Failure of the immune system during blood poisoning (sepsis) can be reversed by a specific sugar. This restores the ability of immune cells to respond effectively to infections.
This week, researchers from Radboud University and Radboudumc published an article on this topic in Cell. These insights can lead to improved treatment of sepsis.
Sepsis is a life threatening complication during infections that occurs when the immune system is unable to gain control of the infection-causing microorganism. Afterwards, the immune system of many sepsis patients (30%-40%) becomes compromised. This can continue for several weeks to several months. As a result, the immune system can no longer respond to new infections, and sepsis patients have a high risk of additional complications and death due to a second infection.
In an article that was published on 17 November in the journal Cell, the molecular biologist Henk Stunnenberg of Radboud University, in cooperation with internist-infectiologist Mihai Netea and other colleagues at Radboudumc, shows that this immune paralysis can be reversed. This is good news for sepsis patients, for whom treatments are currently lacking in efficiency.
In developed countries, each year approximately 2 to 30 people in every 10000 get sepsis. In the Netherlands, an estimated annual 9000 patients are admitted to the intensive care unit (ICU) with severe sepsis. Sepsis can lead to serious, permanent complications, and 20% of the sepsis patients die in the ICU.
The role of sugars
In the bloodstream, monocytes – a type of white blood cell – play a key role in the defense against infections. Monocytes can become macrophages, which remove harmful invaders. In 2014, the Nijmegen researchers showed that differentiation of monocytes into macrophages can be controlled by the environment. Monocytes that are exposed to a lipopolysaccharide (LPS), a molecule from the outer cell membrane of specific bacteria, mature into macrophages with a greatly reduced capacity to fend off foreign cells. This reflects sepsis-induced immunosuppression. The opposite occurs upon exposure to beta glucan, a sugar found in fungal cell walls.
At the molecular level, Stunnenberg then looked at the epigenetic setting of these different types of macrophages. The epigenome is involved in regulating gene expression; it varies by cell type and person and can change due to nutrition, stress and illness.
As a result, he discovered one of the “control switches” of the immune system that is driven by a sugar, beta-glucan. “By adding beta-glucan to blood samples of trial subjects with a disabled immune system, the macrophages were re-activated”.
Time for a clinical trial
Stunnenberg tested the effects of beta glucan in blood in the laboratory. “A clinical trial with patients is an obvious step for the near future. We could begin with blood samples of people who have been admitted to the ICU with sepsis” says Mihai Netea.
Now that the researchers have an indication of how they can reactivate a disabled immune system, they also hope to determine how they can temper an overactive system. Autoimmune diseases such as rheumatism, or inflammatory disorders such as Crohn’s disease, are the result of an overactive immune system.
Learn more: Compromised immune system can be re-activated
Thousands of new immune system signals have been uncovered with potential implications for immunotherapy, autoimmune diseases and vaccine development.
The researchers behind the finding say it is the biological equivalent of discovering a new continent.
It’s as if a geographer would tell you they had discovered a new continent, or an astronomer would say they had found a new planet in the solar system. And just as with those discoveries, we have a lot of exploring to do.
– Professor Michael Stumpf
Our cells regularly break down proteins from our own bodies and from foreign bodies, such as viruses and bacteria. Small fragments of these proteins, called epitopes, are displayed on the surface of the cells like little flags so that the immune system can scan them. If they are recognised as foreign, the immune system will destroy the cell to prevent the spread of infection.
In a new study, researchers have discovered that around one third of all the epitopes displayed for scanning by the immune system are a type known as ‘spliced’ epitopes.
These spliced epitopes were thought to be rare, but the scientists have now identified thousands of them by developing a new method that allowed them to map the surface of cells and identify a myriad of previously unknown epitopes.
The findings should help scientists to better understand the immune system, including autoimmune diseases, as well as provide potential new targets for immunotherapy and vaccine design.
The research was led by Dr Juliane Liepe from Imperial College London and Dr Michele Mishto from Charité – Universitätsmedizin Berlin in Germany in collaboration with the LaJolla Institute for Allergy and Immunology and Utrecht University, and it is published today in Science.
Co-author of the study Professor Michael Stumpf from the Department of Life Sciences at Imperial said: “It’s as if a geographer would tell you they had discovered a new continent, or an astronomer would say they had found a new planet in the solar system.
“And just as with those discoveries, we have a lot of exploring to do. This could lead to not only a deeper understanding of how the immune system operates, but also suggests new avenues for therapies and drug and vaccine development.”
Prior to the new study, scientists thought that the machinery in a cell created signalling peptides by cutting fragments out of proteins in sequence, and displaying these in order on the surface of the cell.
However, this cell machinery can also create ‘spliced’ peptides by cutting two fragments from different positions in the protein and then sticking them together out of order, creating a new sequence.
Scientists knew about the existence of the spliced epitopes, but they were thought to be rare. The new study suggests that spliced epitopes actually make up a large proportion of signalling epitopes: they make up around a quarter of the overall number of epitopes, and account for 30-40 per cent of the diversity – the number of different kinds of epitopes.
PROS AND CONS
These extra epitopes give the immune system more to scan, and more possibilities of detecting disease. However, as the spliced epitopes are mixed sequences, they also have the potential to overlap with the sequences of healthy signallers and be misidentified as harmful.
This could help scientists understand autoimmune diseases, where the immune system turns against normal body tissues, such as in Type 1 diabetes and multiple sclerosis.
The study’s lead author, Dr Juliane Liepe from the Department of Life Sciences at Imperial, said: “The discovery of the importance of spliced peptides could present pros and cons when researching the immune system.
“For example, the discovery could influence new immunotherapies and vaccines by providing new target epitopes for boosting the immune system, but it also means we need to screen for many more epitopes when designing personalised medicine approaches.”
UBC researchers have discovered how cancer cells become invisible to the body’s immune system, a crucial step that allows tumours to metastasize and spread throughout the body.
“The immune system is efficient at identifying and halting the emergence and spread of primary tumours but when metastatic tumours appear, the immune system is no longer able to recognize the cancer cells and stop them,” said Wilfred Jefferies, senior author of the study working in the Michael Smith Laboratories and a professor of Medical Genetics and Microbiology and Immunology at UBC.
“We discovered a new mechanism that explains how metastatic tumours can outsmart the immune system and we have begun to reverse this process so tumours are revealed to the immune system once again.”
Cancer cells genetically change and evolve over time. Researchers discovered that as they evolve, they may lose the ability to create a protein known as interleukein-33, or IL-33. When IL-33 disappears in the tumour, the body’s immune system has no way of recognizing the cancer cells and they can begin to spread, or metastasize.
The researchers found that the loss of IL-33 occurs in epithelial carcinomas, meaning cancers that begin in tissues that line the surfaces of organs. These cancers include prostate, kidney breast, lung, uterine, cervical, pancreatic, skin and many others.
Working in collaboration with researchers at the Vancouver Prostate Centre, and studying several hundred patients, they found that patients with prostate or renal (kidney) cancers whose tumours have lost IL-33, had more rapid recurrence of their cancer over a five-year period. They will now begin studying whether testing for IL-33 is an effective way to monitor the progression of certain cancers.
“IL-33 could be among the first immune biomarkers for prostate cancer and, in the near future, we are planning to examine this in a larger sample size of patients,” said Iryna Saranchova, a PhD student in the department of microbiology and immunology and first author on the study.
Researchers have long tried to use the body’s own immune system to fight cancer but only in the last few years have they identified treatments that show potential.
In this study Saranchova, Jefferies and their colleagues at the Michael Smith Laboratories, found that putting IL-33 back into metastatic cancers helped revive the immune system’s ability to recognize tumours. Further research will examine whether this could be an effective cancer treatment in humans.
A biomaterials hack can boost cells’ ability to combat inflammation and potentially treat autoimmune diseases
With a trick of engineering, scientists at the Gladstone Institutes improved a potential weapon against inflammation and autoimmune disorders. Their work could one day benefit patients who suffer from inflammatory bowel disease or organ transplant rejection.
The Body’s Natural Defense
Mesenchymal stromal cells (MSCs) reside in bone marrow and have been found to secrete anti-inflammatory proteins that help regulate the immune system. More than 500 clinical trials are trying to use these cells to fight diseases, but so far, many have failed.
Scientists think this failure may be because, like a match needs to be sparked to create a flame, MSCs must be triggered by pro-inflammatory proteins to produce their immune-suppressing effects. Some studies have tried soaking MSCs in a bath of pro-inflammatory chemicals before injecting the cells into a patient. However, the effects are short-lived, wearing off after just a few days.
“The success of therapies involving MSCs depends on the cells’ environment,” explained Todd McDevitt, PhD, a senior investigator at Gladstone. “A patient taking anti-inflammatory medication may not have high enough levels of inflammation to trigger the cells. We engineered the MSCs to ensure that they are consistently activated, so they can reliably dampen the immune response for longer.”
Engineering A Better Method
In the new study, published in Stem Cells Translational Medicine, the scientists engineered tiny sugar-based particles that they loaded with pro-inflammatory proteins and stuck into the middle of clusters of MSCs. The particles slowly delivered the inflammatory trigger to the cells in a steady dose. This method increased the amount of anti-inflammatory proteins produced by the MSCs, enhancing the suppression of immune cells. In short, the cell-protein packets worked better and longer than other treatments.
“No one has successfully used biomaterials to deliver pro-inflammatory signals to control how MSCs affect the immune system,” said first author Josh Zimmermann, PhD, a former graduate student in the McDevitt lab. “Our research suggests bioengineering has real potential to improve the anti-inflammatory and therapeutic abilities of MSCs. The next step is to test this method in a mouse model of autoimmune disease.”
Learn more: How to Engineer a Stronger Immune System
TSRI Study Points Way to Better Vaccines and New Autoimmune Therapies
A new international collaboration involving scientists at The Scripps Research Institute (TSRI) opens a door to influencing the immune system, which would be useful to boost the effectiveness of vaccines or to counter autoimmune diseases such as lupus and rheumatoid arthritis.
The research, published August 1, 2016, in The Journal of Experimental Medicine, focused on a molecule called microRNA-155 (miR-155), a key player in the immune system’s production of disease-fighting antibodies.
“It’s very exciting to see exactly how this molecule works in the body,” said TSRI Associate Professor Changchun Xiao, who co-led the study with Professor Wen-Hsien Liu of Xiamen University in Fuijan province, China.
An Immune System Tango
Our cells rely on molecules called microRNAs (miRNAs) as a sort of “dimmer switches” to carefully regulate protein levels and combat disease.
“People know miRNAs are involved in immune response, but they don’t know which miRNAs and how exactly,” explained TSRI Research Associate Zhe Huang, study co-first author with Liu and Seung Goo Kang of TSRI and Kangwon National University.
In the new study, the researchers focused on the roles of miRNAs during the critical period when the immune system first detects “invaders” such as viruses or bacteria. At this time, cells called T follicular helpers proliferate and migrate to a different area of the lymph organs to interact with B cells.
“They do a sort of tango,” said Xiao.
This interaction prompts B cells to mature and produce effective antibodies, eventually offering long-term protection against infection.
“The next time you encounter that virus, for example, the body can respond quickly,” said Xiao.
Identifying a Dancer
Using a technique called deep sequencing, the team identified miR-155 as a potential part of this process. Studies in mouse models suggested that miR-155 works by repressing a protein called Peli1. This leaves a molecule called c-Rel free to jump in and promote normal T cell proliferation.
This finding could help scientists improve current vaccines. While vaccines are life-saving, some vaccines wear off after a decade or only cover around 80 percent of those vaccinated.
“If you could increase T cell proliferation using a molecule that mimics miR-155, maybe you could boost that to 90 to 95 percent,” said Xiao. He also sees potential for using miR-155 to help in creating longer-lasting vaccines.
The research may also apply to treating autoimmune diseases, which occur when antibodies mistakenly attack the body’s own tissues. Xiao and his colleagues think an mRNA inhibitor could dial back miR-155’s response when T cell proliferation and antibody production is in overdrive.
For the next stage of this research, Xiao plans to collaborate with scientists on the Florida campus of TSRI to test possible miRNA inhibitors against autoimmune disease.
In order to fight invading pathogens, the immune system uses “outposts” throughout the body, called lymph nodes. These are small, centimeter-long organs that filter fluids, get rid of waste materials, and trap pathogens, e.g. bacteria or viruses. Lymph nodes are packed with immune cells, and are known to grow in size, or ‘swell’, when they detect invading pathogens. But now, EPFL scientists have unexpectedly discovered that lymph nodes also produce more immune cells when the host is infected with a more complex invader: an intestinal worm.
The discovery is published in Cell Reports, and has significant implications for our understanding of how the immune system responds to infections.
The discovery was made by the lab of Nicola Harris at EPFL. Her postdoc and first author Lalit Kumar Dubey noticed that the lymph nodes of mice that had been infected with the intestinal wormHeligmosomoides polygyrus bakeri had massively grown in size. This worm is an excellent tool for studying how the worm interacts with its host, and is therefore used as a standard throughout labs working in the field.
Lymph nodes have microscopic compartments called “follicles”, where they store a specific type of immune cells, the B-cells. Stored in the follicles, B-cells pump out antibodies into the bloodstream to attack invading pathogens.
The researchers found that the mouse lymph nodes were actually producing more follicles, suggesting they were producing more B-cells in response to the worm infection. Of course, this is not a simple event. Like many biological processes, it involves an entire sequence of molecular signals that result in the formation of new cells and tissue.
The EPFL scientists were able to reconstruct the molecular sequence, which is fairly complex: when the mouse is infected with the intestinal worm, a “cytokine” molecule is produced. This cytokine then stimulates B-cells in the lymph nodes to produce a molecule called a lymphotoxin. The lymphotoxin then interacts with the cells that form the foundation of the actual lymph node – the so-called “stromal cells”. The stromal cells then produce another cytokine, which stimulates the production of new follicles in the lymph node.
People who have had an infection that made them so sick they had to be hospitalized may have IQs that are slightly lower than average, a new study suggests.
Researchers from the University of Copenhagen and Aarhus University in Denmark examined the hospital records of 190,000 Danish men born between 1974 and 1994. All the men took IQ tests at age 19, as part of the process of signing up for Denmark’s mandatory draft. The tests were designed to assess their logical, verbal, numerical and spatial reasoning.
After adjusting for factors known to track with people’s IQ scores, such as social conditions and the education levels of their parents, the researchers found that the average IQ score of the men who had been hospitalized for an infection before they took the IQ test — about 35 percent of the study cohort — were 1.76 points below the average of the men in the study who had not been hospitalized for an infection.
“Infections in the brain affected the cognitive ability the most, but many other types of infections severe enough to require hospitalization can also impair a patient’s cognitive ability,” study author Dr. Michael Eriksen Benrós, a researcher at the National Centre for Register-Based Research, said in a statement.
A crucial ‘on switch’ that boosts the body’s defences against infections has been successfully identified in new scientific research.
The breakthrough made by researchers at the University of Aberdeen and the University of Dundee could lead to the development of new drugs to enhance the body’s immune responses to attack, which could benefit people suffering from cancer and other serious conditions.
Their findings have been published in the Journal of Molecular and Cell Biology.
“We have shown that the cells which turn on our immune responses to defend against, for example, infectious diseases, require a particular protein to activate them in order to function properly,” explains Dr Martin-Granados formerly of the University of Aberdeen and now at Cambridge.
“This protein, or enzyme, (PTP1B) effectively acts as a kind of ‘on switch’ and if it is missing or dysfunctional in our body, we cannot mount effective immune responses to tumours or infections.”
There’s a good reason people over 60 are not donor candidates for bone marrow transplantation. The immune system ages and weakens with time, making the elderly prone to life-threatening infection and other maladies, and a UC San Francisco research team now has discovered a reason why.
“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies,” said Emmanuelle Passegué, PhD, a professor of medicine and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Passegué, an expert on the stem cells that give rise to the blood and immune system, led a team that published the new findings online July 30, 2014 in the journal Nature.
Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called “hematopoietic stem cells.” Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division, Passegué’s lab team determined.