blood vessels can make them leaky, causing blood flow to the brain and other organs to become severely diminished. When this occurs, a person’s blood pressure may become dangerously low, which is a severe form of sepsis known as septic shock. </p>
<p>Without prompt and proper treatment – and sometimes even despite treatment – sepsis can cause organ damage and even death. Once shock develops, mortality from sepsis is estimated <a href="https://doi.org/10.1001/jama.2016.0287">to jump from 10% to as high as 40%</a>.</p>
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<figcaption><span class="caption">An illustrated explanation of how sepsis attacks the body.</span></figcaption>
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<p>Sepsis can result from nearly any infection. Most commonly it develops from pneumonia or a urinary tract infection. Severe <a href="https://www.ama-assn.org/delivering-care/public-health/sepsis-survival-has-lessons-severe-covid-19-care-recovery">COVID-19 can also cause sepsis</a>. Often, sepsis patients are seen by a medical professional for infection symptoms <a href="https://doi.org/10.4037/ajcc2021456">in the week preceding sepsis hospitalization</a>. However, predicting which infected patients will go on to develop sepsis is very difficult.</p>
<h2>Treatment options</h2>
<p>The cornerstones of sepsis treatment are prompt recognition of sepsis symptoms, followed by antibiotics and fluids. But even the most careful and attentive physicians can miss the early signs of sepsis. </p>
<p>This is largely because there is no single test to positively diagnose sepsis. Sepsis symptoms may mimic other life-threatening conditions such as heart attacks, blood clots, bleeding or even an allergic reaction. Patients often display vague and variable symptoms such as weakness, lightheadedness and rapid breathing, making the diagnosis even more challenging. </p>
<p>For example, a young, otherwise healthy person with sepsis due to pneumonia may look much different from an older diabetic who develops sepsis from a smoldering skin infection.</p>
<p>Sepsis patients nearly always require admission to the hospital or even the ICU, and those with severe forms of sepsis often require life support. This may include dialysis or mechanical ventilation to support failing organs. The source of infection needs to be identified and, in some cases, surgically removed. Delaying sepsis treatment by even a few hours <a href="https://doi.org/10.1007/s00134-021-06506-y">can have deadly consequences</a>. </p>
<figure>
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<figcaption><span class="caption">Sepsis can affect those of any age, not just the elderly.</span></figcaption>
</figure>
<h2>Recognizing sepsis before it’s too late</h2>
<p>Differences in sepsis go beyond symptoms. COVID-19 has laid bare that severe illness isn’t a game of chance. Like COVID-19 infection, sepsis susceptibility – and who is most likely to get sick and die – is part of a complex interplay of social influences that <a href="https://doi.org/10.1001/jama.2021.22583">include racism, poverty, geography and community dynamics</a>.</p>
<p>Research strongly suggests that certain people are at <a href="https://doi.org/10.1093/ofid/ofy305">far higher risk of developing sepsis</a> than others. Much like COVID-19, older people with underlying chronic diseases like obesity and diabetes face a heightened risk for sepsis. Such factors as race, poverty and even driving distance to the hospital <a href="https://doi.org/10.1016/j.chest.2016.07.004">may have a significant impact</a> on who survives sepsis. </p>
<p>Most of the work done to improve sepsis detection and treatment has focused on the hospital setting. Doctors, researchers and even government agencies have concentrated their efforts on improving sepsis recognition and treatment once a patient reaches the hospital. Research aimed at understanding an individual’s sepsis risk has focused on personal health history and social and economic factors such as income and race, or community features such as primary care access. </p>
<p>While these approaches have advanced the field’s understanding of sepsis, they have led to little progress in reducing the incidence of sepsis in the U.S.</p>
<figure>
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<figcaption><span class="caption">Sepsis is sometimes mistaken for the flu.</span></figcaption>
</figure>
<h2>New approaches to catching a killer</h2>
<p>Given what is known about the importance of early sepsis treatment, researchers like us are taking a closer look at the role of communities in improving sepsis detection and understanding sepsis risk.</p>
<p>The early stages of sepsis can evolve rapidly when a patient is at home. Scientists estimate that <a href="https://www.cdc.gov/sepsis/what-is-sepsis.html">87% of sepsis cases start outside the hospital</a>. When a patient does present for care, it’s often in a clinic or emergency medical services setting in the days and even hours <a href="https://doi.org/10.1164/rccm.201204-0713OC">preceding sepsis hospitalization</a>. These critical treatment windows may mean the difference between life and death for a sepsis patient. </p>
<p>Alongside researchers based at Kaiser Permanente Northern California, we are now working to advance sepsis care by studying sepsis patient symptoms, community factors, diagnosis and treatment patterns outside the hospital. We are also expanding work to <a href="https://doi.org/10.1038/s41746-022-00580-2">improve sepsis diagnosis among hospitalized patients</a>. This coast-to-coast collaboration will study patients cared for at over 40 hospitals, 30 EMS agencies and a critical mass of ambulatory clinics. We hope that our work will shed light on the early stages of sepsis, including signs that may signal that an infected patient is progressing to sepsis, and explore diagnostic and treatment approaches that could help stop sepsis before it advances too far. </p>
<p>We are also learning a great deal more about the complicated role of community factors like poverty on health outcomes, including sepsis. Using “syndemic theory” – a framework to describe synergistic epidemics that <a href="https://doi.org/10.1016/S0140-6736(17)30003-X">arise from harmful social conditions</a> – we are studying how two co-occurring epidemics, like poverty and asthma, can work together to increase negative health outcomes. Though this framework is only beginning to be used to study acute illness, it has the potential to transform the way we think about sepsis.</p><img src="https://counter.theconversation.com/content/175650/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Emily Brant works for the University of Pittsburgh School of Medicine and UPMC Health System. She has received grant funding from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) and the Gordon and Betty Moore Foundation. She has no relevant conflicts of interest to report. </span></em></p><p class="fine-print"><em><span>Kristina E. Rudd works for the University of Pittsburgh and UPMC Health System. She consults for Janssen Pharmaceuticals. She receives grant funding from the National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute (National Institutes of Health).</span></em></p>Sepsis onset can be difficult to recognize, in part because its symptoms can mimic those of many other conditions. A treatment delay of even a few hours can make the difference between life and death.Emily Brant, Assistant Professor of Critical Care and Emergency Medicine, University of PittsburghKristina E. Rudd, Assistant Professor of Critical Care Medicine, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1707722022-01-24T13:31:35Z2022-01-24T13:31:35ZHow mRNA and DNA vaccines could soon treat cancers, HIV, autoimmune disorders and genetic diseases<figure><img src="https://images.theconversation.com/files/441838/original/file-20220120-9603-u5kjhi.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C3840%2C2160&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Nucleic acid vaccines use mRNA to give cells instructions on how to produce a desired protein.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/messenger-rna-or-mrna-strand-3d-rendering-royalty-free-image/1295693748?adppopup=true">Libre de Droit/iStock via Getty Images</a></span></figcaption></figure><p><em>The two most successful coronavirus vaccines developed in the U.S. – the Pfizer and Moderna vaccines – are both mRNA vaccines. The idea of using genetic material to produce an immune response has opened up a world of research and potential medical uses far out of reach of traditional vaccines. <a href="https://scholar.google.com/citations?user=eNprtJEAAAAJ&hl=en&oi=ao">Deborah Fuller is a microbiologist</a> at the University of Washington who has been studying genetic vaccines for more than 20 years. We spoke to her about the <a href="https://theconversation.com/mrna-vaccines-asteroid-missions-and-collaborative-robots-what-to-watch-in-science-in-2022-podcast-174413">future of mRNA vaccines for The Conversation Weekly podcast</a>.</em> </p>
<p><em>Below are excerpts from that conversation which have been edited for length and clarity.</em> </p>
<h2>How long have gene-based vaccines been in development?</h2>
<p>This type of vaccine has been in the works for <a href="https://doi.org/10.1038/356152a0">about 30 years</a>. Nucleic acid vaccines are based on the idea that DNA makes RNA and then RNA makes proteins. For any given protein, once we know the genetic sequence or code, we can design an mRNA or DNA molecule that prompts a person’s cells to start making it. </p>
<p>When we first thought about this idea of putting a genetic code into somebody’s cells, we were studying both DNA and RNA. The mRNA vaccines did not work very well at first. They <a href="https://www.nature.com/articles/nrd.2017.243">were unstable</a> and they caused pretty strong immune responses that were <a href="https://doi.org/10.1038/nrd.2017.243">not necessarily desirable</a>. For a very long time DNA vaccines took the front seat, and the very <a href="https://dx.doi.org/10.1038%2Fnrg2432">first clinical trials were with a DNA vaccine</a>.</p>
<p>But about seven or eight years ago, mRNA vaccines started to take the lead. Researchers solved a lot of the problems – notably the <a href="https://doi.org/10.1038/mt.2008.200">instability</a> – and discovered <a href="https://doi.org/10.1073/pnas.1209367109">new technologies to deliver mRNA</a> into cells and ways of modifying the coding sequence to <a href="https://doi.org/10.1038/nrd.2017.243">make the vaccines a lot more safe to use in humans</a>.</p>
<p>Once those problems were solved, the technology was really poised to become a revolutionary tool for medicine. This was just when COVID-19 hit. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A scanning electron microscope image of blue lumpy sphere of a T cell." src="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441840/original/file-20220120-8772-9mk8e5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">DNA and mRNA vaccines are much better at producing T cells than are normal vaccines.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/photolist-2mEvEdt-a4RLoY-2mEn5zV-bo51Vz-MSuhWU-bo5rrZ-2kLN4tU-2kLN4uF-SjQFf7-2ewYf1r-rx2LVN-su1wdR-2j4icVg-2iKmbjG-2mfURRa-a7RGBX-xvJ8TV-2hVm2XZ-2hVhUoD-2iKjyJj-51svu9-51ojDi-51sByA-ni2rkv-2iKgNob-Fwbp7g-EpF3rg-HKERqY-51sBff-51ojop-2mfSkUp-2mfMhmB-2mfLV8V-2mfQZZp-2mfLTAG-2mfVWsD-2mfRRSs-2mfQJMF-2mfUQ1m-2mfSjPU">NIAID/NIH via Flickr</a></span>
</figcaption>
</figure>
<h2>What makes nucleic acid vaccines different from traditional vaccines?</h2>
<p>Most vaccines induce antibody responses. Antibodies are the primary immune mechanism that blocks infections. As we began to study nucleic acid vaccines, we discovered that because these vaccines are expressed within our cells, they were also <a href="https://www.gavi.org/vaccineswork/what-are-nucleic-acid-vaccines-and-how-could-they-be-used-against-covid-19#:%7E:text=Nucleic%20acid%20vaccines%20use%20genetic,immune%20response%20against%20it">very effective at inducing a T cell response</a>. This discovery really prompted additional thinking about how researchers could use nucleic acid vaccines not just for infectious diseases, but also for immunotherapy to treat cancers and chronic infectious diseases – like HIV, hepatitis B and herpes – as well as autoimmune disorders and even for gene therapy.</p>
<h2>How can a vaccine treat cancers or chronic infectious diseases?</h2>
<p>T cell responses are very important for identifying cells infected with chronic diseases and aberrant cancer cells. They also play a big role in eliminating these cells from the body.</p>
<p>When a cell becomes cancerous, it <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neoantigen">starts producing neoantigens</a>. In normal cases, the immune system detects these neoantigens, recognizes that something’s wrong with the cell and eliminates it. The reason some people get tumors is that their immune system isn’t quite capable of eliminating the tumor cells, so the cells propagate.</p>
<p>With an mRNA or DNA vaccine, the goal is to make your body better able to recognize the very specific neoantigens the cancer cell has produced. If your immune system can recognize and see those better, it will <a href="https://doi.org/10.1038/d41586-019-03072-8">attack the cancer cells and eliminate them from the body</a>. </p>
<p>This same strategy can be applied to the <a href="https://www.genengnews.com/insights/immunotherapy-targets-emerging-infectious-diseases/">elimination of chronic infections</a> like HIV, hepatitis B and herpes. These viruses infect the human body and stay in the body forever unless the immune system eliminates them. Similar to the way nucleic acid vaccines can train the immune system to eliminate cancer cells, they can be used to train our immune cells to recognize and eliminate chronically infected cells. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A syringe inserted into a vaccine vial." src="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441842/original/file-20220120-9349-1yi871k.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">There are dozens of ongoing trials testing the efficacy of mRNA or DNA vaccines to treat cancers or chronic diseases.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/syringe-and-coronavirus-vaccine-royalty-free-image/1287271384?adppopup=true">Stefan Cristian Cioata/Moment via Getty Images</a></span>
</figcaption>
</figure>
<h2>What is the status of these vaccines?</h2>
<p>Some of the very first clinical trials of nucleic acid vaccines happened in the 1990s and <a href="https://doi.org/10.1073/pnas.90.23.11307">were for cancer</a>, particularly for <a href="https://doi.org/10.1038/nrg2432">melanoma</a>.</p>
<p>Today, there are a <a href="https://www.cancernetwork.com/view/messenger-rna-vaccines-beckoning-of-a-new-era-in-cancer-immunotherapy">number of ongoing mRNA clinical trials</a> for the treatment of melanoma, prostate cancer, ovarian cancer, breast cancer, leukemia, glioblastoma and others, and there have been some promising outcomes. Moderna recently announced promising results with its phase 1 trial using mRNA to <a href="https://www.businesswire.com/news/home/20211112005897/en/Moderna-Announces-Presentation-of-Interim-Data-from-Phase-1-Study-of-mRNA-Triplet-Program-at-2021-SITC-Annual-Meeting">treat solid tumors and lymphoma</a></p>
<p>There are also a lot of ongoing trials looking at cancer DNA vaccines, because DNA vaccines are <a href="https://doi.org/10.1186/s13046-019-1154-7">particularly effective in inducing T cell responses</a>. A company called Inovio recently demonstrated a significant impact on cervical cancer caused by human papilloma virus in women <a href="https://ir.inovio.com/news-releases/news-releases-details/2021/INOVIO-Highlights-Key-Updates-on-Phase-3-Program-for-VGX-3100-its-DNA-based-Immunotherapy-for-the-Treatment-of-Cervical-HSIL-Caused-by-HPV-16-andor-HPV-18/default.aspx">using a DNA vaccine</a>.</p>
<h2>Can nucleic acid vaccines treat autoimmune disorders?</h2>
<p>Autoimmune disorders occur when a person’s immune cells are actually attacking a part of the person’s own body. An example of this is multiple sclerosis. If you have multiple sclerosis, your <a href="https://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/symptoms-causes/syc-20350269">own immune cells are attacking myelin</a>, a protein that coats the nerve cells in your muscles.</p>
<p>The way to eliminate an autoimmune disorder is to modulate your immune cells to prevent them from attacking your own proteins. In contrast to vaccines, whose goal is to stimulate the immune system to better recognize something, treatment for autoimmune diseases seeks to dampen the immune system so that it stops attacking something it shouldn’t. Recently, researchers created an mRNA vaccine encoding a myelin protein with slightly tweaked genetic instructions to prevent it from stimulating immune responses. Instead of activating normal T cells that increase immune responses, the vaccine caused the body to <a href="https://doi.org/10.1126/science.aay3638">produce T regulatory cells</a> that specifically suppressed only the T cells that were attacking myelin.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A diagram showing DNA turning into mRNA which turns into proteins." src="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=618&fit=crop&dpr=1 600w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=618&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=618&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=776&fit=crop&dpr=1 754w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=776&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/441841/original/file-20220120-8832-1sa98ad.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=776&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many diseases result when people have mutations or are missing certain genes, and nucleic acid vaccines could act as temporary replacements for the missing genes.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/mrna-and-protein-synthesis-difference-royalty-free-illustration/1323350905?adppopup=true">ttsz/iStock via Getty Images</a></span>
</figcaption>
</figure>
<h2>Any other applications of the new vaccine technology?</h2>
<p>The last application is actually one of the very first things that researchers thought about using DNA and mRNA vaccines for: gene therapy. Some people are born missing certain genes. The goal with gene therapy is to supply cells with the missing instructions they need to produce an important protein. </p>
<p>[<em>Over 140,000 readers rely on The Conversation’s newsletters to understand the world.</em> <a href="https://memberservices.theconversation.com/newsletters/?source=inline-140ksignup">Sign up today</a>.]</p>
<p>A great example of this is cystic fibrosis, a genetic disease caused by mutations in a single gene. Using DNA or an mRNA vaccine, researchers are investigating the feasibility of essentially replacing the missing gene and allowing someone’s body to <a href="https://www.cff.org/gene-therapy-cystic-fibrosis#rna-therapy">transiently produce the missing protein</a>. Once the protein is present, the symptoms could disappear, at least temporarily. The mRNA would not persist very long in the human body, nor would it integrate into people’s genomes or change the genome in any way. So additional doses would be needed as the effect wore off.</p>
<p>Research has shown that this concept is feasible, but it still needs some work.</p><img src="https://counter.theconversation.com/content/170772/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Deborah Fuller is co-founder of Orlance, Inc, a biotechnology company developing a needle free technology to deliver RNA and DNA vaccines. She also serves as a scientific advisor for HDT Bio, a biotechnology company developing RNA vaccines for COVID19 and other infectious diseases; scientific advisor for Abacus, Inc., a biotechnology company developing cancer vaccines and scientific advisor for SQZ Biotech, a biotechnology company developing cell-based therapies for cancer and infectious diseases. She is also serving as a vaccine expert for Wilmerhale on legal matters. She receives funding supporting basic and translational research in RNA and DNA vaccines from the National Institutes of Health.</span></em></p>DNA and mRNA vaccines produce a different kind of immune response than traditional vaccines, allowing researchers to tackle some previously unsolvable problems in medicine.Deborah Fuller, Professor of Microbiology, School of Medicine, University of WashingtonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1726092021-11-29T04:25:59Z2021-11-29T04:25:59ZDoes AstraZeneca’s COVID vaccine give longer-lasting protection than mRNA shots?<p>Last week, AstraZeneca’s chief executive officer <a href="https://www.bloomberg.com/opinion/articles/2021-11-24/did-astrazeneca-covid-vaccine-really-keep-britain-safer-than-europe-not-so-fast">said</a> the company’s COVID vaccine may provide longer-lasting protection than mRNA vaccines like Pfizer’s, especially in older people.</p>
<p>CEO Pascal Soriot said this might explain the United Kingdom’s <a href="https://www.ft.com/content/92e77bf1-2266-4534-a043-daa6c8bb413f">more stable hospitalisation rate</a> compared to the escalating COVID situation in continental Europe.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1463204217674420234"}"></div></p>
<p>The UK used the AstraZeneca vaccine a lot more widely than other European countries, many of which <a href="https://www.theguardian.com/world/2021/nov/23/astrazeneca-chief-links-europes-covid-surge-to-rejection-of-firms-vaccine">restricted its use</a> to older age groups or <a href="https://www.bbc.com/news/world-europe-56744474">abandoned using it altogether</a> after reports of very rare blood clots.</p>
<p>The theory behind this is the AstraZeneca vaccine may provide more durable “T cell protection”. T cells are a crucial part of our immune system, and differ from antibodies.</p>
<p>There’s not enough evidence yet to support the CEO’s claim. But we do know a lot more about adenovirus vector vaccines, such as AstraZeneca’s, as they’ve been around for decades, while mRNA vaccines are relatively newer.</p>
<p>Theoretically, it is possible adenovirus vector vaccines do give more durable protection against COVID via T cells.</p>
<p>Let me explain.</p>
<h2>What is AstraZeneca’s vaccine again?</h2>
<p>AstraZeneca’s COVID vaccine is an adenovirus vector vaccine.</p>
<p>This means it uses an adenovirus – a common type of virus that affects humans and many other animals. The adenovirus is genetically modified so it doesn’t replicate.</p>
<p>It’s used as a way to deliver the vaccine’s information into our cells.</p>
<p>In this case, the information packaged in the adenovirus tells our body how to make the coronavirus <a href="https://theconversation.com/revealed-the-protein-spike-that-lets-the-2019-ncov-coronavirus-pierce-and-invade-human-cells-132183">spike protein</a>. This teaches our immune system how to deal with the coronavirus if we’re exposed.</p>
<p>Adenovirus vectors have been used in medicine for a few decades in other vaccines and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507798/">also cancer therapy</a>. They’re very good at stimulating both antibody production and T cell responses.</p>
<h2>What are T cells?</h2>
<p><a href="http://www.biology.arizona.edu/immunology/tutorials/antibody/structure.html">Antibodies</a> bind tightly to a specific target, locking onto invading viruses and preventing them from entering our cells.</p>
<p>But the immune system is more than just antibodies.</p>
<p>T cells are also really important for our immune response, and have different roles. One type, known as “killer T cells”, attack and destroy virus-infected cells.</p>
<p>Another type, known as “helper T cells”, interpret the nature of the infection and help the immune system respond appropriately. This includes activating killer T cells to destroy virus-infected cells, and also helping B cells make antibodies. </p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1463237807753900040"}"></div></p>
<p>Antibodies wane over time, which can lead to more breakthrough infections <a href="https://theconversation.com/why-are-we-seeing-more-covid-cases-in-fully-vaccinated-people-an-expert-explains-166741">in fully vaccinated people</a>.</p>
<p>When viruses are not stopped by antibodies, we rely on killer T cells to eradicate the virus. And T cells almost certainly help prevent severe outcomes if you get COVID.</p>
<p>It’s a lot harder for a virus to escape a T cell-based immune response. So a vaccine that generates strong T cell immunity should help retain effectiveness over time against variants including Delta and Omicron.</p>
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Read more:
<a href="https://theconversation.com/why-are-we-seeing-more-covid-cases-in-fully-vaccinated-people-an-expert-explains-166741">Why are we seeing more COVID cases in fully vaccinated people? An expert explains</a>
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<p>All COVID vaccines stimulate our bodies to produce both antibodies and T cells.</p>
<p>So the key questions are: does AstraZeneca’s vaccine produce a longer-lasting T cell response than the mRNA vaccines? And might this be one reason why the UK, which relied heavily on the AstraZeneca vaccine, has a more stable hospitalisation rate than other parts of Europe?</p>
<p>Unfortunately, there are not enough data yet to answer these conclusively.</p>
<p>There are many reasons why hospitalisation rates can vary between countries, so it’s difficult to know how much of a factor the use of AstraZeneca’s vaccine would be.</p>
<p>But we can lean on what we know about adenovirus vector vaccines to break down this theory.</p>
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Read more:
<a href="https://theconversation.com/from-adenoviruses-to-rna-the-pros-and-cons-of-different-covid-vaccine-technologies-145454">From adenoviruses to RNA: the pros and cons of different COVID vaccine technologies</a>
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<h2>It’s plausible</h2>
<p>Adenovirus vector vaccines are very good at stimulating immune responses, <a href="https://ashpublications.org/blood/article/110/6/1916/24190/Adenoviral-vectors-persist-in-vivo-and-maintain">particularly T cell responses</a>.</p>
<p>Current wisdom tells us the mRNA vaccines <a href="https://www.bloomberg.com/news/articles/2021-11-15/pfizer-shot-generated-the-most-antibodies-in-a-comparative-study">provide a stronger antibody response</a> than the viral vector vaccines like AstraZeneca’s.</p>
<p>But this antibody protection seems to <a href="https://theconversation.com/why-its-normal-for-covid-19-vaccine-immunity-to-wane-and-how-booster-shots-can-help-171786">wane relatively quickly</a> over 4-6 months.</p>
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<p>It’s possible immune memory with the mRNA vaccines isn’t as strong, and the AstraZeneca vaccine may produce a longer-lasting T cell response that supports more durable immune memory.</p>
<p>This could slow the loss of antibodies and generate a better killer T cell response.</p>
<h2>Why might AstraZeneca produce a longer-lasting response?</h2>
<p>One reason might be because the RNA in Pfizer’s and Moderna’s vaccines doesn’t last very long in the body, <a href="https://theconversation.com/no-covid-vaccines-dont-stay-in-your-body-for-years-169247">only a week or so</a>, because RNA is very fragile.</p>
<p>But the DNA delivered by adenovirus vector vaccines will likely hang around in the body for a bit longer.</p>
<p>DNA is more stable than RNA, and might allow for a more prolonged, low-level activation of our immune system that provides longer-lasting protection.</p>
<p>This might explain longer-lasting T cell responses with the AstraZeneca vaccine.</p>
<p>But this is only speculative for now as such direct tests haven’t been done yet.</p>
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Read more:
<a href="https://theconversation.com/no-covid-vaccines-dont-stay-in-your-body-for-years-169247">No, COVID vaccines don't stay in your body for years</a>
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<h2>If true, we can learn from this</h2>
<p>This isn’t about which vaccine is “<a href="https://theconversation.com/which-covid-vaccine-is-best-heres-why-thats-really-hard-to-answer-161185">better</a>”, or picking and choosing which vaccine to get. </p>
<p>Both are excellent vaccines that have saved many, many lives already. We shouldn’t <a href="https://theconversation.com/covid-vaccination-has-turned-into-a-battle-of-the-brands-but-not-everyones-buying-it-162181">play a tribal game</a> where we say we’re only going to get one type of vaccine.</p>
<p>It’s important to learn from both types of vaccine, while we continue to learn about immunity to COVID, so we can incorporate the best characteristics of both into next-generation vaccines that help us better fight COVID and future pandemics.</p>
<p>I’m sure mRNA vaccine producers will learn from this and develop new formulas to give a longer-lasting response. </p>
<p>It’s worth remembering Pfizer and Moderna’s vaccines are the first mRNA vaccines ever approved for use in humans.</p>
<p>There was an immediate need to get antibodies against COVID in our bodies as soon as possible, and they’ve done a fantastic job doing that.</p><img src="https://counter.theconversation.com/content/172609/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Nathan Bartlett does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>There’s not enough evidence yet to support the AstraZeneca CEO’s statement. But it is theoretically plausible.Nathan Bartlett, Associate Professor, School of Biomedical Sciences and Pharmacy, University of NewcastleLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1653782021-08-25T18:18:38Z2021-08-25T18:18:38ZSpecialized cells maintain healthy pregnancy by teaching the mother’s immune system not to attack developing fetus<figure><img src="https://images.theconversation.com/files/416609/original/file-20210817-21-c1kxf9.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C392%2C547&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">During pregnancy, the body's specialized immune cells must learn to recognize the fetus as part of the self so that they don't attack it.</span> <span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/1/15/Surrogate_mother_and_child.jpg">Raja Segar via Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p><em>The <a href="https://theconversation.com/us/topics/research-brief-83231">Research Brief</a> is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>During pregnancy, immune educator cells teach the mother’s immune system to recognize the developing fetus as part of her “self,” protecting it from being attacked as something “other,” according to our <a href="https://doi.org/10.1126/sciimmunol.abf1968">new study published in Science Immunology</a>.</p>
<p>The immune system normally protects the body from such invaders as infections and cancers. But how exactly does it know what to attack and what to leave alone? How does it learn not to target one’s own organs or tissues, or, in the case of pregnancy, the developing fetus?</p>
<p>A fetus shares a blood supply and immune system with its mother, which presents unique challenges – the fetus is genetically different from the mother, and it also develops specialized organs like the placenta that might seem foreign to the mother’s immune system. How her system learns not to attack the fetus and placenta is incredibly important to understanding pregnancy and its common complications, like miscarriage. </p>
<p>Scientists have sought to understand a more basic version of this question for years: How does the immune system generally learn what to attack and what not to attack?</p>
<p>In a process known as immune self-education, which happens in an organ called the thymus, specialized “educator cells” teach developing immune cells what not to attack by showing off a <a href="https://doi.org/10.1126/science.1075958">diverse array of the body’s own proteins</a>. Essentially, this process teaches immune cells what constitutes “self.” These educator cells require a unique protein called the autoimmune regulator, or Aire, to teach the complete curriculum of the body’s own proteins, and <a href="https://doi.org/10.1038/ng1297-393">mutations in Aire lead to a devastating autoimmune disease</a>.</p>
<p>Previously, we and others <a href="https://doi.org/10.1126/science.1159407">discovered a new class of educator cells</a> living outside of the thymus, predominantly in the lymph nodes and spleen, that make this same Aire protein. We called them extrathymic Aire-expressing cells, or eTACs, and suspected they might serve as a kind of “continuing education” for the immune system. Our <a href="https://doi.org/10.1126/sciimmunol.abf1968">newest discovery</a> is that eTACs are essential for protecting pregnancy by teaching the mother’s immune system not to attack the fetus and placenta as something foreign. This study, done in mice that we engineered to be able to delete Aire-expressing cells, shows that in the absence of eTACs, the mother’s immune system gets overactivated and attacks the pregnancy.</p>
<h2>Why it matters</h2>
<p>Pregnancy complications like miscarriage are <a href="https://www.thelancet.com/series/miscarriage">common</a>, but the cause is frequently a mystery. Understanding how the immune system works to protect pregnancy may help scientists and doctors better identify, and hopefully prevent or treat, more of these pregnancy complications.</p>
<p>[<em>Over 100,000 readers rely on The Conversation’s newsletter to understand the world.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=100Ksignup">Sign up today</a>.]</p>
<p>More broadly, understanding what role extrathymic Aire-expressing cells play in immune self-education may have implications for a wide range of diseases. While the thymus and its educator cells shrink and die off during normal development, eTACs circulate around the body for the duration of one’s life. If researchers can understand their biology and function, physicians may be able to treat autoimmune diseases like juvenile diabetes, cancers that evade immune detection and organ transplants rejected by the immune system. It would be groundbreaking, for example, to be able to rewrite the curriculum of the immune system to accept a new organ in the same way it accepts a fetus.</p>
<h2>What’s next</h2>
<p>Our initial study showed that eTACs are essential for maintaining a healthy pregnancy by keeping the mother’s immune system in check, but exactly how they do this remains a mystery. Also unknown is the precise role that the Aire protein plays in the process and in these cells. We also don’t know yet whether eTACs play a role in other diseases, such as cancer and juvenile diabetes, that also involve self-recognition by the immune system. We hope that by understanding the fundamentals of how the immune system learns, we may be able to use this knowledge to fine-tune immune self-education to ultimately treat a wide range of diseases.</p><img src="https://counter.theconversation.com/content/165378/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Eva Gillis-Buck has recieved funding from the Howard Hughes Medical Institute</span></em></p><p class="fine-print"><em><span>James Gardner receives funding from the National Institutes of Health, the National Human Genome Research Institute, and the UCSF Sandler PSSP Program.</span></em></p><p class="fine-print"><em><span>Tippi MacKenzie receives funding from the NIH, the California Institute for Regenerative Medicine, and the Burroughs Wellcome Fund; her work on preterm labor has previously been funded by the March of Dimes. She is on the scientific advisory board of Acrigen, a gene editing company.</span></em></p>How the immune system learns not to attack a developing fetus and placenta is important to understanding pregnancy and its common complications, like miscarriage.Eva Gillis-Buck, Resident Physician, University of California, San FranciscoJames Gardner, Assistant Professor in Transplant Surgery, University of California, San FranciscoTippi MacKenzie, Professor of Surgery, University of California, San FranciscoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1600982021-05-09T19:45:40Z2021-05-09T19:45:40ZTaking one for the team: 6 ways our cells can die and help fight infectious disease<figure><img src="https://images.theconversation.com/files/399422/original/file-20210507-15-1umzp1t.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C389%2C243&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">White blood cells dying</span> </figcaption></figure><p>We have all heard of COVID-19, the flu and bacterial infections. But what is actually happening to our cells when we contract these diseases? Many of our body’s cells don’t live to tell the tale. But cell death isn’t necessarily a bad thing — in fact, the death of infected cells can provide a sacrificial mechanism to stop pathogens in their tracks before they can spread through our body. </p>
<p>Over the years, researchers have realised there are many ways for our cells to die. Our genetics contain a comprehensive “licence to die”, with the route to cell death dictated by both the type of the cell and the pathogen. Let’s check some out:</p>
<h2>The dancing death</h2>
<p>In the time it takes you to read this sentence, ten million cells in your body will have died, through a type of death called <em>apoptosis</em>. This term, coined in 1972 by <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2008650/">Australian pathologist John Kerr</a>, comes from the Greek phrase for “leaves falling from a tree”.</p>
<p>Apoptosis is the most common form of cell death, and has also been nicknamed the “dance of death”, because of the extraordinary shape changes exhibited by the cells under a microscope as they sacrifice themselves. </p>
<p>For example, apoptotic cells dying from radiation or <a href="https://www.nature.com/articles/s42003-020-0955-8">infection with influenza A virus</a> (aka, the flu) generate large, bubble-like structures on their surface called blebs, before shooting out long beaded necklace-like protrusions and finally shattering into pieces. </p>
<p>The death of flu-infected cells is suggested to both <a href="https://www.nature.com/articles/s41419-018-1035-6">aid and limit viral spread</a>. Nevertheless, it’s a spectacular event to witness (and an excellent reminder to get your flu shot this winter).</p>
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<figcaption><span class="caption">White blood cell blebbing and dying.</span></figcaption>
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<h2>Out with a bang</h2>
<p>Vaccinia virus is used worldwide to vaccinate against <a href="https://www.who.int/news-room/feature-stories/detail/smallpox-vaccines">smallpox</a>. In fact, it was the very first vaccine, developed in 1796 by Edward Jenner.</p>
<p>We now also know that vaccinia virus can make our cells more sensitive to a particular type of cell death, caused by a molecule called <a href="https://www.cell.com/fulltext/S0092-8674(09)00642-4">TNF</a>. This can help prevent the disease spreading by killing off infected cells before the virus has a chance to replicate.</p>
<p>Many of our cells have a roughly spherical or balloon-like shape, encapsulated by a protective layer called the cell membrane. Just like bursting a balloon with a pin, puncture to the cell membrane marks the point of no return.</p>
<p>This process occurs during <a href="https://www.nature.com/articles/s41467-020-16887-1"><em>necroptosis</em></a> — an explosive type of cell death in which proteins inside the cell punch holes in the membrane. The cell pops and dies, shutting down the machinery needed for viral replication.</p>
<h2>The spider web of death</h2>
<p>When they aren’t busy haunting our nightmares, spiders can be found weaving silken masterpieces of extraordinary detail and strength. The web of a <a href="https://australian.museum/learn/animals/spiders/golden-orb-weaving-spiders/">golden orb weaving spider</a>, for example, is strong enough to entangle small birds. </p>
<p>On a smaller but equally impressive scale, our immune system contains specialised cells called neutrophils that can weave a deadly web of their own and entrap bacteria. Neutrophils gallantly sacrifice themselves in the process of casting their web, in a type of cell death perhaps fittingly called <em>NETosis</em>. </p>
<p>When infected with bacteria such as <em><a href="https://link.springer.com/article/10.1007/s00281-013-0384-6">Streptococcus pneumoniae</a></em>, which causes pneumonia and meningitis, neutrophils eject a specialised web made from their own DNA. These webs can entangle nearby bacteria to prevent their escape until other immune cell reinforcements arrive to clear the infection. Sometimes, proteins found in these webs can also kill the bacteria - quite an impressive defence mechanism!</p>
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<a href="https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cartoon illustrating different forms of cell death" src="https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=662&fit=crop&dpr=1 600w, https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=662&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=662&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=832&fit=crop&dpr=1 754w, https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=832&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/398843/original/file-20210505-17-z3zgx4.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=832&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">There are a surprising number of ways cells can lay down their lives for the greater good.</span>
<span class="attribution"><span class="license">Author provided</span></span>
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<h2>The last meal</h2>
<p>Just as our bodies are compartmentalised into organs such as the stomach, liver or heart, our individual cells also have specialised compartments. One of the cell’s “stomachs” (a structure called the “autophagosome”) engulfs and digests cellular contents such as damaged molecules through the process of <em>autophagy</em>.</p>
<p>However, in some circumstances, the machinery that drives this Pac-Man-style action can also facilitate the cell’s demise. Coincidentally, the bacteria <em>Helicobacter pylori</em> can infect cells of the human stomach lining, called epithelial cells, which can cause ulcers and gastritis. The cells can respond with a process called <a href="https://www.nature.com/articles/s41419-017-0011-x">autophagic cell death</a>, in which the induction of autophagy causes the cell to die. </p>
<h2>A fiery death</h2>
<p>Pyromania, derived from the Greek word <em>pyr</em>, meaning fire, is an obsessive desire to set things ablaze. Some of our immune cells also have the ability to self-immolate and cause inflammation as part of our response to infection.</p>
<p>Since its relatively recent discovery in <a href="https://pubmed.ncbi.nlm.nih.gov/11303500/">2001</a>, this type of cell death, called <em>pyroptosis</em>, has become a hot topic (sorry) among cell biologists, and is often facilitated by a molecular complex called the <a href="https://www.sciencedirect.com/science/article/pii/S0092867410000759">inflammasome</a>.</p>
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Read more:
<a href="https://theconversation.com/what-is-autoinflammatory-disease-the-rare-immune-condition-with-waves-of-fever-128696">What is autoinflammatory disease, the rare immune condition with waves of fever?</a>
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<p>In 2021, understanding pyroptosis is more important than ever, as it has been linked to <a href="https://www.jimmunol.org/content/205/2/307">infection with SARS-CoV-2 infection</a>, the virus that causes COVID-19.</p>
<p>Activation of the factors that cause pyroptosis may help explain the excessive inflammation seen in patients with severe COVID-19. And this could potentially offer a new way to combat the disease.</p>
<h2>Overdosing on iron and fat</h2>
<p>There’s no doubt the key to a long and healthy life is a balanced diet and exercise. However, sometimes we can’t resist the urge to devour a burger and fries with ice cream for dessert. With enough hard work, we can burn it off again. But for individual cells, overindulging can be fatal. </p>
<p>Too much iron and/or harmful types of fat molecules can cause cells to die by <em>ferroptosis</em>. Cells infected with <em><a href="https://rupress.org/jem/article/216/3/556/120345/A-major-role-for-ferroptosis-in-Mycobacterium">Mycobacterium tuberculosis</a></em>, the bacterium that causes TB, can increase their iron content and cause ferrototic cell death! Pass the salad, thanks.</p>
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Read more:
<a href="https://theconversation.com/tick-tock-how-stress-speeds-up-your-chromosomes-ageing-clock-127728">Tick, tock... how stress speeds up your chromosomes' ageing clock</a>
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<p>The survival of the human body is a fine balancing act between cell growth and cell death. Understanding our cells’ complex “licence to die” could give us new ways to combat disease.</p><img src="https://counter.theconversation.com/content/160098/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Georgia Atkin-Smith receives funding from the CASS Foundation (Medicine/Science Grant) and is a postdoctoral researcher at both La Trobe University and the Walter and Eliza Hall Institute of Medical Research.</span></em></p><p class="fine-print"><em><span>Ivan Poon receives funding from the National Health and Medical Research Council and the Australian Research Council. Ivan is an Associate Professor at the La Trobe Institute for Molecular Science. </span></em></p>The survival of the human body is a fine balancing act between cell growth and cell death. Understanding our cells’ complex “licence to die” could give us new ways to combat disease.Georgia Atkin-Smith, Research scientist, La Trobe UniversityIvan Poon, Associate Professor, Biochemistry, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1560082021-03-01T14:16:35Z2021-03-01T14:16:35ZWhy breastfed babies have improved immune development – new findings<figure><img src="https://images.theconversation.com/files/386995/original/file-20210301-17-65q5na.jpg?ixlib=rb-1.1.0&rect=40%2C0%2C6669%2C4476&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Our study revealed breastfed babies had twice the number of regulatory T cells.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/serious-calm-careful-young-black-mom-1426845311">SeventyFour/ Shutterstock</a></span></figcaption></figure><p>Life outside the womb is tough – not least because of the many bacteria, viruses, and other pathogens that can harm a baby. Not only does a baby’s immune system need to be able to recognise and eliminate pathogens, it also needs to be able to distinguish harmless substances and helpful bacteria important for health – such as those in our gut microbiome, which help break down foods and protect us from pathogens. </p>
<p><a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01024-7/fulltext">Breastfeeding</a> is known to be important for a baby’s immune development, and is also linked to numerous long-term health benefits, such as lower rates of obesity, asthma and autoimmune disorders compared to those who were formula fed. But until recently, researchers haven’t quite known why the immune systems of breastfed babies are better equipped compared to formula-fed infants.</p>
<p>Our <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/all.14736">latest study</a> may have the answer. We found that breastfeeding is important for helping babies to develop important immune cells in their first weeks of life. These immune cells, known as regulatory T cells, provide balance in the immune system by controlling its response to pathogens, and preventing autoimmune responses (where the immune system mistakenly attacks your body).</p>
<p>We studied blood and stool samples from a cohort of 38 healthy mother and baby pairs. All babies in the study were born by elective Caesarean section and samples were taken at birth and at three weeks of life.</p>
<p>We found that the population of regulatory T cells was nearly twice as abundant in breastfed babies at three weeks of age compared to babies who were formula-fed. This shows that these babies’ immune systems are better equipped to know which pathogens they should attack and which pathogens are harmless to the body. We demonstrated that this change is likely to be driven by interaction with the mother’s cells during breastfeeding.</p>
<figure class="align-center ">
<img alt="An image of regulatory T cells." src="https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=360&fit=crop&dpr=1 600w, https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=360&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=360&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=452&fit=crop&dpr=1 754w, https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=452&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/386996/original/file-20210301-19-bpwqbi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=452&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Regulatory T cells balance the immune system.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/tregt-lymphocytest-cells-3d-render-1233772858">ratlos/ Shutterstock</a></span>
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<p>During pregnancy, the immune systems of the mother and baby are known to interact via cells moving through the placenta. Our results show that their immune systems continue interacting after birth via breastfeeding. We uncovered this by isolating immune cells from both the mother and baby, and growing them together in the lab. </p>
<p>The baby’s cells were less likely to see the mother’s cells as foreign if the baby was breastfed compared to formula-fed – an effect mediated by regulatory T cells. This means that the baby’s immune system “tolerates” these maternal cells from breastmilk and does not launch an immunological reaction, like it would do with any other foreign cell.</p>
<p>The early development of regulatory T cells is likely to be a key element in effective immune function in later life. This response is essential in <a href="https://www.jacionline.org/article/S0091-6749(16)30499-7/abstract">preventing allergies</a>, where the immune system mounts an undesirable response against harmless substances, and decreasing the risk of <a href="https://www.sciencedirect.com/science/article/abs/pii/S0896841120300779">autoimmune disorders</a>, where the immune system reacts against the body’s own cells. </p>
<p>Regulatory T cells are also of great importance in <a href="https://www.sciencedirect.com/science/article/abs/pii/S1044532311001540?via%3Dihub">building an effective gut microbiome</a>, which evolves gradually after birth. If the immune system eliminated, rather than tolerated, these gut microbes in early life, several of their beneficial health effects would be hindered. For example, this could lead to digestive problems, or could increase the risk of intestinal infections.</p>
<p>We also examined the composition of the gut microbiome in stool samples collected from babies at three weeks of age to understand how it is linked with immune development. We found subtle but important differences between breastfed and formula-fed babies. Two distinct bacterial strains, <em>Veillonella</em> and <em>Gemella</em>, were more abundant in samples of breastfed babies. These strains are known to produce short-chain fatty acids which are essential for the <a href="https://www.nature.com/articles/nature12726">development and normal function</a> of regulatory T cells. Greater presence of these strains in the gut may contribute to regulatory T cells being more abundant in blood samples of breastfed babies. </p>
<p>Although the number of participants in our study may appear small, we worked with a unique cohort of babies, creating the largest study of its kind to date. But our study also had some other shortcomings. For instance, we only followed up participants up to three weeks of life. It will be interesting to see in future studies how long the observed changes are present for in the immune system, and whether the number of regulatory T cells equalises in later life between breastfed and formula-fed babies. </p>
<p>And while we intentionally studied babies born by Caesarean section to observe a group exposed to as similar birthing conditions as possible, it will also be interesting for future studies to see whether our observations are also true for babies born by normal delivery.</p>
<p>While breastfeeding is recommended for infant nutrition by the <a href="https://www.who.int/health-topics/breastfeeding#tab=tab_1">World Health Organization</a>, there are of course many reasons why a mother may need to formula-feed her baby. And in most developed countries, this alternative is safe for babies, and the composition of many infant formulas is frequently changed to be as close to breastmilk as possible. Although it’s unlikely that breastmilk can ever be fully mimicked, research like ours may help to guide the tailoring of formula milk to offer better health advantages to all babies.</p><img src="https://counter.theconversation.com/content/156008/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gergely Toldi does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Until now, researchers haven’t quite known why the immune systems of breastfed babies are better equipped.Gergely Toldi, Consultant Neonatologist, University of BirminghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1434552020-08-20T01:41:23Z2020-08-20T01:41:23ZExposure to common colds might give some people a head start in fighting COVID-19<figure><img src="https://images.theconversation.com/files/352643/original/file-20200813-20-1bf49cy.jpg?ixlib=rb-1.1.0&rect=33%2C11%2C7315%2C4891&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p>Could we have some immunity to SARS-CoV-2, the virus that causes COVID-19, without ever having been exposed to it?</p>
<p>Some <a href="https://www.nature.com/articles/s41577-020-0389-z">new studies</a> found people who were never symptomatic, exposed to, or tested positive for COVID-19 have immune cells that can recognise and possibly kill virus-infected cells.</p>
<p>How is this possible? And what does it mean for our fight against COVID-19? </p>
<h2>Many common colds are coronaviruses</h2>
<p>There are seven known coronaviruses that can infect humans. Three can cause severe respiratory symptoms: SARS-CoV-2, SARS-CoV-1 (which caused the <a href="https://www.who.int/ith/diseases/sars/en/">2002-04</a> SARS outbreak), and <a href="https://www.who.int/emergencies/mers-cov/en/">MERS-CoV</a> (which was first identified in 2012).</p>
<p>The other four cause relatively mild colds, and are known as the common cold coronaviruses. It’s hard to find an exact figure, but one estimate suggests <a href="https://dx.doi.org/10.1128%2FJVI.00269-12">up to 30% of all common colds</a> are caused by these coronaviruses, and <a href="https://doi.org/10.1128/cvi.00124-08">up to 90% of us</a> will have some antibodies against them in our blood. Like the other viruses that cause common colds (such as rhinoviruses), they show a strong seasonality, with a wave of coronavirus infections each winter.</p>
<p>Immunity to these common cold coronaviruses is not very long–lasting, so we get re-infected with them <a href="https://doi.org/10.1101/2020.04.27.20082032">all the time</a>. We don’t know yet if our immunity to SARS-CoV-2 will also wane over time, and whether that means we could get re-infected. </p>
<figure class="align-center ">
<img alt="A TEM image of cells under the microscope of a coronavirus disease that infects birds" src="https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=445&fit=crop&dpr=1 600w, https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=445&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=445&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=559&fit=crop&dpr=1 754w, https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=559&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/352632/original/file-20200813-22-56dpip.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=559&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Coronaviruses are a family of RNA viruses that infect humans and other animals. They are named after their crown-like spikes, derived from ‘corona’ in Latin which means ‘crown’.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/L0jLHqF7Q94">CDC/Unsplash</a></span>
</figcaption>
</figure>
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Read more:
<a href="https://theconversation.com/immunity-to-covid-19-may-not-last-this-threatens-a-vaccine-and-herd-immunity-142556">Immunity to COVID-19 may not last. This threatens a vaccine and herd immunity</a>
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<h2>What did new studies find?</h2>
<p>What these <a href="https://www.nature.com/articles/s41577-020-0389-z">new studies</a> did was expose some people’s blood to SARS-CoV-2. These blood samples were taken specifically from “healthy donors” - people who have never been confirmed to have coronavirus, or from whom blood was collected years before SARS-CoV-2 emerged.</p>
<p>Depending on the study, between 20 and 50% of these people were found to have immune cells (called T cells) that could recognise SARS-CoV-2. This is unexpected, as usually specific T cells are only present after infection with the virus. </p>
<p>There are two possible explanations. Either those “healthy donors” were mildly infected with SARS-CoV-2 and didn’t show symptoms or develop antibodies, but they did develop a T cell response. Or, in the case of samples taken before the disease emerged, it means these T cells can recognise multiple coronaviruses, including common colds and SARS-CoV-2.</p>
<h2>More than just antibodies</h2>
<p>When we get infected with a virus like SARS-CoV-2, our immune system responds in a range of ways. It generates antibodies, which can neutralise the virus to stop it entering our cells. These antibodies are specific to the virus, and thus can be used to test <a href="https://theconversation.com/antibody-tests-to-get-a-grip-on-coronavirus-we-need-to-know-whos-already-had-it-134547">whether we’ve had the virus before</a>.</p>
<p>But besides antibodies, we have a host of other immune weapons in our arsenal for fighting off viruses.</p>
<p>T cells are specialised immune cells that have lots of functions (including helping us make antibodies) but are best known for being able to recognise and kill virus-infected cells. This is really important, because if the virus has evaded antibodies and managed to get into the cells, it can start replicating. Eliminating the infected cell is one of the most efficient ways to stop the infection.</p>
<figure class="align-center ">
<img alt="A human T cell" src="https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/352662/original/file-20200813-24-i4lbmo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">T cells can recognise fragments of virus across different coronaviruses, which could help our body fight COVID-19 infection.</span>
<span class="attribution"><span class="source">NIAID/Wikimedia Commons</span></span>
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Read more:
<a href="https://theconversation.com/antibody-tests-to-get-a-grip-on-coronavirus-we-need-to-know-whos-already-had-it-134547">Antibody tests: to get a grip on coronavirus, we need to know who's already had it</a>
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<h2>T cells are master detectives</h2>
<p>How do T cells know which of our body’s cells are infected with a virus? Because they can recognise small but specific snippets of viral proteins that our cells “present” on their surface. These viral snippets on the infected cell surface act like a beacon for the T cells to recognise and eliminate the virus-infected cells. Like antibodies, after the infection is cleared, we keep some of those T cells around in case we get reinfected with the same virus. </p>
<p>The small bits of virus presented on the infected cell’s surface can come from all parts of the virus, including the ones from inside the virus, which tend to be very similar across the different coronaviruses. That means a T cell that recognises a viral protein fragment from one type of coronavirus could potentially recognise the same fragment of viral protein that comes from a different coronavirus.</p>
<p>For example, if a virus was like a car, the antibody might recognise and bind to the outside, and it would only recognise a certain colour, year, and type of car.</p>
<p>But the T cell could recognise the specific bits, like the engine. So if the same engine was in loads of different cars, even though you might have really different cars, as long as it’s a petrol engine the T cell would recognise it. So it’s possible some of our T cells that were formed during a common cold infection are recognising SARS-CoV-2 and helping our immune system have a headstart for fighting SARS-CoV-2. </p>
<p>So these T cells can be cross protective — they work against different coronaviruses — and they can be very longlasting. In patients who recovered from SARS-CoV-1, specific T cells were still detectable <a href="https://doi.org/10.1016/j.vaccine.2016.02.063">up to 11 years later</a>. This T cell memory could protect us from developing severe COVID-19, and could possibly explain why some people get so sick with COVID-19 while other people do not. </p>
<h2>It’s not all rosy</h2>
<p>While T cells represent another measure of whether people have been infected or not, we can’t use them as a quick diagnostic tool because detecting virus-specific T cells is far more slow, laborious and difficult than detecting antibodies. </p>
<p>We also don’t know yet what this pre-existing T cell immunity means for immune protection. We don’t even know whether the specific T cells generated during SARS-CoV-2 infection will be enough to protect us from COVID-19, and how important they are compared with the antibody responses.</p>
<p>Therefore, the most successful vaccines will likely induce both protective antibody and T cell responses to SARS-CoV-2.</p>
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<strong>
Read more:
<a href="https://theconversation.com/vaccine-progress-report-the-projects-bidding-to-win-the-race-for-a-covid-19-vaccine-141412">Vaccine progress report: the projects bidding to win the race for a COVID-19 vaccine</a>
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<img src="https://counter.theconversation.com/content/143455/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Larisa Labzin receives funding from the National Health and Medical Research Council and the University of Queensland. </span></em></p><p class="fine-print"><em><span>Stefan Emming receives funding from The University of Queensland. </span></em></p>Some people’s blood can mount an immune response against SARS-CoV-2, even if those blood samples were taken from before the COVID-19 pandemic started.Larisa Labzin, Research Fellow, Institute for Molecular Bioscience, The University of QueenslandStefan Emming, Postdoctoral Research Fellow, Institute for Molecular Bioscience, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1415842020-06-29T12:59:14Z2020-06-29T12:59:14ZCoronavirus: could it be burning out after 20% of a population is infected?<figure><img src="https://images.theconversation.com/files/344557/original/file-20200629-155322-dhp1c3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Is coronavirus over in some cities?</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/tokyo-japan-march-2020-crowd-people-1683442477">StreetVJ/Shutterstock</a></span></figcaption></figure><p>More than <a href="https://coronavirus.jhu.edu/map.html">half a million people</a> have died from COVID-19 globally. It is a major tragedy, but perhaps not on the scale some <a href="https://www.independent.co.uk/news/health/coronavirus-news-latest-deaths-uk-infection-flu-a9360271.html">initially feared</a>. And there are finally signs that the pandemic is shuddering in places, as if its engine is running out of fuel. This has encouraged many governments to relinquish lockdowns and allow everyday life to restart, albeit gingerly. </p>
<p>The spread of SARS-CoV-2 has been difficult to predict and understand. On the <a href="https://www.nature.com/articles/d41586-020-00885-w">Diamond Princess cruise ship</a>, for example, where the virus is likely to have spread relatively freely through the air-conditioning system linking cabins, only 20% of passengers and crew were infected. Data from military ships and cities such as <a href="https://medicalxpress.com/news/2020-05-stockholm-virus-antibodies-sweden.html">Stockholm</a>, <a href="https://www.nytimes.com/2020/04/23/nyregion/coronavirus-antibodies-test-ny.html">New York</a> and <a href="https://newseu.cgtn.com/news/2020-05-22/UK-tests-reveal-17-of-Londoners-have-COVID-19-antibodies-QGoxm5G2Ig/index.html">London</a> also suggest that infections have been around 20% – much lower than earlier mathematical models suggested. </p>
<p>This has led to <a href="https://www.spectator.co.uk/article/covid-has-all-but-left-london-why-">speculation</a> about whether a population can achieve some sort of immunity to the virus with as little as 20% infected – a proportion well below the widely accepted herd immunity threshold (60-70%). </p>
<p>The Swedish public health authority announced in late April that the capital city, Stockholm, was “<a href="https://www.yahoo.com/news/coronavirus-sweden-stockholm-herd-immunity-144733606.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAADMKtFuXe068dmGqj74a6-gAj-JTPrvfEwN0e2SUeGY3M3AFY8Uf0rmZYiGBqZTLZVfjONhhY3Qaw_QD7FjeYMm-yDoutiGDSUW51gLfBNDxDFZuWLGKc6Bcs-3GDK-SQzdhfwL8Fe4vkQ8uMbV0ulv3qAVxJiZPZgrbaZOFrSLd">showing signs of herd immunity</a>” – estimating that about half its population had been infected. The authority had to backtrack two weeks later, however, when the results of their own antibody study revealed just <a href="https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2020/maj/forsta-resultaten-fran-pagaende-undersokning-av-antikroppar-for-covid-19-virus/">7.3%</a> had been infected. But the number of deaths and infections in Stockholm <a href="https://mitti.se/nyheter/minskar-smittspridningstakten-nastan/">is falling rather than increasing</a> – despite the fact that Sweden hasn’t enforced a lockdown.</p>
<p>Hopes that the COVID-19 pandemic may end sooner than initially feared have been fuelled by speculation about “<a href="https://www.theguardian.com/world/2020/jun/07/immunological-dark-matter-does-it-exist-coronavirus-population-immunity">immunological dark matter</a>”, a type of pre-existing immunity that can’t be detected with SARS-CoV-2 antibody tests. </p>
<p>Antibodies are produced by the body’s B-cells in response to a specific virus. Dark matter, however, involves a feature of the innate immune system termed “T-cell mediated immunity”. T-cells are produced by the thymus and when they encounter the molecules that combat viruses, known as antigens, they become programmed to fight the same or similar viruses in the future. </p>
<p>Studies show that people infected with SARS-CoV-2 indeed have <a href="https://www.cell.com/cell/pdf/S0092-8674(20)30610-3.pdf">T-cells that are programmed to fight this virus</a>. Surprisingly, people never infected <a href="https://www.medrxiv.org/content/10.1101/2020.04.17.20061440v1">also harbour protective T-cells</a>, probably because they have been exposed to other coronaviruses. This may lead to some level of protection against the virus – potentially explaining why some outbreaks seem to burn out well below the anticipated herd immunity threshold. </p>
<p>Young people and those with mild infections are more likely to have a T-cell response than old people – we know that the reservoir of programmable T-cells <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822389/pdf/nihms171795.pdf">declines with age</a>.</p>
<p>In many countries and regions that have had very few COVID-19 cases, hotspots are now cropping up. Take Germany, which quickly and efficiently battled the virus and has had one of the <a href="https://coronavirus.jhu.edu/data/mortality">lowest death rates</a> among the large northern European countries. </p>
<p>Here, the R number – reflecting the average transmission rate – has risen again, below 1 until June 18, but rocketing to <a href="https://www.bbc.com/news/world-europe-53149762">2.88 just days later</a>, only to drop again a few days later. It may be tempting to argue that this could be because the hotspots never got close to the 20% infection that was seen in other regions.</p>
<p>But there are counter examples, albeit particularly in older and immunocompromised populations. In the Italian COVID-19 epicenter in Bergamo, a town where one in four residents are pensioners, <a href="https://www.telegraph.co.uk/news/2020/06/09/half-people-tested-italys-coronavirus-epicentre-bergamo-have/">60% of the population had antibodies by early June</a>. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/344523/original/file-20200629-155353-1h9miqb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">60% of people in Bergamo have antibodies.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/epidemiologist-antibody-blood-tube-cured-covid19-1742536169">angellodeco/Shutterstock</a></span>
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<p>The same is true in some prisons: at the Trousdale Turner Correctional Center in Hartsville, US, 54% of inmates <a href="https://www.nytimes.com/2020/05/05/us/coronavirus-deaths-cases-united-states.html">had tested positive for COVID-19 by early May</a>. And more than <a href="https://www.ecdc.europa.eu/sites/default/files/documents/covid-19-long-term-care-facilities-surveillance-guidance.pdf">half of the residents</a> in some long-term care facilities have also been infected.</p>
<h2>Genes and environment</h2>
<p>So how do we explain this? Could people in places with higher rates of positive antibodies have a different genetic make-up?</p>
<p>Early in the pandemic, there was much speculation about whether specific genetic receptors affected susceptibility to the SARS-CoV-2 virus. Geneticists thought that DNA variation in the <a href="https://www.wired.co.uk/article/coronavirus-ace2"><em>ACE2</em></a> and <a href="https://accp1.onlinelibrary.wiley.com/doi/10.1002/jcph.1641"><em>TMPRSS2</em></a> genes might affect susceptibility to, and severity of, infection. But studies so far have shown no compelling evidence supporting this hypothesis. </p>
<p><a href="https://www.medrxiv.org/content/10.1101/2020.03.11.20031096v2">Early reports from China</a> also suggested that blood types may play a role, with blood type A raising risk. This was recently <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2020283">confirmed</a> in studies of Spanish and Italian patients, which also discovered a new genetic risk marker termed “3p21.31”.</p>
<p>While genetics may be important, the environment also matters. It is well known that airborne transmission of droplets is enhanced in colder climates. Super-spreading events in several meat production facilities where the indoor climate is cold suggest <a href="https://www.bbc.com/news/uk-wales-politics-53152362">this has enhanced contagion</a>. People also tend to spend more time indoors and in close proximity during inclement weather.</p>
<p>Warm weather, however, brings people together, albeit outdoors. Indeed, June has been uncharacteristically hot and sunny in many northern European countries, causing parks and beaches to be overrun and social distancing rules <a href="https://www.bbc.com/news/uk-53190209">flouted</a>. This will likely drive contagion and cause new COVID-19 outbreaks in the weeks to come.</p>
<p>Yet another factor is how interpersonal interactions affect contagion. Some <a href="https://aip.scitation.org/doi/pdf/10.1063/1.5054569#:%7E:text=Mathematical%20models%20have%20become%20important,and%20control%20of%20infectious%20diseases.&text=For%20diseases%20that%20have%20longer,is%20then%20called%20SEIR%20model.">previous models</a> have assumed that people interact in the same way regardless of age, well-being, social status and so forth. But this isn’t likely to be the case – young people, for example, are likely to have more acquaintances than the elderly. Accounting for this reduces the herd immunity threshold to <a href="https://science.sciencemag.org/content/early/2020/06/22/science.abc6810">around 40%</a>.</p>
<h2>Will COVID-19 disappear?</h2>
<p>The lockdowns enforced far and wide, combined with the responsible actions of many citizens, have undoubtedly mitigated the spread of SARS-CoV-2 and saved lives. Indeed, in cases such as Sweden – where lockdown was eschewed and social distancing rules were relatively relaxed – the virus has claimed an order of magnitude more lives than in its pro-lockdown neighbours, Norway and Finland.</p>
<p>But it is unlikely that lockdowns alone can explain the fact that infections have fallen in many regions after 20% of a population has been infected – something that, after all, happened in Stockholm and on cruise ships. </p>
<p>That said, the fact that more than 20% of people have been infected in other places means that the T-cell hypothesis is unlikely to be the sole explanation either. Indeed, if a 20% threshold does exist, it applies to only some communities, depending on interactions between many genetic, immunological, behavioural and environmental factors, as well as the prevalence of pre-existing diseases. </p>
<p>Understanding these complex interactions is going to be necessary if one is to meaningfully estimate when SARS-CoV-2 will burn itself out. Ascribing any apparent public health successes or failures to a single factor is appealing – but it is unlikely to provide sufficient insight into how COVID-19, or whatever comes next, can be defeated.</p><img src="https://counter.theconversation.com/content/141584/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Paul Franks receives research funding from Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk A/S, Sanofi Aventis and Servier, has received consulting fees from Eli Lilly, Novo Nordisk and Zoe Global Ltd and has stock options in Zoe Global Ltd. Zoe Global Ltd is the company behind the COVID Symptom Study app.</span></em></p><p class="fine-print"><em><span>Joacim Rocklöv receives funding for research projects from the EU, including Horizon2020, the Swedish research agency Formas, Kempe foundation, and SIDA. He has consultancy projects for the European Centre for Disease Prevention and Control and the World Health Organization.</span></em></p>There is speculation about whether a population can achieve some sort of immunity to the virus with as little as 20% infected.Paul W Franks, Professor of Genetic Epidemiology, Lund UniversityJoacim Rocklöv, Professor of Epidemiology, Umeå UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1371452020-05-05T12:20:41Z2020-05-05T12:20:41ZYour genes could determine whether the coronavirus puts you in the hospital – and we’re starting to unravel which ones matter<figure><img src="https://images.theconversation.com/files/332506/original/file-20200504-83725-1ijhd03.jpg?ixlib=rb-1.1.0&rect=286%2C0%2C8411%2C4900&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The relationship between the coronavirus and human genetics is murky. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/virus-cells-attacking-a-dna-strand-royalty-free-image/1183281148?adppopup=true">fatido/E+ via Getty Images</a></span></figcaption></figure><p><em>The Research Brief is a short take about interesting academic work.</em></p>
<h2>The big idea</h2>
<p>When some people become infected with the coronavirus, they only develop <a href="https://theconversation.com/infected-with-the-coronavirus-but-not-showing-symptoms-a-physician-answers-5-questions-about-asymptomatic-covid-19-137029">mild or undetectable cases of COVID-19</a>. Others suffer severe symptoms, fighting to breathe on a ventilator for weeks, if they survive at all. </p>
<p>Despite a concerted global scientific effort, doctors <a href="https://fivethirtyeight.com/features/why-are-some-young-healthy-people-getting-severe-covid-19/">still lack a clear picture</a> of why this is. </p>
<p>Could genetic differences explain the differences we see in symptoms and severity of COVID-19?</p>
<p>To test this, we used computer models to analyze known genetic variation within the human immune system. The <a href="https://dx.doi.org/10.1128/JVI.00510-20">results of our modeling</a> suggest that there are in fact differences in people’s DNA that could influence their ability to respond to a SARS-CoV-2 infection.</p>
<h2>What we did</h2>
<p>When a virus infects human cells, the body reacts by turning on what are essentially anti-virus alarm systems. These alarms identify viral invaders and tell the immune system to send cytotoxic T cells – a type of white blood cell – to destroy the infected cells and hopefully slow the infection.</p>
<p>But not all alarm systems are created equal. People have different versions of the same genes – called alleles – and some of these alleles are more <a href="https://dx.doi.org/10.1128%2FCMR.00048-08">sensitive to certain viruses or pathogens than others</a>. </p>
<p>To test whether different alleles of this alarm system could explain some of the range in immune responses to SARS-CoV-2, we first retrieved a list of all the proteins that make up the coronavirus from an <a href="https://www.ncbi.nlm.nih.gov/refseq/">online database</a>.</p>
<p>We then took that list and used existing computer algorithms to predict how well different versions of the anti-viral alarm system detected these coronavirus proteins. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=802&fit=crop&dpr=1 600w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=802&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=802&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1008&fit=crop&dpr=1 754w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1008&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/332509/original/file-20200504-83745-1qdcr8d.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1008&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">A model of an HLA protein (green and yellow) bound to a piece of a virus (orange and blue) – in this case, influenza.</span>
<span class="attribution"><a class="source" href="https://en.wikipedia.org/wiki/HLA-B27#/media/File:HLA-B*2705-peptide_in_complex_with_influenza_nucleoprotein_NP383-391.png">Prot reimage via Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>Why it matters</h2>
<p>The part of the alarm system that we tested is called the human leukocyte antigen system, or HLA. Each person has multiple alleles of the genes that make up their HLA type. Each allele codes for a different HLA protein. These proteins are the sensors of the alarm system and find intruders by binding to various peptides – chains of amino acids that make up parts of the coronavirus – that are foreign to the body.</p>
<p>Once an HLA protein binds to a virus or piece of a virus, it transports the intruder to the cell surface. This “marks” the cell as infected and from there the immune system will kill the cell.</p>
<p>In general, the more peptides of a virus that a person’s HLAs can detect, the <a href="https://dx.doi.org/10.4049%2Fjimmunol.1302101">stronger the immune response</a>. Think of it like a more sensitive sensor of the alarm system. </p>
<p>The results of our modeling predict that some HLA types bind to a large number of the SARS-CoV-2 peptides while others bind to very few. That is to say, some sensors may be better tailored to SARS-CoV-2 than others. If true, the specific HLA alleles a person has would likely be a factor in how effective their immune response is to COVID-19. </p>
<p>Because our study only used a computer model to make these predictions, we decided to test the results using clinical information from the 2002-2004 SARS outbreak.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1216&fit=crop&dpr=1 600w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1216&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1216&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1528&fit=crop&dpr=1 754w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1528&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/332520/original/file-20200504-83769-qfcp35.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1528&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The section of DNA that codes for HLAs is on the sixth chromosome.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:HLA_MHC_Complex_illustration.jpg">Pdeitiker at English Wikipedia / Wikipedia</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>We found similarities in how effective alleles were at identifying SARS and SARS-CoV-2. If an HLA allele appeared to be bad at recognizing SARS-CoV-2, it was also bad at recognizing SARS. Our analysis predicted that one allele, called B46:01, is particularly bad with regards to both SARS-CoV-2 and SARS-CoV. Sure enough, previous studies showed that people with this allele tended to have more <a href="https://doi.org/10.1186/1471-2350-4-9">severe SARS infections</a> and higher viral loads than people with other versions of the HLA gene. </p>
<h2>What’s next?</h2>
<p>Based on our study, we think variation in HLA genes is part of the explanation for the huge differences in infection severity in many COVID-19 patients. These differences in the HLA genes are probably not the only genetic factor that affects severity of COVID-19, but they may be a significant piece of the puzzle. It is important to further study how HLA types can clinically affect COVID-19 severity and to test these predictions using real cases. Understanding how variation in HLA types may affect the clinical course of COVID-19 could help identify individuals at higher risk from the disease.</p>
<p>To the best of our knowledge, this is the first study to evaluate the relationship between viral proteins across a wide range of HLA alleles. Currently, we know very little about the relationship between many other viruses and HLA type. In theory, we could repeat this analysis to better understand the genetic risks of many viruses that currently or could potentially infect humans.</p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/137145/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Reid Thompson receives funding from the Department of Veterans Affairs, and the Sunlin and Priscilla Chou Foundation. </span></em></p><p class="fine-print"><em><span>Abhinav Nellore and Austin Nguyen do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Researchers from Oregon Health and Science University found that variations in genes that code for parts of the cellular alarm system might play a role in how well people fight off COVID-19.Austin Nguyen, PhD Candidate in Computational Biology and Biomedical Engineering, Oregon Health & Science UniversityAbhinav Nellore, Assistant Professor of Biomedical Engineering & Surgery, Oregon Health & Science UniversityReid Thompson, Assistant Professor of Radiation Medicine, Oregon Health & Science UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1286962020-02-10T05:01:54Z2020-02-10T05:01:54ZWhat is autoinflammatory disease, the rare immune condition with waves of fever?<figure><img src="https://images.theconversation.com/files/313866/original/file-20200206-149802-8eqdou.jpg?ixlib=rb-1.1.0&rect=0%2C8%2C1000%2C657&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/pediatrician-taking-temperature-professional-thermometer-229346311">from www.shutterstock.com</a></span></figcaption></figure><p>Just over 20 years ago, people from three generations of an American family were referred to the <a href="https://www.nih.gov/">National Institutes of Health</a> (NIH) in Washington DC with an unknown disease. </p>
<p>They were ten to 82 years old and had symptoms including monthly episodes of unexplained high fevers (up to 41°C), lasting two to seven days. </p>
<p>They also had painful swollen <a href="https://www.healthdirect.gov.au/lymph-nodes">lymph nodes</a>, enlarged <a href="https://www.health.qld.gov.au/news-events/news/facts-about-your-spleen-splenectomy-immune-system-what-is">spleens</a> and livers, abdominal pain, mouth ulcers, joint pain, and a patchwork of other symptoms.</p>
<p>The symptoms, which they’d had since shortly after birth, seemed like an inflammatory reaction. However, doctors could not trace the episodes to an infection.</p>
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<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-inflammation-and-how-does-it-cause-disease-84997">Explainer: what is inflammation and how does it cause disease?</a>
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<p>We now know these symptoms are typical of <a href="https://www.wehi.edu.au/research-diseases/immune-health-and-infection/autoinflammatory-diseases">autoinflammatory diseases</a> – rare conditions with seemingly unprovoked episodes of fever and inflammation. </p>
<p>Because the inflammatory episodes occur regularly, the diseases are also known as “<a href="https://my.clevelandclinic.org/health/articles/17354-periodic-fever-syndrome">periodic fever syndromes</a>”. In addition to being painful and debilitating, some of the conditions can damage vital organs, such as the heart and lungs.</p>
<h2>What causes autoinflammatory disease?</h2>
<p>Autoinflammatory diseases are <a href="https://www.ncbi.nlm.nih.gov/pubmed/24247370">caused by</a> abnormal activation of the <a href="https://www.ncbi.nlm.nih.gov/books/NBK26846/">innate immune system</a>, the body’s first-line defence against invading pathogens.</p>
<p>The innate immune system is a hard-wired response that can quickly mobilise to fight foreign invaders. Among its many roles is the release of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785020/">cytokines</a>. </p>
<p>These are immune messengers critical for alerting and recruiting other cells to the fight, increasing blood circulation and inducing fever. More about cytokines later.</p>
<p>However, in autoinflammatory diseases, invading microbes don’t cause the fever and inflammation. Instead, genetic changes (mutations) lead to the innate immune system being activated for what appears to be no reason, causing uncontrolled inflammation.</p>
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<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
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<p>Autoinflammatory diseases typically begin in childhood, often from birth, and are lifelong conditions. The genetic mutations can be passed from parents to their children, leading to multiple cases of disease in an extended family. </p>
<p>Autoinflammatory diseases are different from autoimmune diseases, such as <a href="https://theconversation.com/explainer-multiple-sclerosis-32662">multiple sclerosis</a>, which are caused by defects in the adaptive immune system, a different arm of the immune response.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-are-autoimmune-diseases-22577">Explainer: what are autoimmune diseases?</a>
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<p>There are a number of different autoinflammatory diseases, often caused by different genetic mutations.</p>
<h2>How do we treat autoinflammatory disease?</h2>
<p>Autoinflammatory diseases cannot be cured, and treatment is usually to relieve symptoms during an attack. Patients are often treated with high doses of <a href="https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/corticosteroids">corticosteroids</a>, a broad-brush approach to suppress the immune system.</p>
<p>Autoinflammatory diseases are also <a href="https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associated-periodic-syndrome#statistics">quite rare</a>, which in the past has made it difficult to develop specific treatments.</p>
<p>Because autoinflammatory diseases are typically associated with excess production of cytokines, they are sometimes treated with so-called biologics – antibodies that mop up these excess cytokines.</p>
<p>These are usually antibodies to the cytokines <a href="https://www.medicalnewstoday.com/articles/324841.php">tumour necrosis factor</a> (TNF) or <a href="https://www.rndsystems.com/resources/articles/interleukin-1">interleukin-1</a>. </p>
<p>However biologics are expensive, and can have <a href="https://jamanetwork.com/journals/jama/article-abstract/202873">significant</a> <a href="https://www.nature.com/articles/s41467-017-02466-4">side-effects</a>.</p>
<p>Without knowing the cause of an inflammatory disease, treatment is a trial and error process; a drug that works for one person may not work for another.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=541&fit=crop&dpr=1 600w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=541&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=541&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=679&fit=crop&dpr=1 754w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=679&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/313868/original/file-20200206-149747-11f116p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=679&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Antibodies against the molecule TNF (above) can be used to treat excess inflammation.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/tumor-necrosis-factor-alpha-tnf-cytokine-1246006945">from www.shutterstock.com/StudioMolekuul</a></span>
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<h2>Can genetic testing help?</h2>
<p>The discovery of mutations in genes causing autoinflammatory diseases has led to the development of genetic tests to help diagnosis.</p>
<p>However, some people with autoinflammatory disease do not have a change in one of the known disease-causing genes. </p>
<p>So our researchers have established the <a href="https://www.aadry.org/">Australian Autoinflammatory Disease Registry</a> to help identify other genetic causes of autoinflammatory diseases. </p>
<h2>How we found out about the underlying mechanism</h2>
<p>While the NIH researchers were looking for a cause of the American family’s disease, another strand of the story was playing out in Australia.</p>
<p>We were looking at the role of the master cytokine TNF, which controls many aspects of the body’s inflammatory response, and its partner RIPK1.</p>
<p>Usually, the body has many checks and balances to ensure these molecules are tightly controlled. </p>
<p>But we worked with the <a href="https://www.nature.com/articles/s41586-019-1828-5_">US scientists who found</a> a critical mutation in the gene coding for RIPK1. We found this mutation, leading to changes in just one amino acid, was enough to supercharge its partner TNF into an elite killer. </p>
<p>This is what triggered the uncontrolled inflammation behind the American family’s disease.</p>
<p>Our team named this condition <a href="https://pursuit.unimelb.edu.au/articles/the-genetic-mutation-behind-a-new-autoinflammatory-disease">CRIA syndrome</a> (cleavage-resistant RIPK1-induced autoinflammatory syndrome).</p>
<h2>So what does this mean?</h2>
<p>Understanding the molecular mechanism by which CRIA syndrome causes inflammation gives us an opportunity to get to the root of the problem, and to offer an alternative to existing treatments.</p>
<p>For this American family, treatment with an agent that inhibits the faulty RIPK1 might be a tailored option.</p>
<p>Lastly, the discovery of CRIA syndrome now confirms RIPK1 can play an important role in regulating inflammation in humans. So it <a href="https://www.nature.com/articles/ni.3206">may also play</a> a role in far more common human illnesses, such as colitis (inflammation of the colon), rheumatoid arthritis and the skin condition psoriasis.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/what-is-rheumatoid-arthritis-the-condition-tennis-champion-caroline-wozniacki-lives-with-119537">What is rheumatoid arthritis, the condition tennis champion Caroline Wozniacki lives with?</a>
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<img src="https://counter.theconversation.com/content/128696/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>John Silke consults for Anaxis, an Australian company developing drugs to inhibit inflammatory diseases. He has a fellowship from the NHMRC and the work on RIPK1 cleavage was also funded by the NHMRC (Project #1163581).</span></em></p><p class="fine-print"><em><span>Najoua Lalaoui receives funding from the Cancer Australia and Cure Cancer Australia Foundation (Project grant 1145588) and the Victorian Cancer Agency Mid-career Fellowship 17030. </span></em></p>A rare type of inflammatory disease that causes repeated bouts of high temperatures can run in families. Here’s what we know so far.John Silke, Leader, Infection, Inflammation and Immunity theme, Walter and Eliza Hall InstituteNajoua Lalaoui, Postdoctoral research fellow, Inflammation Division, Walter and Eliza Hall InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1218932019-09-16T15:27:35Z2019-09-16T15:27:35ZHow pregnancy changes women’s metabolism and immune systems<figure><img src="https://images.theconversation.com/files/292449/original/file-20190913-8687-1qf52er.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some changes are more noticeable than others during pregnancy.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/beautiful-asian-pregnant-woman-sit-on-1379423480?src=dzESJwf_iRMiEcz-Hoq1lA-3-24">Thanakorn.P/Shutterstock</a></span></figcaption></figure><p>Some of the changes that happen to a woman’s body during pregnancy are more obvious than others. We all know that women usually get a visible bump, they might have morning sickness initially, and swollen ankles later on, but pregnancy can also change some of their key bodily processes and functions too.</p>
<p>One of these less obvious changes occurs to women’s metabolism. This is the way the body uses dietary sugars, fats and proteins to provide the energy and building blocks needed to ensure the proper functioning of cells, tissues and organs.</p>
<p>As pregnancy progresses, <a href="https://www.ncbi.nlm.nih.gov/pubmed/23549674">women develop insulin resistance</a>, becoming diabetic-like. This is to ensure plenty of glucose reaches the baby and the placenta so that they grow and develop appropriately. To ensure her own energy demands are met too, a pregnant woman stores fat early on and then burns it as an energy source later. So, when a pregnant woman is at her largest – during the last 13 weeks of pregnancy – she is burning fat perhaps like never before.</p>
<h2>Immune system changes</h2>
<p>The immune system changes during pregnancy too. These changes contribute to the success of the pregnancy, and are generally thought to be caused by the many <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376705/">hormonal changes</a> that occur while women are with child. </p>
<p>If we consider that a baby is half-mum and half-dad, the mother’s immune system must be tightly regulated so that it doesn’t reject the baby like it would a transplanted organ. This is achieved by altering the numbers, location and/or activity of multiple subsets of maternal immune cells. Monocytes (a type of white blood cell) become more active, for example, while neutrophils (another type of white blood cell) increase in number. Both of these cell types play a role in defending the body against bacteria, fungi and viruses. </p>
<p>Changes also occur in the body’s T cells – a type of lymphocyte (which are also white blood cells) that has an important role in what is known as immunological memory. This is where the immune system “remembers” that it has encountered a particular danger before and enables the immune system to make a quicker response on a second or subsequent exposure. T cells do this by secreting lots of different types of proteins and other mediators (chemicals that are secreted to make other cells respond in a particular way). Different patterns of these mediators support different types of immune responses. Some are good for fighting viruses, others for fighting bacteria. And disruption of these patterns of mediators is linked to <a href="https://www.hindawi.com/journals/jir/2014/149185/">cancer</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189547/">autoimmune disease</a>. </p>
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<p>While these immune system changes protect babies, they also make pregnant women more vulnerable to severe responses to viruses such as influenza. This is because of changes to their immune response. We don’t really understand what the changes are yet, but it is why flu vaccination is recommended to pregnant women. </p>
<p>Women who suffer autoimmune diseases can also experience changes in their disease symptoms while they are pregnant. For example, women with <a href="https://www.nejm.org/doi/full/10.1056/nejm199807303390501">multiple sclerosis</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/26697768">rheumatoid arthritis</a> often feel better, while women with systemic <a href="https://www.sciencedirect.com/science/article/pii/S0889857X0700004X">lupus erythematosus</a> often suffer worsening of their symptoms. Very soon after the baby is born, patterns of autoimmune disease symptoms return to what they were like pre-pregnancy. Again, we don’t really understand why this occurs just yet, but changes to the patterns of mediators made by T cells in pregnancy probably contributes to this. </p>
<p>Cleverly, some of these immune system changes are also harnessed in the womb to optimise growth and development of the baby and placenta. Some immune cell subsets – like the T cells mentioned above and cells known as natural killer (NK) cells - <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=prabhudas+m+2015">accumulate in the uterus</a>, and provide signalling factors such as proteins and hormones. These act on the placenta via specific receptors to support the passage of nutrients to, and waste from, the baby. Keeping the placenta working properly helps to ensure the baby grows steadily and happily over the course of pregnancy.</p>
<h2>Physiological phenomenon</h2>
<p>These changes in metabolism and immune function are more than just points of interest, or factors for individual women to be aware of during pregnancy, however. Understanding them can not only help us better understand the natural physiological phenomenon of pregnancy but also why things like miscarriages or preterm births happen, or why some women develop gestational diabetes or pre-eclampsia. </p>
<p>In addition, if we can understand why symptoms of autoimmune disease fluctuate before, during and after pregnancy we might be able to better appreciate the immune system features that drive the occurrence of these diseases in general, and identify new ways to treat them. </p>
<p>There is already lots of interest in the overlap between metabolism and the immune system – for example, how energy substrates (sugars, fats and proteins) are used by immune system cells to regulate the immune response, especially when a person has cancer. We think it is changes in the use of these energy substrates by immune cells that also drives the immune system changes that occur in pregnancy. </p>
<p>This is something that our research group is now looking into. Using blood samples from pregnant and not pregnant women, we are studying how different subsets of immune cells use different energy substrates to support their functions. We are mapping how this changes over pregnancy and contributes to the dynamic immune system changes that occur with pregnancy.</p>
<p>If we can learn how our body naturally changes the way it uses these sugars, fats and proteins before, during and after pregnancy we might be able to identify new ways to switch these pathways on or off, and use this to treat cancer and other diseases.</p><img src="https://counter.theconversation.com/content/121893/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span><a href="mailto:c.a.thornton@swansea.ac.uk">c.a.thornton@swansea.ac.uk</a> receives funding from Diabetes UK. </span></em></p><p class="fine-print"><em><span>April Rees and Ben Jenkins do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Understanding how pregnancy changes some of the body’s fundamental systems could help treat cancer and other diseases.April Rees, PhD Researcher in Immunology, Swansea UniversityBen Jenkins, PhD Researcher in Immunology, Swansea UniversityCatherine Thornton, Professor of Human Immunology, Swansea UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1183952019-06-13T20:16:32Z2019-06-13T20:16:32ZSick with the flu? Here’s why you feel so bad<figure><img src="https://images.theconversation.com/files/279276/original/file-20190613-32351-h8a0v9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">You might feel terrible. But your runny nose, sore throat and aches are signs your body is fighting the flu virus. And that's a good thing.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/man-sick-flu-532749466?src=ugnCY8Mf95INcLve4TvIGw-1-20&studio=1">from www.shutterstock.com</a></span></figcaption></figure><p>“You never forget the flu”. This is the title of the Victorian health department’s <a href="https://dhhs.vic.gov.au/news/you-never-forget-flu">current campaign</a>, which highlights people’s recollections of having the flu. </p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=436&fit=crop&dpr=1 600w, https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=436&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=436&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=547&fit=crop&dpr=1 754w, https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=547&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/279259/original/file-20190612-32361-6j36og.JPG?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=547&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">‘The flu knocked me out for weeks’, part of the Victorian health department’s winter flu campaign.</span>
<span class="attribution"><span class="source">Vic Dept Health & Human Services</span></span>
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<p>Phrases include “I’ll never forget the pain of the fever”, “the flu flattened me”, “the flu knocked me out for weeks”.</p>
<p>This gives the impression that when you have the flu, you know you have it. What makes the flu so memorable is the severe symptoms. These include fever, aches and pains, a sore throat, runny nose, cough, and feeling weak and lethargic. </p>
<p>But what causes the flu? And why are the symptoms so severe?</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/health-check-how-long-should-you-stay-away-when-you-have-a-cold-or-the-flu-98702">Health Check: how long should you stay away when you have a cold or the flu?</a>
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<h2>What causes the flu?</h2>
<p>Influenza is caused by a <a href="https://microbiologyonline.org/about-microbiology/introducing-microbes/viruses">virus</a>, a small microbe that needs to enter our cells to replicate and produce more viruses. The influenza virus infects cells that line our airways and so is <a href="https://www.cdc.gov/flu/about/disease/spread.htm">easily transmitted</a> via the spread of droplets released when we sneeze or cough.</p>
<p>Coughs, sneezes and the other symptoms we feel after getting the flu, are largely due to our bodies fighting the infection.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/ive-always-wondered-why-is-the-flu-virus-so-much-worse-than-the-common-cold-virus-83495">I've always wondered: why is the flu virus so much worse than the common cold virus?</a>
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<h2>The immune response is a double-edge sword</h2>
<p>When you are infected with the flu virus, your <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346783/">innate immune system</a> kicks in. Special receptors recognise unique parts of the virus, triggering an alarm system to alert our bodies that an infection is under way.</p>
<p>This produces a rapid but non-specific response — inflammation.</p>
<hr>
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Read more:
<a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">Explainer: what is the immune system?</a>
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<p>Inflammation results from the action of small proteins called cytokines. A primary role of cytokines is to act locally in the lung to help limit the initial infection taking hold. </p>
<p>They can also make their way into the circulation, becoming systemic (widespread in the body) and act as a “call to arms” by alerting the rest of the immune system there is an infection.</p>
<p>Unfortunately, your body’s inflammatory response, while trying to fight your infection, results in the flu symptoms we experience.</p>
<p>Inflammation can trigger increased mucus production. Mucus (or phlegm) is a sticky substance that helps capture virus in the lungs and upper airways. The increased amount of mucus in the airways can trigger coughing and/or sneezing, and can lead to a runny nose. This helps expel the virus from our body before it can infect other airway cells.</p>
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<em>
<strong>
Read more:
<a href="https://theconversation.com/health-check-what-you-need-to-know-about-mucus-and-phlegm-33192">Health Check: what you need to know about mucus and phlegm</a>
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<p>Inflammation also results in an increase in body temperature or fever, which creates an inhospitable environment for the flu virus to replicate. </p>
<p>While an increased body temperature helps fight the infection, it also results in you feeling colder than usual. That’s because you feel a greater temperature difference between your body and the outside environment.</p>
<p>This can induce rapid muscle contractions in an effort to heat you up. This is why you can feel like you can’t stop shivering while at the same time burning up.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/mondays-medical-myth-feed-a-cold-starve-a-fever-13661">Monday's medical myth: feed a cold, starve a fever</a>
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<p>Finally, some of these inflammatory molecules act directly on infected cells to stop the virus replicating. They can do this by either interfering with the replication process directly, or alternatively, by actually killing the infected cell. </p>
<p>One of these factors is <a href="https://www.ncbi.nlm.nih.gov/pubmed/16817757">tumour necrosis factor alpha</a> (TNF-alpha). While its actions limit where the flu virus can replicate, its side effects include fever, loss of appetite and aching joints and muscles. </p>
<h2>Calling in the big guns</h2>
<p>Inflammation induced by the innate response also <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346783/">helps alert</a> the adaptive immune system that there is an infection. </p>
<p>While innate immunity provides an immediate, albeit non-specific, response to viral infection, it is the adaptive immune response that can efficiently clear the infection. </p>
<p>The adaptive immune system consists of specialised white blood cells called T and B cells that when activated provide a highly specific response to infection.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/279271/original/file-20190613-32321-1j2uo5g.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Your flu symptoms are likely the result of your body fighting off infection with the the tiny flu virus.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/740932939?src=i31VjifJup_n5HFxZMuhgA-1-0&studio=1&size=medium_jpg">from www.shutterstock.com</a></span>
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<p>Activation of flu-specific T and B cells in tissues called lymph nodes results in the generation of hundreds of thousands of clones, all specific for the flu virus. These can migrate into the lungs and specifically target the virus and its ability to replicate. </p>
<p>This enormous expansion of T and B cell numbers in response to infection results in swelling of the lymph nodes, which you can feel under your armpits or chin, and which can become sore. </p>
<p>Flu-specific T cells are also a source of the inflammatory molecule TNF-alpha and help fight influenza infection by killing off virus-infected cells. Both actions can contribute to the flu symptoms. </p>
<h2>Why can flu become a serious problem?</h2>
<p>Our ability to see off a flu infection requires a coordinated response from both our innate and adaptive immune responses. </p>
<p>If our immune system function is diminished for some reason, then it can prolong infection, lead to more extensive damage to the lung and extended symptoms. This can then result in secondary bacterial infections, leading to pneumonia, hospitalisation and eventually death.</p>
<p>Then there are people whose immune system doesn’t work work so efficiently who are particularly susceptible to the flu and its complications. These include:</p>
<ul>
<li>the very young, whose immune system is still yet to mature</li>
<li>the elderly, whose immune system function wanes with age</li>
<li>people with other conditions where immune function might be compromised, or be taking medication that might suppress the immune system. </li>
</ul>
<h2>Preventing the flu</h2>
<p>Washing your hands and covering your mouth when coughing and sneezing are simple things we can all do to reduce the chance of catching the flu in the first place.</p>
<p>And getting the flu vaccine activates your adaptive immune response to induce the sort of immunity efficient at protecting us from infection. </p>
<p>With the flu season well under way, prevention is our best bet that you won’t be saying “Remember the time I got the flu”.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/what-the-flu-does-to-your-body-and-why-it-makes-you-feel-so-awful-91530">What the flu does to your body, and why it makes you feel so awful</a>
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<img src="https://counter.theconversation.com/content/118395/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Stephen Turner receives funding from the National Health and Medical Research Council of Australia, the Australian Research Council and the National Institutes of Health Centre of Excellence for Influenza Research and Surveillance. </span></em></p>How can a tiny flu virus make you feel so bad, all over? Here’s what’s behind your high temperature, muscle aches and other flu symptoms.Stephen Turner, Professor, viral immunology, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/874972018-01-17T03:10:12Z2018-01-17T03:10:12ZHow rejuvenation of stem cells could lead to healthier aging<figure><img src="https://images.theconversation.com/files/198797/original/file-20171212-9389-cjsjns.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/group-senior-retirement-exercising-togetherness-concept-477077380?src=ZDmjg_uzXTaytUXq7fqnWg-1-5">Rawpixel.com/Shutterstock.com</a></span></figcaption></figure><p>“Rampant” and “elderly” are words rarely used in the same sentence, unless we are talking of the percentage of people over 65 years old worldwide. <a href="https://ourworldindata.org/life-expectancy/">Life expectancy</a> has considerably increased, but it is still unknown how many of those years are going to be lived in good health. </p>
<p>As a researcher of blood cancers and aging, I inevitably think about how in the next few decades a very large part of the population will deal with cancer treatments. Are we doing the best to manage the side effects, or even to manage aging itself? Could we accumulate just wisdom, instead of aches and pain?</p>
<p><a href="https://www.newscientist.com/article/mg22429894-000-everyday-drugs-could-give-extra-years-of-life/">Rejuvenation strategies</a> once sounded like science fiction, but they are becoming more and more promising. New research from my institute, Weill Cornell Medical College, suggests that transplantation of young blood vessel cells rejuvenates aged stem cells in mice, boosting older blood system function. It also shows signs that it could aid in recovery of the side effects of cancer therapy for humans. </p>
<h2>What happens to our blood system as we age?</h2>
<p>Of the over 7 billion people on Earth, more than <a href="http://www.who.int/world-health-day/2012/toolkit/background/en/">600 million are age 65</a> and older. This group, for the first time in human history, is expected by 2020 to be larger than the number of children below age 5. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544764/">Aging is a risk factor</a> for many conditions, such as blood cancer, so we can foresee that aging countries should prepare to deal with the consequences in health care. </p>
<p>The blood system, also called <a href="https://theconversation.com/essays-on-blood-why-do-we-actually-have-it-75064">the hematopoietic system</a>, is responsible for producing blood cells throughout a person’s life. We know that, with age, its function declines. </p>
<p>All blood cells derive from a hierarchical system, with common ancestor cells, called hematopoietic stem cells, at its apex. Over the course of a person’s life, these cells will continuously supply all types of blood cells that we need, including different types of immune cells. </p>
<p>As we age, blood stem cells become less able to perform at the best of their capability. This results in a decreased ability to fight infections and <a href="http://news.cornell.edu/stories/2017/10/transplantation-young-blood-vessel-cells-boosts-aging-stem-cells">increased incidence of blood cancer</a> in the over-65 population. </p>
<p>Older patients are also frequently not good candidates for bone marrow transplant, the cure for many blood disorders. This is because of a higher degree of complications after transplant, which is also limited by having enough numbers of stem cells to reconstitute the hematopoietic system in an adult. Therefore, strategies to support blood stem cell recovery are needed to expand the pool of possible bone marrow transplant recipients.</p>
<h2>Blood vessel cells and how they work</h2>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=481&fit=crop&dpr=1 600w, https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=481&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=481&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=605&fit=crop&dpr=1 754w, https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=605&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/198793/original/file-20171212-9396-y18q87.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=605&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Aged blood vessel cells, shown in red and green, with blue nuclei, with an age-associated defect.</span>
<span class="attribution"><span class="source">Michael Gutkin</span>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
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</figure>
<p>Blood vessel cells, or <a href="https://www.ncbi.nlm.nih.gov/books/NBK26848/">endothelial cells</a>, are a particular cell type that lines the inside of blood vessels. They contribute to form arteries, veins and capillaries. For a long time, endothelial cells have been perceived as a passive conduit for blood. </p>
<p>However, in recent years, scientists have seen a new role for these cells. They discovered that blood vessel cells actively sustain nearby stem cells and guide organ regeneration. </p>
<p>So, instead of a pipe system, we can think of blood vessel cells more like active supporters lined up along a cyclist’s race. This dynamic role has been found to be true for many organs, including the one responsible for making new blood cells, the bone marrow. </p>
<p>In the marrow, blood stem cells are found in close contact with blood vessels cells, which provide many types of substances, such as <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=632169">KIT ligand</a> that stem cells need to keep performing at their best. </p>
<p>As we get older, endothelial cell supportive function declines, and they become dysfunctional. They can still perform the basic function of architectural support for blood flow, but they are less able to support nearby stem cells. </p>
<p>A <a href="https://www.jci.org/articles/view/93940">recent study</a> from Weill Cornell Medical College shows that older blood vessel cells made young blood stem cells act old. Led by Dr. Jason Butler and Dr. Michael Poulos, the research isolated blood vessel cells from young or old mice and grew them in petri dishes with blood stem cells. </p>
<p>The young blood stem cells bias showed a tendency toward producing more of one type of immune cells, myeloid cells, which is a hallmark of aging. </p>
<p>In a complementary experiment in the study, the youngster cells rejuvenated the old ones. The team found out that the rejuvenated old cells were able to create a healthy blood system when transplanted back into mice.</p>
<p>The group then gave mice a strong dose of whole body radiation, similar to what patients undergo prior to <a href="https://bethematch.org/patients-and-families/about-transplant/what-is-a-bone-marrow-transplant-/">bone marrow transplant</a>. Then, they infused the mice with endothelial cells isolated from young mice. They found that the blood vessel infusions enhanced the recovery of the hematopoietic system and restored blood stem cell function in aged mice.</p>
<p>When the team modeled a bone marrow transplant on the mice, they even observed that mice infused with endothelial cells regained a healthy blood system, even if the number of blood stem cell transplanted was suboptimal.</p>
<h2>Benefits ahead?</h2>
<p>The study shows that young blood vessels can potentially rejuvenate blood stem cell functions, and mitigate the effects of medically induced stress, such as <a href="https://www.mayoclinic.org/tests-procedures/radiation-therapy/details/risks/cmc-20325837">radiation therapy</a>. The endothelial cells also protected other organs affected by radiation throughout the body, including the gut, skin, spleen and liver. </p>
<p>This global protection has many <a href="https://news.weill.cornell.edu/news/2017/10/transplantation-of-young-blood-vessel-cells-boosts-function-of-aging-stem-cells">potential benefits</a> for those undergoing cancer therapy, Butler explained in a statement. Those benefits include a shorter recovery time, less susceptibility to infections and lower the number of blood stem cells needed to achieve a successful transplant. The infusion of endothelial cells could thus lower the complication rates for elderly patients, Butler said.</p>
<p>At this time several groups are exploring endothelial cells as support strategy for blood stem cells, in <a href="http://www.bloodjournal.org/content/109/6/2365.long?sso-checked=true">mice</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442761/">nonhuman primates</a>. </p>
<p>Researchers agree on two very relevant issues that will influence the clinical application of these findings. </p>
<p>First, the infused blood vessel cells stick around transiently, which means lower chances of any potential toxic or unwanted side effect. Second, the infusions would work as an adjunct therapy for clinical protocols already in place, a sort of upgrade on standard treatment. This could potentially speed up the clinical translation of these findings.</p>
<p>“The bullets are already there; this is a better one,” said Poulos.</p><img src="https://counter.theconversation.com/content/87497/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Elisa Lazzari works for Weill Cornell Medical College.</span></em></p>As people’s bodies age, so do their blood cells. This affects immunity and an ability to withstand certain cancer treatments. A recent study in mice suggests that those cells can be rejuvenated.Elisa Lazzari, Postdoctoral Associate in Biomedical Sciences, Cornell UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/459752015-09-11T03:18:56Z2015-09-11T03:18:56ZCould a weekend of binge-drinking worsen your cold?<figure><img src="https://images.theconversation.com/files/93468/original/image-20150901-25771-1ehxgvb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">People who have big weekends tend to take more sickies at work.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>People who binge drink on the weekend take more days off work, but the cost may be more than just economic. </p>
<p>Recently published research suggested alcohol and drug-related absenteeism costs the Australian economy <a href="http://onlinelibrary.wiley.com/doi/10.1111/1753-6405.12414/abstract">around AU$3 billion</a> a year. One of the report’s authors was <a href="http://www.theage.com.au/national/health/australias-3b-hangover-alcohol-and-drugs-causing-115m-sick-days-20150810-givsg0.html">quoted in the media</a> as saying that “alcohol puts a bit of a tax on your immune system”. She said people may not realise drinking or drug-taking was:</p>
<blockquote>
<p>causing their stomach upset, headache or worsening cold by Monday… </p>
</blockquote>
<p>From the few studies that explore this, we know excess alcohol intake affects the immune system. But how does this effect manifest itself? Can a “big weekend” make people more susceptible to illness? </p>
<h2>Heavy drinking</h2>
<p>Complex and tightly controlled, <a href="https://theconversation.com/explainer-what-is-the-immune-system-19240">the immune system is</a> made up of different cells and tissues, that together protect us from viruses and bacteria. </p>
<p>Chronic alcohol abuse can definitely <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887500/">alter</a> the way our body responds to pathogens - <a href="http://www.ncbi.nlm.nih.gov/pubmed/26146763">reducing the numbers</a> of killer T cells, for instance. These are white blood cells that act like the immune system’s soldiers, working to eliminate infected cells. </p>
<p>A reduction in killer T cells leaves people more prone to infections. But it’s possible other factors sometimes present in people who chronically abuse alcohol, such as poor diet, can also have that effect.</p>
<p>Drinking can influence the inflammatory response too. Inflammation is an important part of the immune mechanism that helps immune cells travel to the infection site (although if uncontrolled, inflammation can cause chronic disease and pain). </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/25572859">One recent study found</a> that in the 20 minutes after a binge drinking session, participants had developed higher than normal levels of inflammation in their body. But two hours later, inflammation had dropped below the original levels.</p>
<p>As their blood alcohol level fell, the number of monocytes (types of white blood cells known as “phagocytes” because they’re able to recognise and ingest microbes) also fell. Participants’ blood showed decreased numbers of natural killer cells as well. These play a similar role as the killer T cells.</p>
<p>Similar results were found in a 2014 study on <a href="http://www.ncbi.nlm.nih.gov/pubmed/24689549">binge-drinking mice</a>; their phagocytic cells decreased along with other changes to the immune system. These findings suggest even a single session of binge drinking may increase the risk of viral infections, such as colds. But moderate drinking (one drink per day for women and two for men) shows a different picture. </p>
<h2>Moderate drinking</h2>
<p>A <a href="http://www.ncbi.nlm.nih.gov/pubmed/8363004">1993 study</a> looked at the association between smoking, drinking and the risk of developing the common cold - with volunteers given saline drops containing cold-causing viruses. It found drinking one or more glasses of alcohol a day decreased the risk. But this was only true for non-smokers; smokers were more prone to colds regardless of how much they drank.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=405&fit=crop&dpr=1 600w, https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=405&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=405&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=509&fit=crop&dpr=1 754w, https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=509&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/93487/original/image-20150901-25759-1b3vpf7.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=509&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">An increase in alcohol seems to decrease the risk of developing a cold, but only for non-smokers.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/linconllogg/139522889/in/photolist-dk6i4-5eR7Jw-9XoNB1-dz5JBC-c7BZc-9dBGGw-dT9EW7-mbdV6D-4rNcvE-fCFdX-82LE6-BGbWj-a8UXnw-ehfJa-81rgpX-6ifiMD-pX1Ti-8tKZr-BVSZH-axQknU-tDeK8-BVTeJ-71aFws-ehfqw-BVSTh-9uP45J-BVSUs-BVSX7-7xXk2-4fBK7S-5ewkyq-a5Gf5q-9x8bR1-BG9yx-47DFJ-4vfZXV-a1Tyy-8F8qPo-ovARyw-csvZv-JKSWh-5HEg8Q-5btwTW-vdz5f-866bsB-fQZjR-4aXBcD-sH3fn-5UQa6H-4WRfA">Velo_Montana/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>A <a href="http://www.ncbi.nlm.nih.gov/pubmed/11978590">larger 2002 study</a> examined the effects of wine, beer and spirits on the risk of developing the common cold. Participants were asked about their drinking and other lifestyle habits, as well as any colds they had over the course of a year. </p>
<p>People who drank wine - red wine in particular - had fewer colds than those who didn’t drink at all. And people who drank more than 14 glasses of wine per week had been the least ill that year. Beer and spirits didn’t appear to be protective against infection. But nor did they increase the risk of developing colds.</p>
<p>But these studies looked at the association between alcohol and colds. What about alcohol’s effect on the immune system itself?</p>
<h2>The immune system</h2>
<p>A 2014 study in which <a href="http://www.ncbi.nlm.nih.gov/pubmed/24200973">rhesus monkeys were given open access to alcohol</a> found monkeys who consumed moderate amounts of alcohol responded better to a vaccine. And monkeys who abstained, or drank heavily, had a lower immune response.</p>
<p>It also found monkeys who were moderate drinkers had slightly increased levels of certain cytokines. These are small proteins that help coordinate the immune response to infections and cell damage, either enhancing or dampening the response. </p>
<p>In these monkeys, the number of immune response-enhancing cytokines had increased, and that might be the mechanism that helped their improved response to the vaccine. It’s possible moderate drinking in humans may also enhance the immune response to vaccines and viral infections.</p>
<p>Different types of alcohol, as well as different intake levels, seem to play a strong role in our susceptibility to colds. And a weekend of binge drinking may indeed increase your susceptibility to viral infections, such as colds. </p>
<p>Given drinking is a social activity, going out for a drink increases exposure to infections as well. Still, like many other things in life, exercising moderation when drinking could help boost your immune response to the common cold and other viral illnesses.</p><img src="https://counter.theconversation.com/content/45975/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kim Murphy does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>There’s no doubt chronic alcohol abuse changes the body’s infection-defence system. But here’s what the research says on whether a binge-drinking weekend can make people more susceptible to illness.Kim Murphy, Immunology researcher, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/409442015-07-28T10:20:27Z2015-07-28T10:20:27ZFour challenges we have to crack before immune therapy can revolutionize how we fight cancer<figure><img src="https://images.theconversation.com/files/89822/original/image-20150727-7671-11i949l.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Attack.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-133427873/stock-photo--d-rendered-illustration-of-leukocytes-attacking-a-cancer-cell.html?src=DiEecaBguw-Np8gGVEU0Vw-1-50">Cancer cells and leukocytes via www.shutterstock.com.</a></span></figcaption></figure><p>Most of us know about the conventional treatment of cancer: surgery to remove tumors, chemotherapy and radiation. But within the last five years, a new class of drugs that use our immune systems to fight cancer are gaining traction in cancer treatment. This is called “immunotherapy.” Instead of killing cancer cells with radiation or chemotherapy, immunotherapy mobilizes the immune system to fight against cancer much like it does against bacteria and viruses. </p>
<p>For a training immunologist like myself, immune therapies have opened new doors to understanding and treating cancers. In the future, immunotherapy could mean a personalized treatment, entirely tailored to an individual. As exciting as that sounds, we still have plenty of work to do, as there remains a lot we don’t know about the immune system. Here are some of the challenges we need to overcome to create these personalized treatments.</p>
<h2>Challenge #1: Tumors don’t want the immune system to know they are tumors</h2>
<p>In the late 1980s, researchers started to wonder if the immune system could fight tumors the same way it fought foreign invaders. Studies in <a href="http://dx.doi.org/10.1126/science.3489291">mice</a> and in <a href="http://dx.doi.org/10.1056/NEJM198812223192527">humans</a> showed that when immune cells were extracted from a body, reprogrammed and transferred back into the same body, they caused tumors to temporarily shrink, giving first indications of immunotherapy at work.</p>
<p>In turns out that tumors are pretty vicious in avoiding the immune system. In the 1990s, researchers discovered that tumors can actively put “<a href="https://theconversation.com/immunotherapy-drugs-could-herald-new-era-in-cancer-treatment-39264">brakes</a>” on the body’s immune system to evade <a href="http://dx.doi.org/10.1016/1074-7613(94)90071-X">detection</a> by T-cells, a special kind of immune cell. T-cells search for signs of infection within cells by looking for specific protein codes on the cell surface. When T-cells decide that protein codes displayed on a cell don’t look like they belong to normal cells, they attack these abnormal cells and kill them (as shown in this fantastic video). </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/cJU7ZaWe5-o?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Cytotoxic (Killer) T-cells in action destroying a cancer cell.</span></figcaption>
</figure>
<p>Tumors can block T-cells from recognizing these protein codes. By doing this, tumors essentially go into stealth mode, flying under the radar of immune detection. </p>
<p>We’ve figured this challenge out – sort of. Extensive research on the T-cell brakes eventually led to drugs that <a href="http://dx.doi.org/10.1126/science.271.5256.1734">block</a> the effects of these brakes – allowing the immune system to detect and attack tumors that would otherwise be invisible to it – and present-day cancer immunotherapy was born.</p>
<h2>Challenge #2: Immunotherapy drugs are highly effective, but not in everyone</h2>
<p>Today there are three drugs approved as immune therapies – Ipilumimab, Nivolumab and Pembrolizumab. All three drugs act by releasing the T-cell brakes in different ways, freeing T-cells to look for the small protein codes characteristic of tumor cells.</p>
<p>These drugs have provided long-term remissions in patients with metastatic relapses in cancers such as melanoma and lung cancer. This means that patients whose cancers came back after an initial chemotherapy treatment (often a 3-month death sentence) remarkably survived, in some cases for several years, after their T-cells were rebooted to attack cancer. Very few conventional treatments can offer a comparable second chance after relapse.</p>
<p>But there is a problem: these drugs do not work for everyone. They are approved only to treat melanoma and certain types of lung cancer, and even in these cancers, these drugs only work in some patients. For instance, in about 20% of people with metastatic melanoma, Ipilimumab can <a href="http://dx.doi.org/10.1200/JCO.2014.56.6018">double</a> the long-term survival. For the other 80%, the drug is much less effective. </p>
<p>Scientists say that part of the reason why immunotherapy drugs can be amazingly effective in some patients, and much less effective is others, boils down to differences in our DNA. </p>
<p>Although we share 99.9% of our DNA with each other, there is massive variation from one individual to the next, partly because of our genetics and partly due to the environment. This variation extends to our tumors and our <a href="https://med.stanford.edu/news/all-news/2015/01/environment-not-genes-plays-starring-role-in-immune-variation.html">immune system</a>. Because of this genetic variation that makes us who we are, our immune systems, and thus our cancers, have their own life story. </p>
<p>To try to solve this problem, researchers are trying to understand the <a href="http://dx.doi.org/10.1056/NEJMoa1406498">genetic basis of clinical response to immunotherapies</a>, and developing techniques to identify whether a patient who walks into the clinic with cancer will benefit from these drugs before going under treatment. </p>
<h2>Challenge #3: Survival of the fittest tumors</h2>
<p>In recent years we’ve learned that one of the reasons tumors are hard to treat is because they <a href="http://dx.doi.org/10.1038/nature10762">evolve</a>. Some researchers believe that tumors exist only because they have evolved to hide from the immune system. This process takes years of natural selection, where only the fittest tumor cells, which effectively hide from or actively fight against the immune system, manage to survive, grow and cause major complications. </p>
<p>This means that we can expect that at least in some patients undergoing immune therapy, their tumors can evolve resistance to immune system detection and can come back. Although our immune system is capable of constantly evolving to counter viruses and bacteria, tumor evolution is a formidable enemy to overcome, and we are just beginning to understand this aspect of the disease.</p>
<h2>Challenge #4: The immune system ‘blind spot’</h2>
<p>Our immune system carries out a fine balancing act between hunting down and attacking cells that can harm us, such as viruses and bacteria, and leaving healthy “self” cells in our bodies (or good bacteria) alone. Immune cells that recognize our own normal “self” cells are killed off early during development, which prevents us from developing autoimmune disorders. </p>
<p>But most tumors result from our own cells. So how do we get the immune system to fight “self” cells it is supposed to ignore, and how do we make sure the immune system targets tumor cells, but not healthy cells? This is a big challenge for immune therapies.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/84013/original/image-20150604-3400-1u4ymou.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Immunotherapies let T-cells do their job.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/niaid/5950870236/in/album-72157627714446209/">Healthy human T-cell via NIAID</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>By freeing T-cell brakes, current immunotherapies often work by overcoming these blind spots: immune cells suddenly start seeing our own “self” cells, which is very effective against tumors disguised as our own normal cells. The downside, however, is that this often upsets the delicate balance between autoimmunity and cancer.</p>
<p>As a result, some patients treated with immunotherapy experience <a href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf">autoimmune reactions</a>.
Some melanoma patients undergoing immunotherapy have been known to develop Vitiligo, a condition where that leads to the loss of skin color. Other patients undergoing treatment also report gastrointestinal distress as a common side effect from the immune system being overactivated. In extreme cases, severe life-threatening autoimmune reactions such as organ rejection can happen, indicating that immunotherapy drugs need careful examination and regulation.</p>
<h2>Overcoming the challenges</h2>
<p>Researchers are starting to sequence the DNA of tumors to get a better understanding of how they work at the <a href="http://cancergenome.nih.gov/cancergenomics/whatisgenomics/whatis">genetic level</a>. We have just begun to understand how different they are from other cells of our body. </p>
<p>Tumor DNA sequencing, along with emerging technologies, like <a href="http://www.esmo.org/Conferences/Past-Conferences/ESMO-2014-Congress/News-Articles/Liquid-biopsies-Tumour-diagnosis-and-treatment-monitoring-in-a-blood-test">liquid biopsies</a> on the blood to diagnose and monitor tumors, will help us understand how cancers evade the immune system and who will actually benefit from these treatments. In patients who do not respond to regular immunotherapies, it has been proposed that immunotherapies might be combined with conventional chemotherapies (“immunochemotherapy”) to improve potency of treatment.</p>
<p>We are also at the beginning of personalized immune therapies. This treatment involves designing vaccines made of <a href="http://dx.doi.org/10.1126/science.aaa3828">engineered immune cells</a> from a patient’s own body, to treat their own tumors. In the not too distant future, a patient may walk into a clinic, have their tumors sequenced and their immune system analyzed to decide on the best course of personalized immune therapy. </p>
<p>For now, though, we have to be careful in regulating immune therapies, and get better at understanding the intricate dance between cancers and our immune systems.</p><img src="https://counter.theconversation.com/content/40944/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sri Krishna Ph.D. does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Finding ways to use our immune system to fight cancer could pave the way for personalized cancer treatment. But to get there, we need to overcome some pretty big obstacles.Sri Krishna Ph.D., PhD Candidate, Biological Design, School of Biological and Health Systems Engineering, Arizona State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/318062014-09-23T05:21:20Z2014-09-23T05:21:20ZNumber of immune cells in tumours could soon help predict and treat cancers<figure><img src="https://images.theconversation.com/files/59321/original/svt9nn3p-1410968593.jpg?ixlib=rb-1.1.0&rect=0%2C6%2C507%2C315&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Head and neck cancer underway.</span> <span class="attribution"><a class="source" href="http://upload.wikimedia.org/wikipedia/commons/f/f4/PET-CT_scanning_of_lymph_node_metastases_in_cancer_2.jpg">Akira Kouchiyama</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also <a href="http://www.ncbi.nlm.nih.gov/pubmed/24218361">keep us free from cancer</a>. Patients with less efficient immune systems such as organ transplant recipients or those with untreated HIV, for example, are more susceptible to cancers. It is also becoming increasingly apparent that we can use immune cells to predict survival in people who do develop cancer. And that, in fact, there are immune cells within cancers.</p>
<p>The number of immune cells inside a tumour can hugely vary: some patients have vast numbers while some have very few. <a href="http://www.ncbi.nlm.nih.gov/pubmed/24169344">In a recent study</a>, we showed that in head and neck cancers, the survival of a patient depends on how many immune cells are within the tumour. This could be a valuable way of individualising cancer treatments. Patients with lots of immune cells, for example, could be offered less toxic cancer treatment while those with few immune cells may need more aggressive treatment to improve their chances of survival. </p>
<p>Not all immune cells within the tumour are able to “attack” the cancer. By looking at specific cell markers – proteins on the cell exterior that allow us to see whether, for example, cells are exhausted – we can determine which individual immune cells in the tumour will be effective in tackling the cancer, or if they are exhausted and not able to perform any useful function. It’s possible that these exhausted cells could be reinvigorated to become useful again with targeted immunotherapy treatments currently in development. </p>
<p>These include vaccines, so if a cancer has been caused by a virus, we can vaccinate the patient with a short segment of the same virus to encourage the immune system to react to it. Around 30% of head and neck cancers, for example, are the result of human papillomavirus (HPV). There has been a 225% increase in these types of cancers <a href="http://www.ncbi.nlm.nih.gov/pubmed/21969503">over the past 15-20 years</a> and in the US, HPV will cause more of these cancers than cervical ones. In these cases, cancer cells continue to express part of the HPV on their surface. The hope is that following vaccination, immune cells will be better able to identify these HPV cancer cells and kill them. </p>
<p>For people who simply don’t have many immune cells in tumours, specific, targeted immunotherapy could be one option. But also broader “brush stroke” treatments. These broader treatments cover all immunotherapies that encourage a patient’s immune system in a fairly non-specific way. Our immune cells are normally very tightly regulated and include many fail-safe systems to prevent them from over-reacting primarily to infections. General immunotherapy takes the brakes off and allows the immune cells to react to the cancer cells.</p>
<p>It may be that a combination of specific vaccine and non-specific immune treatments could be enough in combination to tip the balance in favour of the patient’s immune system so that it is able to overcome the cancer.</p>
<p>We’re going to further investigate how immune cells might help us to fight cancer and two head and neck cancer immunotherapy trials are due to start at the University of Southampton in the next six months. One of these trials will look at a HPV cancer vaccine, while the other will investigate a non-specific immunotherapy molecule for those 70% of patients that develop head and neck cancer independent of HPV. Our hope is that within five years the results of these trials could influence the way we treat cancers.</p><img src="https://counter.theconversation.com/content/31806/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Emma King receives funding from CRUK. </span></em></p><p class="fine-print"><em><span>Christian Ottensmeier receives funding from CRUK. </span></em></p>Immune cells in the blood primarily defend us against infection. But we’re now learning that these cells can also keep us free from cancer. Patients with less efficient immune systems such as organ transplant…Emma King, CRUK Senior Lecturer Head and Neck Surgery, University of SouthamptonChristian Ottensmeier, Professor of Experimental Medicine, University of SouthamptonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/196482013-10-30T04:11:04Z2013-10-30T04:11:04ZWomen experience more chronic pain than men – now we know why<figure><img src="https://images.theconversation.com/files/34070/original/4ynch5nb-1383098381.jpg?ixlib=rb-1.1.0&rect=0%2C2188%2C3432%2C2096&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The cellular and molecular generators of pain are fundamentally different between males and females.</span> <span class="attribution"><span class="source">Image from shutterstock.com</span></span></figcaption></figure><p>It’s long been a household debate: who really is the stronger sex, men or women? It’s no secret that physically, men often outperform women. But women have long argued that the gruelling experiences of childbirth and the monthly hormone fluctuations validate their strength and superiority as the tougher sex.</p>
<p>Over many years, pain researchers have firmly <a href="http://www.ncbi.nlm.nih.gov/pubmed/23794645">established</a> that women <em>do</em> experience more pain than men. Unfortunately, the majority of chronic pain conditions predominately affect the female sex. Women are at a greater risk of developing several chronic pain conditions and display increased sensitivity to painful stimuli in the laboratory setting compared with men.</p>
<p>Chronic pain is a highly individualised and insidious clinical problem. It serves no physiological purpose, as it often outlasts the length of the original injury (usually around three months). </p>
<p>Given that pain is perceived and processed in the brain, many of us are unable to adequately communicate what it is, how it feels and the way it destroys lives. For this reason Professor Paul Rolan, University of Adelaide, refers to it as the “cancer of the soul”. </p>
<p>Unlike many other common health conditions where measurements can be taken or scans can be performed to diagnose the problems, chronic pain lacks all these tools. This is not for the lack of trying. It is simply the case that the structures in the brain and spinal cord that generate the chronic pain are anatomically tiny and are hidden from our sight by other important body parts like our spine and skull.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1130&fit=crop&dpr=1 754w, https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1130&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/34075/original/y2y5qqqr-1383102149.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1130&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Chronic pain serves no physiological purpose, as it often outlasts the length of the original injury.</span>
<span class="attribution"><span class="source">Image from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Because women experience more pain than men, there’s a good argument that they are in fact the “stronger” sex, having a greater tolerance for pain. But we also know that women don’t suffer in silence: they’re more likely to seek treatment and take pain-relieving medications than <a href="http://www.ncbi.nlm.nih.gov/pubmed/8826503">men</a>. </p>
<p>Several mechanisms have been proposed to explain these sex differences in pain and the use of pain relief. </p>
<p>Psychosocial factors such as gender roles have been found to partially contribute to the sex differences seen in pain sensitivity and the acknowledgement of the presence of <a href="http://www.ncbi.nlm.nih.gov/pubmed/8826503">pain</a> – men are “supposed” to act tough; women have the ability to seek help. But these factors do not entirely answer the problem. </p>
<p>Additionally, examining structural and functional differences in male and female pain wiring in the brain and spinal cord goes some of the way to explain some sex differences. So, female brains are different in some ways to male brains and female pain wiring is slightly different to that of men.</p>
<p>The search for these elusive mechanisms that contribute to the sex differences in pain led us to look at the “other brain”, the immune like cells of the brain and spinal cord, termed glia. Glia are a collection of immune-like cells that outnumber neurons ten to one throughout the brain and spinal cord. </p>
<p>These cells are critical for the health and well-being of our brains and are known to contribute to several neurological diseases, ranging from neurodegenerative diseases like Parkinson’s and Alzheimer’s, through to depression and anxiety. </p>
<p>Glia have been implicated in chronic pain states for many years, but until recently their role in sex differences in pain had not been examined.</p>
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<img alt="" src="https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=900&fit=crop&dpr=1 600w, https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=900&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=900&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1130&fit=crop&dpr=1 754w, https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1130&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/34074/original/9w4v7rgq-1383102066.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1130&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Glia appear to be central to this sex difference in pain.</span>
<span class="attribution"><span class="source">Image from shutterstock.com</span></span>
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</figure>
<p>Female sex hormones oestrogen and progesterone interact with the brain’s immune cells. The predominant female sex hormone, oestrogen has long been known to influence female pain. But new studies investigating pain across the female menstrual cycle have shown increased pain sensitivity when <a href="http://www.ncbi.nlm.nih.gov/pubmed/22001158">oestrogen</a> levels peak in the cycle. </p>
<p>Our research team has identified that the cellular and molecular generators of pain are fundamentally different between males and females. Critically, glia appear to be central to this sex difference in pain. Female pain is fundamentally different to male pain owing to the different reliance on glia. </p>
<p>The result is that women’s experience of pain is more severe than men’s and the pain is harder to treat.</p>
<p>Excitingly, this discovery provides a new potential treatment option for female chronic pain sufferers: glial-targeted drugs may more effectively treat exaggerated female chronic pain. These drugs aren’t available right now, but if they prove to be safe and continue to show promise in ongoing clinical studies they may be available in the near future.</p>
<p>Considering the immunology of the brain – and glial cells in particular – are <a href="https://theconversation.com/addiction-and-the-brain-how-the-immune-system-takes-over-18837">involved</a> in several neurological conditions, these results may have wide-reaching implications for many brain disorders. </p><img src="https://counter.theconversation.com/content/19648/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Hutchinson receives funding from NHMRC, ARC, NIH & National Cancer Foundation. He is affiliated with the University of Adelaide, Science Technology Australia and is on the editorial board of Brain, Behavior and Immunity.</span></em></p><p class="fine-print"><em><span>Lauren Nicotra received funding from an Australian Postgraduate Award.</span></em></p>It’s long been a household debate: who really is the stronger sex, men or women? It’s no secret that physically, men often outperform women. But women have long argued that the gruelling experiences of…Mark Hutchinson, ARC Research Fellow, University of AdelaideLauren Nicotra, PhD Candidate, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.