Tag: immune system

Categories : COVID Immune SystemTags :

COVID Tracking in Space Company Employees Yields Antibody Clues

On By ModernMedia

SpaceX, an aerospace manufacturing company currently providing satellite launch services as well as transport of crew  to the International Space Station, collaborated with researchers from MIT to monitor the spread of COVID amongst its employees. 

Unusually, the paper included SpaceX CEO Elon Musk as a byline author. The technology entrepreneur is known to be quite hands-on in his company’s projects. However, he has also courted controversy by openly questioning COVID tests and saying he and his family would not take COVID vaccines, saying that achieving herd immunity naturally was a better strategy.

SpaceX was seeking data-driven methods to safeguard its essential workforce. The collaboration allowed the researchers to track the emergence of mild and asymptomatic cases in a cohort of adults as early as April, when data for such cases were rare.

“Essentially, this study indicates that it’s not simply the presence or absence of antibodies that matter; rather, the amount and type of antibodies may play a defining role in the development of a protective immune response,” said Professor Galit Alter, Harvard Medical School and Immunologist, Division of Infectious Diseases, Massachusetts General Hospital. 

The study was originally aimed at measuring antibody levels over time, but when reinfections began to be reported, the team realised their samples had some valuable information.

“In early spring, we weren’t sure if asymptomatic infection could drive long-lived antibodies,” said Prof Alter, “nor whether they possessed the capability to neutralise or kill the virus.”

The researchers knew that 120 participants had mild or asymptomatic COVID infections, resulting in their bodies producing antibodies. Using sophisticated techniques to analyse those antibodies, they found that individuals with stronger symptoms in mild COVID, had a larger number of antibodies and developed immune functions associated with natural immune protection. 

The study found that although the presence of antibodies was sufficient to determine whether an individual had experienced a COVID infection, they did not automatically mean that individual is protected against the virus in the long term.

Antibody effector functions (on the ‘long arm’ of the antibody) linked to long-term protection, such as T cell activation and virus neutralisation were only seen in certain immune responses. These involved high levels of antibodies targetting a part of the virus known as the receptor binding domain.

“Once you hit a certain threshold of these antibodies, it’s like a switch turns on and we can observe antibody effector functions,” said first author Yannic Bartsch, PhD. “These functions were not observed in individuals with lower antibody binding titers, and the level of protection from reinfections is uncertain in these individuals.”

Source: News-Medical.Net

Journal information: Bartsch, Y. C., et al. (2021) Discrete SARS-CoV-2 antibody titers track with functional humoral stability. Nature Communications. doi.org/10.1038/s41467-021-21336-8.

Categories : COVID Immune SystemTags :

COVID Antibody Drugs Work Best with Immune Cells

On By ModernMedia

Research into the current antibody-based drugs for COVID treatment shows that they need to be designed to work in concert with immune cells to be effective.

Three drugs using monoclonal antibodies are approved by the FDA to treat COVID, which provide the patient’s body with ready-made antibodies faster than can be produced by their own immune systems.

The distinctive Y shape of antibodies comes from their two short arms, which latch on to foreign molecules to clear them out, and a long effector arm which interacts with immune cells, inducing them to attack infected cells and release molecules that modulate the immune response.

In antibody-dependent enhancement, the long arm of antibodies can interfere with immune cells, such as in tropical dengue fever. Immunity against one strain against dengue fever causes life-threatening illness if infected with the other strain.

To investigate the possibility of this in COVID, some companies altered the long arm of their antibodies to prevent interaction with immune cells. Other companies took the opposite approach and strengthened antibody effector functions to boost the potency of their drugs.

“Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimise the effector functions,” said senior author Michael S Diamond, MD, PhD, the Herbert S Gasser Professor of Medicine. “Neither of these strategies is backed by data in the context of SARS-CoV-2 infections. Based on our findings, if you have a potently neutralising antibody without effector functions and you give it before infection, as a preventive, it will probably work. But if you give it after infection, it won’t work well; you need to optimise effector functions to get maximal benefit.”

“‘Effector functions’ refers to a complex set of interactions between antibodies and other elements of the immune system,” said Prof Diamond, who also is a professor of molecular microbiology and of pathology and immunology. “You can introduce different point mutations to augment certain kinds of effector functions, and some might be harmful to the immune response while others might be beneficial. There’s a lot of nuance. We are still learning how to harness effector functions so you get what you want but not what you don’t want.”

To find how antibody effectors work with COVID, the researchers took an antibody which was known to be effective against the virus and disabled the effector so it could not interact with immune cells.

They administered the original antibodies, the disabled antibodies and placebo antibodies each to a different group of mice, which were infected a day later with SARS-CoV-2. Both normal and disabled effector antibodies were able to protect against the disease. There were no signs of antibody enhancement of the disease, fortunately.

To find out whether the effector function was needed for treatment after infection, they infected mice with SARS-CoV-2 and administered one of the three sets of antibodies to mice  one, two or three days later. Only the original antibodies protected the mice from the disease. The tests were run in hamsters with the same results.

The researchers discovered in the study that losing effector functions changed the types of immune cells recruited to fight the COVID infection and the way they behaved.

Source: Medical Xpress

Journal information: Emma S. Winkler et al, Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection, Cell (2021). DOI: 10.1016/j.cell.2021.02.026

Categories : COVIDTags :

SARS-CoV-2 Mutation Evolved in Immunocompromised Patient

On By ModernMedia

The discovery of SARS-CoV-2 mutations evolving in an immunocompromised patient treated with convalescent plasma has been revealed by Ravindra Gupta, MD, PhD, of University of Cambridge in England, and team.

“We have documented a repeated evolutionary response by SARS-CoV-2 in the presence of antibody therapy during the course of a persistent infection in an immunocompromised host,” the authors wrote.

Previous research has shown that immunosuppressed patients could serve as reservoirs for norovirus variants.

Although they did not claim the UK variant was created by that particular case, Gupta’s group speculated that the plasma therapy could have unleashed the resistant variants, and could do so in other immunosuppressed patients too.

They wrote that, in such patients, “the antibodies administered [in plasma] have little support from cytotoxic T cells, thereby reducing chances of clearance and theoretically raising the potential for escape mutations.” 

They cautioned that convalescent plasma use should be limited, and only with appropriate infection control in monitoring in immunosuppressed patients.

A man in his 70s, who had received immunotoxic chemotherapy to treat lymphoma eight years previously, was initially hospitalised in May with neutropenic sepsis, and, about a week later, tested positive for SARS-CoV-2. He was discharged later in May, but in late June was readmitted with cough and breathlessness.

His condition worsened and he received dexamethasone and two 10-day courses of remdesivir 5 days apart. On two days around July 20, convalescent plasma was administered; more remdesivir and convalescent plasma was administered about 4 weeks later. He died shortly afterward.

Gupta and team took viral samples from this patient on 23 occasions, and over the first 57 days, they observed little change in viral population upon treatment with remdesivir, but after the July round of convalescent plasma, a shift in viral genotype occurred.

Initially the patient’s viral serotype showed a mutation first reported in China. However, in late July, a variant was observed with two alterations in the spike protein, including the deletion seen in the B.1.1.7 variant. Testing showed a twofold reduced susceptibility to the antibodies in the convalescent plasma.

The team wrote that this sort of evolution is unlikely to emerge in immunocompetent patients. They cautioned against using convalescent plasma in severe COVID patients, and especially those who were immunosuppressed.

The study’s limitations included being only a single case, and samples were taken from the upper respiratory tract and not the lower respiratory tract. 
Given South Africa’s large HIV positive population, if viral evolution is driven by convalescent plasma in immunosuppressed patients, this raises questions for the country’s COVID strategy.

Source: MedPage Today

Journal information: Kemp SA, et al “SARS-CoV-2 evolution during treatment of chronic infection” Nature 2021; DOI: 10.1038/s41586-021-03291-y.

Categories : Gastrointestinal Immune SystemTags :

Jump-starting Macrophages to Help with IBD Tissue Repair

On By ModernMedia

A novel method which prompts immune cells to aid the repair of damaged intestinal tissues has been developed by researchers at KU Leuven and Seoul National University.

This new approach promises new treatments for inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease. Normally, the immune system defends against pathogens that enter the body. In conditions like IBD, the immune system instead attacks tissues that line the gut, creating ulcers. Some 3.9 million women and 3.0 million women suffer from IBD worldwide.

The origin of IBD is not known, so treatments typically dampen immune response, but at the same time this also obstructs the normal repair of damaged intestinal tissue by other parts of the immune system. Macrophages, for example, consume foreign bodies, clean out debris and direct other steps in inflammatory or repair response through released substances. 

Lead author Professor Gianluca Matteoli, an immunologist at the Translational Research Center for Gastrointestinal Disorders (TARGID) KU Leuven, explained the motivation behind the research. “Our idea is that the migration of macrophages to the damaged tissue in IBD is essential to stimulate its recovery.”

Examining macrophages in the intestines of a handful of people with IBD, the researchers found that a sub-group of cells responding to prostaglandin E2 (PGE2). Prostaglandins are messenger molecules involved in homeostatic functions and mediate pathogenic mechanisms, such as the inflammatory response, and are also involved in tissue repair.

“If the patients had acute disease, they had a lower amount of these beneficial cells, and if they went into remission, then amounts of macrophages went up. This suggests that they are part of the reparative process,” said Professor Gianluca Matteoli, immunologist, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven

In mice with ulcerative colitis (one the main forms of IBD), there were fewer macrophages responsive to prostaglandin than in healthy mice. However, when PGE2 levels were increased, those macrophages still responsive released a substance that stimulated tissue repair. When the researchers knocked out the PGE2 receptors on the macrophages, the level of tissue repair dropped.

Getting the macrophages to absorb a liposome containing a substance to trigger the repair stimulation agent restored the macrophages’ repairing effect. Liposomes are bubbles made of two layers of lipids enclosing an aqueous cavity, often used to hold substances for drug delivery.

“We already knew that prostaglandins were important for inducing proliferation of tissue cells, but this study shows that they are also important for controlling the inflammatory effect, so moving the body from the acute stage where inflammation dominates to the reparative stage,” Professor Matteoli said.

New treatments could involve liposomes being used to prompt macrophages into boosting tissue repair, a well-established experimental tool but which would require considerable work for this new application.

“This is one of the first times it has been used to produce a beneficial, therapeutic effect,” said Professor Seok. 

The next step is to closely examine human macrophages at different stages of IBD. “We want to identify other factors that trip the switch that turns macrophages from inflammatory cells to non-inflammatory cells,” said Professor Matteoli. “Then, using the liposome technology that Professor Seok has developed, these could be used to target the macrophages and so produce very precise drugs.”

Source: News-Medical.Net

Categories : Immune SystemTags :

Mystery Protein is an Immune System Component

On By ModernMedia

A protein called ITIH4, the function of which was largely a mystery, has been shown to a as a protease inhibitor, and a component of the innate immune system.

The discovery was made by Professor Steffen Thiel and PhD student Rasmus Pihl at Aarhus University, with the help of a mass spectrometry team led by Professor Jan J Enghild.

Proteases are enzymes which cleave other proteins, and usually occur in cascade networks where proteases cleave each other in a chain reaction. One example of this is blood clotting.

There is also the complement system in the body, which is responsible for eliminating pathogens, and cancerous or dying cells. Immunoglobin G (IgG) and M (IgM) antibodies activate complement proteins which work with them, hence the name “complement”. This system of enzymes is kept in check by protease inhibitors.

The researchers wanted to find out which other proteins in our blood the “MASP” proteases from the complement cascade interact with. They found to their surprise that two MASP proteases formed a strong complex with the ITIH4 protein, about which very little is known, especially its function.

“I was highly surprised when I saw the first data from our partners, showing that ITIH4 could form a complex with the MASP-1 and MASP-2 enzymes. At Biomedicine, we have been studying these two proteases for 25 years, and ITIH4 has simply never been on the radar. But it made good sense, as proteins similar to ITIH4 act as inhibitors of other proteases,” said Rasmus Pihl.

It was also discovered that when ITIH4 formed a complex with MASP-1 and MASP-2, they could still cleave small proteins, but when ITIH4 inhibited them, they could not cleave large proteins.The researchers discovered that ITIH4 performs an inhibitory enzyme function similar to that of one discovered in the 1980s called AM2, but it accomplished it in a new, entirely different manner.

“There is very little knowledge about ITIH4, but it is known that under various pathological conditions, the protein can be cleaved. Our results show that such a cleavage is absolutely necessary for the way ITIH4 can function as an enzyme inhibitor,” Professor Steffen Thiel explained.

Their colleague Gregers R Andersen added: “By using cryo-electron microscopy, we now try to understand in detail how ITIH4 inhibits MASP-1 and MASP-2 via this new inhibition mechanism. We already know that when ITIH4 is cleaved, it forms a complex with both MASP-1 and another ITIH4 molecule. We are very excited to see how it takes place.”

Source: Medical Xpress

Journal information: Rasmus Pihl et al, ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism, Science Advances (2021). DOI: 10.1126/sciadv.aba7381

Categories : COVID Immune SystemTags :

NSAIDs Suppress Antibodies in COVID Infections

On By ModernMedia

A new study has found that non-steroidal anti-inflammatory drugs (NSAIDs) suppress antibody counts as well as inflammatory levels in mice infected with the SARS-CoV-2 virus.

NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are needed for prostaglandin generation – lipid molecules involved in homeostasis and inflammation. The study used ibuprofen and meloxicam in mice infected with SARS-CoV-2. The researchers aimed to observe: viral infection through modified expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, effects on viral replication and modulated response of the immune system. However, they did not observe altered viral infection or replication.

“NSAIDs are arguably the most commonly used anti-inflammatory medications,” said principal investigator Craig B Wilen, Assistant Professor of Laboratory Medicine and Immunology, Yale University School of Medicine.

As well as taking NSAIDs for chronic conditions, eg arthritis, people take them “for shorter periods of time during infections, and [during] acute inflammation as experienced with COVID-19, and for side effects from vaccination, such as soreness, fever, and malaise,” Dr Wilen explained.

“Our work suggests that the NSAID meloxicam dampens the immune response to SARS-CoV-2 infection. Taking NSAIDs during COVID-19 could be harmful or beneficial, depending on the timing of administration,” said Dr Wilen. Dexamethasone, a potent anti-inflammatory but not an NSAID, is detrimental when administered at early stages of COVID but beneficial at later stages. NSAIDs may similarly be detrimental at the early stage because they counteract beneficial inflammation.

An antibody reduction by NSAIDs might not be harmful, but it could also reduce the immune system’s ability to mount a defence early on, or even reduce the length or magnitude of immunity or vaccination protection, Dr Wilen said. Antipyretics such as paracetamol have also been observed to blunt immune system response to vaccination.  

According to Dr Wilen, the original motivation from the study “was a twitter thread, suggesting NSAIDs should not be used during COVID-19. This seemed suspicious to us, so we wanted to investigate.”

Dr Wilen and his team believed there would be no effect of NSAIDs on viral infection, which turned out to be correct. However, they also thought there would be no effect on antibody response.

“In fact, we initially didn’t even carefully look at the antibody response, because we didn’t expect it to be altered by NSAIDs. This turned out to be wrong,” commented Dr Wilen.

Source: Medical Xpress

Journal information: Jennifer S. Chen et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection, Journal of Virology (2021). DOI: 10.1128/JVI.00014-21

Categories : Diseases, Syndromes and Conditions Gastrointestinal Immune SystemTags :

Taurine Boosts Microbiotic Defences in the Gut

On By ModernMedia

A new study has discovered that taurine has a role in triggering the gut’s microbiota to identify and destroy invading bacteria, such as Klebsiella pneumoniae, a bacteria commonly found in the gut and responsible for a variety of infections.

It is already known that gut microbiota can protect against infection, but it is not well understood how they accomplish this. A better of understanding of how they confer protection will aid the development of replacements for current antibiotic drugs, which currently harm gut microbiota and whose effectiveness is waning.

Taurine is a complementary (non-essential amino acid, involved in helping break down fats and is present in bile acid. Most taurine is produced by the body but some is also required in the diet. Certain seafoods, seaweed, poultry and beef are good sources of taurine.

The scientists believed that the taurine helped prevent against bacterial colonisation by producing hydrogen sulphide, but during their research they also discovered that a single infection was sufficient to prepare the gut microbiota to resist a second infection. The liver and gallbladder which produce and store bile acids, can develop long-term protection against infection.

While investigating further, the researchers discovered a particular type of bacteria, Deltaproteobacteria, which protected the gut against colonisation by infectious bacteria and which was activated by taurine. Taurine fed to mice in drinking water helped to shield against infection by boosting the function of the protective bacteria, but those fed bismuth subsalicylate (a common over-the-counter diarrhoea treatment), the infection protection diminished, because bismuth suppresses hydrogen sulphide production in the gut.

Source: News-Medical.Net

Categories : Allergies T-cellsTags :

Itching in Severe Eczema Uses a Different Pathway

On By ModernMedia

A study shows that there are two molecular pathways for conveying sensations of itching, with the itching of severe eczema following an unexpected route.

In normal eczema, cells in the skin convey the itching sensation, releasing histamines. This can be blocked with antihistamines.

“Years ago, we used to think that itch and pain were carried along the same subway lines in the nerves to the brain, but it turned out they weren’t, and these new findings show there’s another pathway entirely that’s causing these episodes of acute itching in eczema patients,” said principal investigator Brian S Kim, MD, Washington University School of Medicine. “The itch can be maddening. Patients may rate their chronic itch at around a 5 on a scale of 10, but that goes up to 10 during acute itch flares. Now that we know those acute flares are being transmitted in an entirely different way, we can target that pathway, and maybe we can help those patients.”

With severe itching in eczema, different cells in the blood are activated, transmitting great quantities of non-histamine molecules which also convey the itching sensation. This renders antihistamines usesles in trying to control the itch. The discovery of this new pathway offers new possibilities for treating other conditions as well. Recent studies have tried to block Immunoglobulin E (IgE) in response to allergies.

“We’ve connected acute itching in eczema to allergic reactions transmitted by an entirely different population of cells,” explained Kim. “In patients who experience episodes of acute itching, their bodies react in the same way as in people with acute allergy. If we can block this pathway with drugs, it might represent a strategy for treating not only itch but other problems, including perhaps hay fever and asthma.”

The team found that when mice with eczema made IgE in response to environmental allergens, they began to itch. However, instead of activating mast cells which produced histamine, the IgE activated basophils (a kind of white blood cell), activating a different nerve pathway to normal itching.

The discovery that eczema is exacerbated by allergens may help people avoid severe itching episodes, as well has helping the development of new targets for treatment.

Source: News-Medical.Net

Journal information: Wang, F., et al, A basophil-neuronal axis promotes itch. Cell, 2021 doi.org/10.1016/j.cell.2020.12.033.

Categories : Diseases, Syndromes and Conditions T-cellsTags :

New Study Reveals T-Cell Role in Periodontitis and Bone Loss

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There are mechanisms involved in diseases of bone loss, such as periodontitis that are still not well understood, but an unexpected behaviour of a type of T-cell may shed new light on the matter.

Looking at periodontal disease in mice, scientists found that regulatory T (Treg) cells start behaving unexpectedly. They lose their ability to regulate bone loss and begin to promote inflammation instead.

“That is important because, in many therapies analyzed in in-vivo models, researchers usually check if the number of regulatory T cells has increased. But they should check if these cells are indeed functioning,” said lead author Dr Carla Alvarez, a postdoctoral researcher at the Forsyth Institute.

In periodontal disease, bone loss occurs because the immune system responds disproportionately, destroying tissue through inflammation. The Treg cells normally suppress the immune system but lose the ability to do so during periodontal disease.

Understanding this falls into the field of osteoimmunology, which is about understanding the interaction of bone metabolism and the immune system. “This is an interesting mechanism highlighting how the bone loss is taking place in periodontal disease,” said Dr Alpdogan Kantarci, at Forsyth and co-author of the paper.

A potential treatment for periodontal disease would involve reactivating the Treg cell’s immunosuppression function, but this is a complex, nonlinear task complicated by the fact that periodontal disease is initiated by oral microbes.

“The relationship between immune response and bone is not so straightforward,” said Alvarez. “There are multiple components. You have to imagine a complex network of signaling and cells that participate.”
The researchers’ next step is to examine the process in humans.

Source:Medical Xpress

Journal information: Alvarez, C., Suliman, S., Almarhoumi, R. et al. Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep 10, 19018 (2020). doi.org/10.1038/s41598-020-76038-w

Categories : HIV Immune SystemTags :

HIV Vaccine Search is a Marathon

On By ModernMedia

While COVID vaccines have appeared in a record-breaking short time, an HIV vaccine is still yet to arrive – though not without good reasons, as The Daily Maverick reports.

Mitchell Warren, executive director of AVAC, a US-based HIV advocacy organisation explained: “There is still no conclusive research on what type of immune response an HIV vaccine should be trying to trigger.”

“With HIV, you’re trying to do better than nature,” continued Warren. “With a Covid-19 vaccine, the jab merely has to do what nature is doing already — in the form of an immune response — just faster. But with HIV, you’re trying to do better than nature because your body isn’t able to successfully fight off the virus.”

HIV mutates quite rapidly, to the point where there are now two distinct strains, HIV-1 and HIV-1, complicating the process. SARS-CoV-2 on the other hand uses a process called proofreading when it replicates, ensuring a lower rate of mutations.

There are currently three vaccines in development; HPX2008/HVTN 705: Imbokodo and HPX3002/HVTN 706: Mosaico both use adenoviruses to deliver protein fragments of the HIV virus to train the immune system to respond to it. The “Imbokodo” is being trialled with young women, and “Mosaico” is being trialled with transgender men and men who have sex with men, and expected to end in 2022 and 2024 respectively. 

The PrEPVacc vaccine uses DNA inserted into plasmids, which induce the body to produce the virus’ proteins, but not the virus itself. The two shots contain a cocktail of proteins and the plasmids to train the immune system. The trial is expected to end in 2023