Tag Archives: immune system

Self-Assembling Nanofibers Prevent Damage from Inflammation

Biomedical engineers at Duke University have developed a self-assembling nanomaterial that can help limit damage caused by inflammatory diseases by activating key cells in the immune system. In mouse models of psoriasis, the nanofiber-based drug has been shown to mitigate damaging inflammation as effectively as a gold-standard therapy. One of the hallmarks of inflammatory diseases, like rheumatoid arthritis, Crohn’s disease and psoriasis, is the overproduction of signaling proteins, called cytokines, that cause inflammation. One of the most significant inflammatory cytokines is a protein called TNF. Currently, the best treatment for these diseases involves the use of manufactured antibodies, called monoclonal antibodies, which are designed to target and destroy TNF and reduce inflammation.

Although monoclonal antibodies have enabled better treatment of inflammatory diseases, the therapy is not without its drawbacks, including a high cost and the need for patients to regularly inject themselves. Most significantly, the drugs also have uneven efficacy, as they may sometimes not work at all or eventually stop working as the body learns to make antibodies that can destroy the manufactured drug. To circumvent these issues, researchers have been exploring how immunotherapies can help teach the immune system how to generate its own therapeutic antibodies that can specifically limit inflammation.

The graphic shows the peptide nanofiber bearing complement protein C3dg (blue) and key components of the TNF protein, which include B-cell epitopes (green), and T-cell epitopes (purple)

We’re essentially looking for ways to use nanomaterials to induce the body’s immune system to become an anti-inflammatory antibody factory,” said Joel Collier, a professor of biomedical engineering at Duke University. “If these therapies are successful, patients need fewer doses of the therapy, which would ideally improve patient compliance and tolerance. It would be a whole new way of treating inflammatory disease.”

In their new paper, which appeared online in the Proceedings of the National Academy of Sciences (PNAS), Collier and Kelly Hainline, a graduate student in the Collier lab, describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. “C3dg is a protein that you’d normally find in your body,” said Hainline. “The protein helps the innate immune system and the adaptive immune system communicate, so it can activate specific white blood cells and antibodies to clear out damaged cells and destroy antigens.”

Due to the protein’s ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

Source: https://pratt.duke.edu/

How to Stop Allergies and Autoimmune Disease

We found this absolutely fascinating mechanism of our own bodies that stops the production of rogue antibodies that can cause either autoimmunity or allergies,” senior author, ANU Professor Carola Vinuesa, said. “It’s been known for years that neuritin has a role in the brain and in the nervous system but we found an abundance of neuritin in the immune system and its mechanism – which has never been described in biology. “We have shown it is one of our immune system’s own mechanisms to prevent autoimmunity and allergy and now we have the evidence, we can go on to harness that for treatment.”

The researchers say they set out over five years ago to bridge a knowledge gap on how the immune system works following an educated guess that neuritin might have a regulatory function in stopping allergies and autoimmune disease.

The study, published today in Cell, found neuritin can prevent the production of pathogenic antibodies.

It is an incredible discovery. We saw that in the absence of neuritin there is increased susceptibility to death from anaphylaxis, highlighting its role in the prevention of life-threatening allergies,” first author, ANU researcher Dr Paula Gonzalez Figueroa, said.

For people with allergies, when the immune system overreacts to allergens – like pollen, dust or peanut butter – it produces antibodies called Immunoglobulin E, (IgE). Allergies happen when the body produces excessive IgE in response to otherwise harmless substances, leading to the release of histamine that causes allergic reactions. “We have discovered neuritin prevents excessive formation of IgE that is typically associated with some common forms of allergy and food intolerances,” Professor Vinuesa said.

Many autoimmune diseases are caused or exacerbated by antibodies that go on to destroy our own tissues and cause autoimmune diseases like lupus and rheumatoid arthritis. “There are over 80 autoimmune diseases, in many of them we find antibodies that bind to our own tissues and attack us instead of targeting pathogens – viruses and bacteria,” Dr Paula Gonzalez-Figueroa said. “We found neuritin supresses formation of rogue plasma cells which are the cells that produce harmful antibodies.”

The researchers hope the discovery will now form the basis of new treatments.

Source: https://www.anu.edu.au/

How to Reverse Parkinson’s Symptoms

Grafting neurons grown from monkeys’ own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson’s disease, researchers at the University of Wisconsin–Madison (UW) reported today.

In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys’ own bodies. This approach avoided complications with the primates’ immune systems and takes an important step toward a treatment for millions of human Parkinson’s patients.

This result in primates is extremely powerful, particularly for translating our discoveries to the clinic,” says UW–Madison neuroscientist Su-Chun Zhang, whose lab grew the brain cells.

Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs like L-DOPA to increase dopamine production.

Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at UW–Madison’s Wisconsin National Primate Research Center. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

Scientists have tried with some success to treat later-stage Parkinson’s in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients’. Zhang’s lab has spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons.

The idea is very simple,” Zhang says. “When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own.

Source: https://news.wisc.edu/

New Variant of SARS-CoV-2 Spreading Fast

A coronavirus variant called B1525 has become one of the most recent additions to the global variant watch list and has been included in the list of variants under investigation by Public Health England.

Scientists are keeping a watchful eye on this variant because it has several mutations in the gene that makes the spike protein – the part of the virus that latches onto human cells. These changes include the presence of the increasingly well-known mutation called E484K, which allows the virus to partly evade the immune system, and is found in the variants first identified in South Africa (B1351) and Brazil (P1).

While there is no information on what this means for B1525, there is growing evidence that E484K may impact how effective COVID vaccines are. But there is no suggestion so far that B1525 is more transmissible or that it leads to more severe disease.

There are other mutations in B1525 that are also noteworthy, such as Q677H. Scientists have repeatedly detected this changeat least six times in different lineages in the US, suggesting that it gives the virus an advantage, although the nature of any benefit has not been identified yet.

The B1525 variant also has several deletions – where “letters” (G, U, A and C) of the virus’s RNA are missing from its genome. These letters are also missing in B117, the variant first detected in Kent, England. Research by Ravindra Gupta, a clinical microbiologist at the University of Cambridge, found that these deletions may increase infectivity twofold in laboratory experiments.

As with many variants, B1525 appears to have emerged quite recently. The earliest example in the shared global database of coronavirus genomes, called Gisaid, dates from 15 December 2020. It was identified in a person in the UK. And like many variants, B1525 had already travelled the world before it came to global attention. A total of 204 sequences of this variant in Gisaid can be traced to 18 countries as of 20 February 2021.

Katalin Kariko, RNA Hero, Future Nobel Prize

The development of the Pfizer-BioNTech coronavirus vaccine, the first approved jab in the West, is the crowning achievement of decades of work for Hungarian biochemist Katalin Kariko, who fled to the US from communist rule in the 1980s.

When trials found the Pfizer-BioNTech coronavirus vaccine to be safe and 95 percent effective in November, it was the crowning achievement of Katalin Kariko’s 40 years of research on the genetic code RNA (ribonucleic acid). Her first reaction was a sense of “redemption,” Kariko told The Daily Telegraph.

I was grabbing the air, I got so excited I was afraid that I might die or something,” she said from her home in Philadelphia. “When I am knocked down I know how to pick myself up, but I always enjoyed working… I imagined all of the diseases I could treat.”

Born in January 1955 in a Christian family in the town of Szolnok in central Hungary – a year before the doomed heroism of the uprising against the Soviet-backed communist regimeKariko grew up in nearby Kisujszellas on the Great Hungarian Plain, where her father was a butcher. Fascinated by science from a young age, Kariko began her career at the age of 23 at the University of Szeged’s Biological Research Centre, where she obtained her PhD.

It was there that she first developed her interest in RNA. But communist Hungary’s laboratories lacked resources, and in 1985 the university sacked her. Consequently, Kariko looked for work abroad, getting a job at Temple University in Philadelphia the same year. Hungarians were forbidden from taking money out of the country, so she sold the family car and hid the proceeds in her 2-year-old daughter’s teddy bear. “It was a one-way ticket,” she told Business Insider. “We didn’t know anybody.”

Not everything went as planned after Kariko’s escape from communism. At the end of the 1980s, the scientific community was focused on DNA, which was seen as the key to understanding how to develop treatments for diseases such as cancer. But Kariko’s main interest was RNA, the genetic code that gives cells instructions on how to make proteins.

At the time, research into RNA attracted criticism because the body’s immune system sees it as an intruder, meaning that it often provokes strong inflammatory reactions. In 1995, Kariko was about to be made a professor at the University of Pennsylvania, but instead she was consigned to the rank of researcher.

Usually, at that point, people just say goodbye and leave because it’s so horrible,” Kariko told medical publication Stat. She went through a cancer scare at the time, while her husband was stuck in Hungary trying to sort out visa issues. “I tried to imagine: Everything is here, and I just have to do better experiments,” she continued. Kariko was also on the receiving end of sexism, with colleagues asking her the name of her supervisor when she was running her own lab.

Kariko persisted in the face of these difficulties. “From outside, it seemed crazy, struggling, but I was happy in the lab,” she told Business Insider. “My husband always, even today, says, ‘This is entertainment for you.’ I don’t say that I go to work. It is like play.” Thanks to Kariko’s position at the University of Pennsylvania, she was able to send her daughter Susan Francia there for a quarter of the tuition costs. Francia won gold on the US rowing team in the 2008 and 2012 Olympics.

It was a serendipitous meeting in front of a photocopier in 1997 that turbocharged Kariko’s career. She met immunologist Drew Weissman, who was working on an HIV vaccine. They decided to collaborate to develop a way of allowing synthetic RNA to go unrecognised by the body’s immune system – an endeavour that succeeded to widespread acclaim in 2005. The duo continued their research and succeeded in placing RNA in lipid nanoparticles, a coating that prevents them from degrading too quickly and facilitates their entry into cells.

The researchers behind the Pfizer-BioNTech and Moderna jabs used these techniques to develop their vaccines.

Source: https://www.france24.com/

COVID: the Risk of Death is 70% Higher for Male than for Female Patients

Evidence increasingly indicates that male sex is a risk factor for more severe disease and death from COVID-19. Male bias in COVID-19 mortality is observed in nearly all countries with available sex-disaggregated data, and the risk of death in males is ∼1.7 times higher than in females. Aging is strongly associated with higher risk of death in both sexes, but at all ages above 30 years, males have a significantly higher mortality risk, rendering older males the most vulnerable group. Sex differences are intertwined with differences in gender roles socially and with behavioral factors, which also influence COVID-19 incidence and outcomes. However, there are also possible biological mechanisms of male sex bias that affect the severity of COVID-19, particularly with respect to immune responses.

Sex differences beyond sex organs are present across species and extend to physiological systems, including the immune system. Infection by different pathogens results in differential immune responses and disease outcomes by sex, and although the pattern depends on age and other host factors, male sex is more often associated with lower immune responses and higher susceptibility and/or vulnerability to infections in animals. This is generally also the case in humans: Male patients have higher viral loads for hepatitis B virus (HBV) and HIV. Conversely, females generally mount a more robust immune response to vaccines, such as influenza vaccines. However, the heightened immune responses in females can also lead to detrimental immunopathology in infections.

The physiological response to virus infection is initiated when virus replication is detected by pattern recognition receptors. This leads to two antiviral programs by the infected cells.
Source: https://science.sciencemag.org/

How Does an mRNA Vaccine Work?

The COVID-19 pandemic has brought unusual attention to everything from handwashing to polymerase chain reaction (PCR) tests. As we move into the later stages of this pandemic, though, a different scientific concept has dominated the national conversation: vaccines. The study of the human immune system and how vaccines influence it is complex and sometimes counterintuitive, and the deployment of a new method for immunization based on mRNA has made it all the more confusing.

The two vaccines that have received Emergency Use Authorizations (EUAs) from the Food and Drug Administration are both mRNA vaccines. And since they’re our only hope for ending this pandemic, it’s crucial to understand how they work—and why you should get one.

Vaccines come in a few main forms, but they share the same central goal: equip our immune systems with the tools to handily defeat a pathogen we might encounter in the future. Think of it like a practice round before your body sees the real thing.

The exact way our bodies develop this preemptive immunity depends on the kind of vaccine we’re given. Live-attenuated vaccines provide our cells with a weakened version of a pathogen; protein subunit vaccines give just one part of a bad guy, so immune cells know how to recognize that part of a virus or bacterium. But mRNA (short for messenger RNA) vaccines actually provide our cells with the instructions for making a protein from the pathogen, in essence creating their own practice dummy. Our own cells produce the viral protein specific to, say, SARS-CoV-2, and then our immune system learns to recognize the proteins.

Source: https://www.popsci.com/

Immune System Killer Cells Controlled By Circadian Rhythms

An analysis of an exhaustive dataset on cells essential to the mammalian immune system shows that our ability to fight disease may rely more heavily on daily circadian cycles than previously assumed.

Malfunctions in , the process that keeps our bodies in tune with the day/night cycles, are increasingly associated with diabetes, cancer, Alzheimer’s, and many other diseases. An investigation published today in Genome Research shows that the activity of macrophagescells within us that seek and destroy intruders like bacteria—may time daily changes in their responses to pathogens and stress through the circadian control of metabolism. In this study, Jennifer Hurley, the Richard Baruch M.D. Career Development Assistant Professor of Biological Sciences at Rensselaer Polytechnic Institute and senior author on this study, and her team investigated how the levels of RNA and proteins in macrophages change over two days.

We have shown there is an incredible amount of circadian timing of macrophage behavior, but the clock is timing macrophages in unexpected ways” said Hurley.

The circadian system is comprised of a set of core clock proteins that anticipate the day/night cycle by causing daily oscillations in levels of enzymes and hormones, and ultimately affecting physiological parameters such as body temperature and the immune response. This molecular clock marks time through a self-regulating cycle of  production and decay. The “positive” element proteins of the clock trigger production of the “negative” element proteins, which in turn block production of positive element proteins until the negative element proteins decay, thus creating a negative feedback cycle that occurs once every 24 hours.

Positive element proteins also regulate fluctuations in a substantial number of gene products, known as messenger RNA or mRNA. Genetic instructions are transcribed from DNA to mRNA, which are then used as a recipe for assembling proteins, the functional building blocks of the cell. It has long been assumed that the levels of each subsequent step could be predicted from the previous. If that were the case, oscillating mRNA would correspond with oscillating levels of cellular proteins, and therefore, if one could track mRNA, they would know what proteins the circadian clock controlled in the cell.

However, this investigation showed that this paradigm may not always be true. The analysis of the macrophage dataset revealed that there was a substantial mismatch between the proteins and mRNAs that are controlled by the circadian clock. This data paralleled research published in Cell Systems in 2018 by the Hurley lab, showing that about 40% of oscillating proteins in the fungus and circadian model system, Neurospora crassa, had no corresponding oscillating mRNA.

But the scale of the difference in macrophages really surprised us,” Hurley said. “Eighty percent of the proteins that oscillate don’t have associated oscillating mRNA in macrophages. That means we were really missing how the clock was timing immunity.”

Source: https://medicalxpress.com/

First Antibody Treatment For COVID-19

Scientists in the UK have just recruited the first participants in the world to be part of a new long-acting antibody study. If the treatment is effective, it could give those who have already been exposed to SARS-CoV-2 protection from developing COVID-19.

We know that this antibody combination can neutralise the virus,explains University College London Hospitals (UCLH) virologist Catherine Houlihan. So we hope to find that giving this treatment via injection can lead to immediate protection against the development of COVID-19 in people who have been exposed – when it would be too late to offer a vaccine.”

This might not be the first antibody treatment for COVID-19 you’ve heard of. Outgoing US President Donald Trump was given monoclonal antibodies when he came down with the disease, and in the US two different antibody treatmentscasirivimab and imdevimab – received emergency approval back in November. But those antibody treatments are given to patients with mild or moderate COVID-19, who risk progressing to a severe version of the disease.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab, administered together, were shown to reduce COVID-19-related hospitalisation or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo,the FDA explained in a press statement when the drugs were approved. This new antibody therapy, called AZD7442 and developed by UCLH and AstraZeneca, is a little different. AZD7442 is a combination of two monoclonal antibodies AZD8895 and AZD1061, which both target the receptor binding domain of the SARS-CoV-2 spike protein.

By targeting this region of the virus’s spike protein, antibodies can block the virus’s attachment to human cells, and, therefore, is expected to block infection,” the team wrote on the US ClinicalTrials.gov website.  “Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector functionin order to decrease the potential risk of antibody-dependent enhancement of disease.”

Antibodies are little Y-shaped proteins that lock on to a particular section – called an antigen – of a virus, bacterium or other pathogen, and either ‘tag‘ it to be attacked by the immune system, or directly block the pathogen from invading our cells. Normal antibodies are produced by your body after an infection, while monoclonal antibodies are cloned in a lab and can be injected into a person already infected, to give the immune system a hand in the fight.

The researchers are hoping that AZD7442 – which is just starting the Storm Chaser study (the name for its phase 3 trial) – provides protection for those that have been exposed to the virus but do not yet have symptoms. Effectively, they’re trying to stop COVID-19 happening in the first place. “If you are dealing with outbreaks in settings such as care homes, or if you have got patients who are particularly at risk of getting severe COVID, such as the elderly, then this could well save a lot of lives,” said University of East Anglia infectious disease expert Paul Hunter.

Source: https://www.sciencealert.com/

Engineered Thymus From Human Cells

Researchers at University College London (UCL)  and the Crick Institute have rebuilt a human thymus, an essential organ in the immune system, using human stem cells and a bioengineered scaffold. Their work is an important step towards being able to build artificial thymi which could be used as transplants.

The thymus is an organ in the chest where T lymphocytes, which play a vital role in the immune system, mature. If the thymus does not work properly or does not form during foetal development in the womb, this can lead to diseases such as severe immunodeficiency, where the body cannot fight infectious diseases or cancerous cells, or autoimmunity, where the immune system mistakenly attacks the patient’s own healthy tissue.

In their proof-of-concept study, published in Nature Communications, the scientists rebuilt thymi using stem cells taken from patients who had to have the organ removed during surgery. When transplanted into mice, the bioengineered thymi were able to support the development of mature and functional human T lymphocytes.

Showing it is possible to build a working thymus from human cells is a crucial step towards being able to grow thymi which could one day be used as transplants,” says Sara Campinoti, author and researcher in the Epithelial Stem Cell Biology and Regenerative Medicine Laboratory at the Crick. 

Source: https://www.ncbi.nlm.nih.gov/
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https://www.ucl.ac.uk/